SAGE-Hindawi Access to Research
Parkinson’s Disease
Volume 2011, Article ID 487450, 25 pages
doi:10.4061/2011/487450
Review Article
The Endotoxin-Induced Neuroinflammation Model of
Parkinson’s Disease
Kemal Ugur Tufekci, Sermin Genc, and Kursad Genc
Department of Neuroscience, Health Science Institute, Dokuz Eylul University, Inciralti, 35340 Izmir, Turkey
Correspondence should be addressed to Kursad Genc, kkursadgenc@hotmail.com
Received 14 September 2010; Revised 18 November 2010; Accepted 16 December 2010
Academic Editor: Enrico Schmidt
Copyright © 2011 Kemal Ugur Tufekci et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA)
neurons in the substantia nigra. Although the exact cause of the dopaminergic neurodegeneration remains elusive, recent
postmortem and experimental studies have revealed an essential role for neuroinflammation that is initiated and driven by
activated microglial and infiltrated peripheral immune cells and their neurotoxic products (such as proinflammatory cytokines,
reactive oxygen species, and nitric oxide) in the pathogenesis of PD. A bacterial endotoxin-based experimental model of PD
has been established, representing a purely inflammation-driven animal model for the induction of nigrostriatal dopaminergic
neurodegeneration. This model, by itself or together with genetic and toxin-based animal models, provides an important tool to
delineate the precise mechanisms of neuroinflammation-mediated dopaminergic neuron loss. Here, we review the characteristics
of this model and the contribution of neuroinflammatory processes, induced by the in vivo administration of bacterial endotoxin,
to neurodegeneration. Furthermore, we summarize the recent experimental therapeutic strategies targeting endotoxin-induced
neuroinflammation to elicit neuroprotection in the nigrostriatal dopaminergic system. The potential of the endotoxin-based PD
model in the development of an early-stage specific diagnostic biomarker is also emphasized.
1. Introduction
Parkinson’s disease (PD) is a progressive neurodegenerative
disorder characterized by tremor, rigidity, bradykinesia, and
postural instability, which result from the progressive loss of
dopaminergic (DA) neurons in the substantia nigra [1]. The
primary cause of PD is still unknown although aging seems
to be a major risk factor.
Parkinson’s disease displays racial differences as can be
seen from recent studies which have shown that incidence
of PD in African-Americans is lower than in Caucasian
whites and Asians [2, 3]. Both environmental and genetic
factor contribute to PD pathogenesis. Pesticides exposure
(paraquat, organophosphates, and rotenone), rural living,
farming, well water drinking, metals (manganese, copper,
mercury, lead, iron, zinc, and aluminum), diet, head trauma,
and infections have been proposed as potential risk factors
[4–6]. Caffeine intake and smoking reduces the risk of PD
[4, 5]. 10%–15% of all PD cases have a genetic component
[7]. Fifteen chromosomal loci have been linked to PD
[8]. Genes associated with PD are α-synuclein, parkin,
ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), PTENinduced putative kinase 1 (PINK1), DJ-1, and leucine-rich
repeat kinase 2 (LRRK2 or dardarin) [6]. Recent data has
shown the involvement of mitochondrial dysfunction in
molecular cell death pathways in PD [9]. Moreover, some
studies revealed that several PD-associated genes impact
on mitochondrial integrity directly or indirectly, which
provides a specific link between mitochondrial dysfunction
observed in sporadic PD [10, 11]. α-syn, Parkin, PTENinduced kinase 1 (PINK1), DJ-1, leucine rich repeat kinase 2
(LRRK2), and HTR2A were found to be localized in the
mitochondria under certain conditions where they maintain
mitochondrial integrity and morphology [11, 12]. Although
mitochondria produce energy for cellular events, during
catabolism, this organelle also produces reactive oxygen
2
species (ROS) that can cause oxidative damage, directly on
mitochondrial enzymes, mitochondrial genome, and mitochondrial membrane permeability resulting in apoptosis.
For neurodegenerative diseases, mitochondrial dysfunction
is one of the hallmarks of pathogenesis caused by ROS
inducing cell death [13]. Mitochondrial dysfunction and
neuroinflammation may simultaneously induce neuronal
cell death. Because mitochondria is the major source of ROS,
and mitochondria can be easily affected by ROS [14, 15].
The α-synuclein mutation is autosomal dominant whereas
the parkin, DJ-1, and PINK1 gene mutations are autosomal
recessive during inheritance. LRRK2 is frequently mutated in
late onset PD [16]. PD diagnosis is based on clinical findings,
but there is no conclusive test for diagnosis yet [17]. The
pathological hallmark of PD is selective loss of dopaminergic,
neuromelanin-containing neurons in the pars compacta of
the substantia nigra and presence of intraneuronal inclusions
called the Lewy body [6]. Mechanisms involved in neurodegeneration in PD are protein misfolding, mitochondrial and
ubiquitin-proteasome dysfunction, oxidative stress, inflammation, and apoptosis [18]. There is no current treatment
in PD, but replacement of L-DOPA- is a viable therapeutic
approach for arresting PD [19].
The current knowledge about pathogenesis of PD is still
limited; therefore, the development of animal models is
essential for better understanding of PD pathogenesis and
the testing of new drugs [20]. An ideal animal model should
mimic clinical and pathological features of the disease.
Available animal models of PD can be divided into two categories: toxin-based and genetic [21]. 6-hydroxydopamine (6OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) selectively destroy catecholaminergic neurons.
Recent studies have shown that environmental toxins such
as rotenone and paraquat induce progressive loss of DA
neurons through inhibition of mitochondrial respiratory
chain complex I [21]. Toxin-based animal models for PD are
limited in that they do not model the slow and progressive
loss of dopaminergic neurons and the decrease in generation
of Lewy bodies [8].
Like toxin-induced models, genetic animal models of
PD have contributed to the understanding of the disease.
Knockout mice with deletion of parkin, DJ-1 or PINK1
genes have been generated [22–24]. Several transgenic mouse
models of α-synuclein gene have been developed, including
mice overexpressing α-synuclein [25], carrying the point
mutations of α-synuclein [26] or knockout mice for αsynuclein [27]. Recently, conditional knockout models of PD
have been generated. In MitoPark mice, the mitochondrial
transcription factor A (TFAM) has been selectively deleted
in dopaminergic neurons [21]. Loss of TFAM activity in
MitoPark mice leads to impaired oxidative phosphorylation
specifically in dopaminergic neurons [21].
There is some evidence that inflammation plays a major
role in the pathogenesis of PD. Activated microglia were
found in the striatum and the substantia nigra in PD [28, 29]
and proinflammatory cytokine such as tumor necrosis factor
(TNF), interleukin-1beta (IL-1β), interleukin-6 (IL-6), and
inducible nitric oxide synthase (iNOS) are increased in cerebrospinal fluid of patients with PD [30, 31]. Epidemiological
Parkinson’s Disease
studies also support the role of inflammation in PD disease.
A study found that the risk of PD was lower in persons
who regularly took nonsteroidal anti-inflammatory drugs
(NSAIDs) than in persons who did not take these drugs
[32]. In addition, inflammation has a major impact on
pathogenesis toxin-induced and even genetic models for PD
[33, 34]. Due to the role of inflammation in PD, the need
for purely inflammation-driven animal models has emerged.
Firstly, an in vitro model developed by (lipopolysaccharide)
LPS-induced neurotoxicity in mixed cortical neuron/glia
cultures [35]. Later, an in vivo LPS-induced PD model
was devoloped by Castaño et al. [36]. Since then, LPSinduced PD model has been widely accepted and used for
understanding pathogenesis of PD and testing new drugs
in the treatment of PD. In this paper, we will summarize
the various in vivo LPS-induced PD models. Furthermore,
we will highlight the combined models of LPS with toxininduced or genetic models and pathogenesis of LPS-induced
PD models. We have mentioned the contribution of LPSinduced PD models to studies of PD pathogenesis and to new
drug development for the treatment of PD.
2. Neuroinflammation in Parkinson’s Disease
(Epidemiological Data, Toxin-Based Animal
Models, Genetic Models, PET Imaging, and
Peripheral Immune System in PD)
The process of neuroinflammation has been shown to be
involved in PD by McGeer et al. in 1988. They have found
that activated microglia and T-lymphocytes are present
around the Substantia Nigra pars compacta (SNpc) of
postmortem PD patients [28, 37, 38]. Followup studies have
confirmed the presence of inflammation related enzymes
iNOS and cyclooxygenase-2 (COX2) in SNpc.; Mogi et al.
reported the increased levels of TNFα, β2-microglobulin,
epidermal growth factor (EGF), transforming growth factor
α (TGFα), TGFβ1, and interleukins 1β, 6, and 2 in striatum
of PD brain at the molecular level [39–42]. When the
cerebrospinal fluid and serum of PD patients were analyzed,
IL-2, TNFα, IL-6, and RANTES levels were found to be
increased [42–45]. Immunological studies have also shown
the presence of activated (CD4+ CD45RO+) T-cells in serum
of PD patients [46, 47]. In order to monitor activated
microglia in the PD brain, [11 C](R)-PK11195, which is a
marker of peripheral benzodiazepine binding sites that is
selectively expressed by activated microglia, is used in PET
studies [48, 49]. It has been found that the density of
activated microglia is highest in clinically affected regions of
the brain, supporting the fact that inflammatory responses
by intrinsic microglia contribute to the progression of PD.
All these studies show that activated microglia take part in
PD pathogenesis; however, in most of the studies, late stages
of PD brains were examined and involvement of microglia
to the inflammation at early or late stages was mere speculations. Recent data from tissue culture studies, however,
supports the notion that microglia contribution occurs in
early stage PD [50, 51]. In addition to etiologic studies, the
determination of risk factors for developing PD has been
Parkinson’s Disease
tried. For genetic analyses, polymorphisms of TNFα, IL-1β,
IL-1α, IL-6, and CD14 genes were analyzed, and association
studies demonstrated that the polymorphisms are common
among patients [52–57].
In 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine(MPTP)
models of PD, mitochondria complex I is inhibited and ATP
levels decrease resulting in cell death. In this model, activated
microglia and infiltration of activated T-lymphocytes were
detected in brains of MPTP-treated animals [58–61]. In
another model for PD, 6-hydroxydopamine (6-OHDA), cells
are selectively killed by generation of free radicals and
oxidative stress. Crotty et al. have recently shown a significant
increase in number of activated microglia in 6-OHDA
lesioned rats [62]. A study by Depino et al. concerning 6OHDA lesioned rats did not find an increase in TNFα both
on the mRNA and protein levels. An increase in IL-1β protein
levels has not been detected whereas significant increase in
mRNA levels of IL-1β has been detected [63].
3. Experimental Considerations
LPS is now well established as an effective initiator of DA
neurodegeneration. The neurotoxic effect of LPS has been
first demonstrated in cell culture-based in vitro models. The
in vitro cell culture model of LPS-mediated neuroinflammation and neurotoxicity is based on the mesencephalic
mixed neuron-glia culture system [64]. In vitro studies on rat
mesencephalic cultures suggest that dopaminergic neurons
are twice as sensitive to LPS as nondopaminergic neurons
and that the toxicity of LPS occurs via microglial activation
[65, 66]. As an economical and efficient system, in vitro studies are still valuable to explore the molecular mechanisms
of LPS-mediated neurotoxicity and for screening candidate
therapeutic compounds.
3.1. Characteristics and Versions of the Model. To extend
the observations made in the in vitro LPS-mediated neuroinflammation model to a physiologically more relevant
setting, the single intranigral LPS injection model has been
developed in 1998 [36]. Compared with the in vitro LPS
model, a single injection of low microgram quantities of
LPS to the SN enables the comparison of the relative vulnerability to inflammatory damage of dopaminergic neurons
in the SN versus those in the VTA, dopaminergic versus
nondopaminergic neurons in the SN, and dopaminergic
versus nondopaminergic neuronal projections in the corpus
striatum [36, 51, 64]. Consistent with previous in vitro
findings, an in vivo endotoxin model has shown that
LPS-induced neurodegeneration is primarily observed in
dopaminergic neurons and nondopaminergic neurons such
as GABAergic neurons. SN are mostly spared by this process;
microglial activation precedes dopaminergic neurodegeneration indicating a temporal relationship between glial
activation and neurodegeneration, and finally LPS-induced
microglial activation plays a more prominent role than
astroglial activation in the release of various neurotoxic
mediators that lead to dopaminergic neurodegeneration
[64]. Acute intranigral or supranigral LPS injections (2 µg)
produce a rapid activation of microglia (within 24 h) and
3
loss of striatal dopamine (by day 4) accompanied by loss of
SN DA neurons (within 21 days) [67, 68]. Injection of LPS
to the SN results in an irreversible, but not progressive loss
of the dopaminergic neurons in SNpc. While striatal DA is
rapidly reduced, no further decline is seen during 1 year,
indicating a permanent lesion but a lack of progression [69].
This model does not induce DA neuron death directly by
activating microglia/monocytes. Although acute intranigral
LPS administration produces rapid and intense microglial
activation, microglia morphology reverts to normal form
within 30 days, indicating a short-lived response and not a
prolonged or progressive state of activation [70]. The successful demonstration of single intracerebral LPS injection
induced dopaminergic neurodegeneration prompted further
examination on whether a less intense and chronic period of
inflammation in the SN would lead to a delayed and progressive nigrostriatal dopaminergic neurodegeneration. Indeed,
chronic infusion of nanogram quantities of LPS to the SN
via an osmotic minipump for two weeks induces significant
glial activation accompanied by delayed, progressive, and
preferential degeneration of SNpc dopaminergic neurons
[71]. Although the SN is far more sensitive than the striatum
to the inflammatory stimulus [69], intrastriatal or intrapallidal injection of LPS also induces neuroinflammation and
dopaminergic neurodegeneration in rodents [72–76]. The
Globus pallidus is an integral component of the basal ganglia
that is important in regulation of movement. The intranigral
LPS model has recently been established in mice [77]. Future
research can be performed using knockout mice to study
other potential mechanisms of neuroinflammation-induced
neurodegeneration [77, 78]. Systemic inflammation has been
suspected to influence the activities of the immune cells
in the brain and consequently contributes to the chronic
neurodegenerative process for diseases such as PD [79].
Systemic administration of LPS has been found to induce
progressive degeneration of nigral dopaminergic neurons in
male C57BL/6 mice [80]. Systemic LPS injection also induces
apoptotic cell death in SN [81]. Interestingly, progressive
dopaminergic cell loss occurs in mice given a single systemic
exposure to LPS, which contrasts with the lack of progressive
dopaminergic neuron loss in rats provided with a single,
acute, intranigral LPS infusion [67, 69, 70].
Several experimental considerations including LPS
strain, administration route and dosing of LPS, strain,
gender, and age differences of experimental animals should
be taken into account for the design of experimental setting
in LPS-based PD model. As discussed above, administration
route and location of LPS determine the characteristics
of the LPS-based PD model. While a single intranigral or
supranigral injection of LPS does not cause progressive
dopaminergic cell loss, chronic infusion of endotoxin to SN
or systemic LPS administration leads to a time-dependent
progression in dopaminergic neurodegeneration. The degree
of dopaminergic neurodegeneration is also concentrationdependent [51]. 14 days after injection of 0.1 µg to 10 µg
LPS into the rat SN, TH-positive (TH+) neurons in the SN
were decreased by 5%, 15%, 20%, 45%, 96%, and 99%,
respectively [82]. The possible effect of the differences
between LPS strains has not been evaluated to date.
4
3.2. Strain, Gender, and Age Differences. Although different
mouse strains present striking differences in the extent
of dopaminergic neurodegeneration induced by neurotoxin
MPTP, injection of LPS to the SN region of Wistar, Fisher, or
Sprague-Dawley rats have a similar loss of SNpc DA neurons
[36, 51, 83]. Differences between rat strains have not been
reported for the acute intracerebral LPS model.
Gender differences seem to be an important factor in the
sensitivity to the LPS-induced dopaminergic neurodegeneration. C57BL/6 female mice are more resistant to systemic LPS
than male mice [80, 81]. Repeated monthly LPS injections
are required to cause both motor behavioral deficits and
dopaminergic neuronal loss in female mice.
Several studies compared the detrimental effects of LPS
on the nigrostriatal pathway and its behavioral consequences
between young and aged animals. Four weeks after bilateral
intrapallidal injection of LPS (10 µg), a greater loss of SNpc
DA neurons in the older (16 months old) than the younger
Fisher F344 rats (3 months old) with alpha-synucleinpositive intracellular inclusions in the SN dopaminergic
neurons of the LPS-injected middle-aged rats could be
observed [76]. While young rats recovered from LPSinduced locomotor deficits four weeks after intrapallidal LPS
injection, aged rats failed to improve on measures of speed
and total distance moved, which may be caused by microglial
activation and proinflammatory cytokine expression [74]. In
addition, greater nitration of proteins like alpha-synuclein
occurred in the SN of elderly rats versus young rats,
accompanied by higher expression level of iNOS. The Lewy
body, a pathological hallmark of PD, contains nitrated alphasynuclein, which is prone to oligomerization. These results
imply that an exaggerated neuroinflammatory response
that occurs with aging might be involved in the increase
in prevalence of neurodegenerative diseases like PD [74].
One month after intrastriatal injection of LPS microglial
activation, lipid peroxidation, ferritin expression, and total
nigral iron content in aged rats significantly increased. In
addition, LPS significantly altered the turnover ratio of HVA
to DA [74]. Injection of LPS into the globus pallidus of young
and middle-aged rats substantially decreased TH as can be
evidenced by immunostaining in SNpc one month after
injection [76]. Loss of TH expression was accompanied by
increase iron and iron-storage protein ferritin levels in glial
cells of the SN pars reticulata. Despite great increase in nigral
iron levels, ferritin induction was less pronounced in older
rats, suggesting the regulation of ferritin is compromised
with age. Intrapallidal LPS injection also increased expression of alpha-synuclein and ubiquitin in TH(+) neurons of
the SNpc. These findings suggest that pallidal inflammation
significantly increases stress on dopaminergic neurons in
the SNpc. Alterations in nigral iron levels may increase the
vulnerability of nigral neurons to degenerative processes.
Thus, an age-related increase in iron as well as susceptibility
to inflammation may play an important role in PD-related
neurodegeneration, as free radicals produced from the
inflammatory response can become more toxic through
increased ferrous iron catalyzed Fenton chemistry. This may
enhance oxidative stress, exacerbate microglia activation, and
drive the progression of PD [76].
Parkinson’s Disease
3.3. Assessment of the Neuroinflammation, Neurodegeneration,
and Their Effect. Several immunohistochemical, histological,
biochemical, and behavioral parameters are used to evaluate
the neuroinflammation and neurodegeneration in LPSbased PD models. Reduction of TH immunoreactivity is used
as an index for dopaminergic cell death. The preferential
degeneration of SNpc DA neurons was further corroborated
by studies that employ fluorogold retrograde labeling of the
striatonigral DA pathway prior to LPS injection.
Similar reduction of TH immunoreactivity and fluorogold-labelled neurons in the SN following LPS administration suggests dopaminergic cell death rather than downregulation of TH [68]. The number of TH(+) cells is determined
using stereological analysis.
TH enzyme activity from striatal tissue can be measured
as an indirect index of dopaminergic neurodegeneration.
A single intranigral injection of LPS causes reduction in
TH enzyme activity [36]. In vivo microdialysis can be
used to measure changes in extracellular concentrations
of dopamine and its metabolites in freely moving rats in
response to administration of an endotoxin. In a recent
study, dopamine metabolites in the dialysate obtained from
the rat brain were measured by high-performance liquid
chromatography (HPLC) using electrochemical detection
[84]. Results showed that intrastriatal perfusion of different
concentrations of LPS produced a dose-dependent decrease
in the extracellular DOPAC output.
Intracerebral injections of LPS (5 or 10 µg) into the
cortex, hippocampus, striatum, or SN of rats enhances the
death of only SN DA neurons, possibly because microglial
cell density in the SN is 4-5 times higher than in other regions
[69, 71, 85]. LPS administration induces a rapid activation of
microglia within hours as demonstrated by morphological
transformation of OX-42-positive microglia. SN microglia
became fully activated exhibiting the characteristic amoeboid
morphology [71]. This is accompanied by intense expression
of glial fibrillary acidic protein- (GFAP-) immunoreactive
astrocytosis in the SN [68]. Double immunostaining of the
tissue slices shows that iNOS and 3-nitrotyrosine (3-NT)immunoreactive cells are predominantly microglia [70].
Activated microglia can even be found in the basal ganglia
and brainstem of PD cases or in rodents using positron
emission tomography (PET) with [11 C](R)-PK11195 [86–
89]. To the best of our knowledge, in vivo PET imaging for
the evaluation of microglial activation has only been used
in intraperitoneally LPS-treated rats in a recent study by Ito
et al. [90]. For this model, the authors have concluded that
the intensity of peripheral benzodiazepine receptor signals in
[(11)C]PK11195 PET may be related to the level of microglial
activation rather than the number of activated microglia.
Neuroinflammation-mediated dopaminergic neuronal
loss induced by LPS may also have functional significance as demonstrated by behavioral tests. Thirty days
following supranigral LPS injection, rats show unilateral
behavioral deficits as evidenced by ipsilateral circling following amphetamine administration [70]. Intrapallidal LPS
injection causes permanently slowed locomotor activity in
aged rats [76]. Automated movement tracking analyses has
shown that young rats (3 months old) recovered from
Parkinson’s Disease
LPS-induced locomotor deficits four weeks after intrapallidal
LPS injection, yet older rats (16 months old) failed to
improve on measures of speed and total distance moved.
In contrast to MPTP and 6-OHDA, intranigral LPS administration does not produce behavioral dysfunction in early
periods (1, 3, and 7 days after the lesions); however, LPS
drastically increases HVA at the first time point, simulating
features of the premotor phase of PD [91]. The combination
of both systemic LPS and MPTP causes striatal DA and
gait instability as revealed by reduced stride length in male
C57Bl/6J mice at 4 months after injection [92].
3.4. Combined Models. In most environmental models for
PD, a single neurodegenerative agent is introduced to cause
nigrostriatal dopamine depletion. However, cell loss in
human PD may often be caused synergistically by multiple
toxins or vulnerabilities. Recent studies have also focused
on the effects of LPS challenge in toxin-based and genetic
models of PD. As discussed in Section 2, the findings of neuroinflammation are also observed in toxin-based and genetic
models of PD. Increased mRNA and protein expression of
both CD14 and TLR4 in the SN, but not in the caudateputamen nuclei of mice treated with MPTP, in comparison
to untreated animals, suggests that the endotoxin receptors
are overexpressed in specific areas of the CNS during
experimental PD [93]. Thus, the neurotoxin challenge may
also cause a predisposition for the exacerbation of chronic
neuroinflammation.
A recent study by Koprich et al. has shown that injection
of a nontoxic dose of LPS into adult rat SNpc leads to
microglial activation and increased levels of IL-1β, without
causing death of dopaminergic neurons in vivo, but causing
increased vulnerability for DA neurons to a subsequent
low dose of 6-OHDA [94]. This exacerbation of 6-OHDAinduced neuronal loss by LPS appears to be partly mediated
by IL-1β, since treatment with both LPS and IL-1 receptor
antagonist rescued some of the dopaminergic neurons from
6-OHDA-induced death following LPS-induced sensitization to dopaminergic degeneration. Another recent study has
shown that 6-OHDA injection into the adult rat striatum
and subsequent nontoxic LPS injection into the SNpc cause
an increased level of dopaminergic neuronal death and
motor deficits compared with the administration of either
toxin alone [95]. Thus, the initial insult causes priming of
microglia, while the second insult shifts microglial activation
towards a proinflammatory phenotype with increased IL-1β
secretion. Specific IL-1β inhibition reversed these effects
and nitric oxide (NO), a downstream molecule of IL-1β
action, is partially responsible for the exacerbation of
the neurodegeneration that has been observed [95]. The
combination of systemic LPS and MPTP, but not either
alone, causes striatal DA and gait instability in male C57Bl/6J
mice about 4 months after injection [92]. MPTP alone
acutely reduced striatal DA levels, but this effect was transient
as striatal DA recovered to normal levels after 4 months.
The nigrostriatal dopaminergic neurons can succumb to
multiple toxic agents that independently may have only
a transient adverse effect. The effect of methamphetamine
(MA) dopaminergic toxicity, like MPTP toxicity, frequently
5
cited as a model of PD, is potentiated by intrastriatal LPS
administration [96]. This combined model leads to behavioral impairment and striatal dopaminergic deficits, but
not to alteration in other monoaminergic systems including
serotonin, norepinephrine, and histamine. The combination
of striatal LPS and MA results in microglial activation
limited to the nigrostriatal region. Furthermore, neuroinflammation, oxidative stress, and proapoptotic changes in
the striatum are more accentuated with combined treatment
of LPS and MA compared to individual treatments. In
addition, cytoplasmic accumulation of alpha synuclein has
been observed in the SN of mice treated with LPS and MA.
L-Dopa treatment, also, significantly attenuates behavioral
changes, and dopaminergic deficits can be induced by LPS
and MA [96].
Inflammatory priming of the SN by LPS influences the
impact of later neurotoxin exposure, and this process was
called as neuroimmune sensitization of neurodegeneration
[97].
Repeated injection with the herbicide paraquat causes
oxidative stress and a selective loss of dopaminergic neurons
in mice. In this model, the first paraquat exposure, though
not sufficient to induce any neurodegeneration, predisposes
neurons to damage by subsequent insults. Multiple toxin
exposure may synergistically influence microglial-dependent
DA neuronal loss and, in fact, pretreatment with one toxin
may sensitize DA neurons to the impact of subsequent
insults. Priming the SNpc neurons with LPS influences the
impact of later exposure to paraquat [97]. LPS infusion
into the SN-sensitized DA neurons to the neurodegenerative
effects of a series of paraquat injections commencing 2 days
later. In contrast, LPS pretreatment protects against some
of neurodegenerative effects of paraquat when the pesticide
is administered 7 days after the endotoxin, suggesting the
importance of the time of exposure. These results suggest
that inflammatory priming may influence DA neuronal sensitivity to subsequent environmental toxins by modulating
the state of glial and immune factors, and these findings may
be important for neurodegenerative conditions, such as PD
[97]. Microglial activation acts as a priming event leading to
paraquat-induced dopaminergic cell degeneration. A study
by Purisai et al. elucidated the mechanism underlying this
priming event. They found that a single paraquat exposure is
followed by an increase in the number of cells with immunohistochemical, morphological, and biochemical characteristics of activated microglia, including induction of NADPH
oxidase [98]. When initial microglial response was inhibited
by the anti-inflammatory drug minocycline, subsequent
exposures to the paraquat fail to cause oxidative stress and
neurodegeneration. If microglial activation was induced by
pretreatment with LPS, a single paraquat exposure suffices
to trigger a loss of dopaminergic neurons. Moreover, mutant
mice lacking functional NADPH oxidase are spared from
neurodegeneration caused by repeated paraquat exposure
[98].
The LPS-based model has also been combined with
a genetic model of PD [77]. In mutant alpha synuclein
(αSYN) transgenic mice, but not synuclein knockout mice,
intranigral LPS administration led to neuroinflammation
6
associated with dopaminergic neuronal death and the accumulation of insoluble SYN aggregates as cytoplasmic
inclusions in nigral neurons. Nitrated/oxidized SYN has also
been detected in these inclusions. These results suggest that
NO and superoxide release by activated microglia may be
the mediator that links inflammation and abnormal αSYN
in PD neurodegeneration [77]. Although loss-of-function
mutations in the parkin gene cause early-onset familial PD,
Parkin-deficient (parkin−/−) mice do not display the nigrostriatal degeneration pathway, suggesting that a genetic factor
is not sufficient, and an environmental trigger may be needed
to cause dopaminergic neuron loss. Upon administration of
low-dose systemic LPS for prolonged periods, parkin−/−
mice display subtle fine-motor deficits and selective loss of
dopaminergic neurons in the SN, suggesting that the loss of
the Parkin function increases the vulnerability of the nigral
DA neurons to inflammation-related degeneration [99].
4. Neuroinflammation Model of
Parkinson’s Disease Induced by
Prenatal Exposure to Lipopolysaccharide
Parkinson’s disease symptoms’ typically manifest in late
adulthood, after loss of dopaminergic neurons in the nigrostriatal system. Lack of heritability for idiopathic PD has
implicated adulthood environmental factors in the etiology
of the disease. However, compelling evidence from recent
experimental studies has shown that exposure to a wide
variety of environmental factors during the perinatal period
(environmental toxins such as pesticides) and during the
prenatal period (bacterial endotoxin LPS) can either directly
cause a reduction in the number of dopamine neurons
or cause an increased susceptibility to degeneration of
these neurons with subsequent environmental insults or
with aging alone [100] (Figure 1). A fraction of pregnant
women suffer from vaginal or cervical bacterial infections,
and there may be a risk for bacterial toxins including
LPS to impact the fetal development. One of the potential
targets for an endotoxin assault may be the developing
nigrostriatal DA pathway [64]. The endotoxin model implies
a role of proinflammatory cytokines, which may relate to
epidemiological studies of early-life infectious agents and
intrauterine infections.
The proinflammatory cytokine TNFα kills DA neurons and is elevated in the brains of patients with PD
(Figure 1). LPS is a potent inducer of TNFα and both are
increased in the chorioamniotic environment of women
who have bacterial vaginosis during pregnancy. This suggests
that prenatal maternal infection might interfere with the
normal development of fetal DA neurons [101]. In utero
exposure to LPS following a single injection of the endotoxin intraperitoneally (10 000 endotoxin units) into gravid
Sprague-Dawley rats at embryonic day 10.5, a critical time
point during embryonic dopaminergic neuron development,
causes a significant reduction in the striatal DA and nigral
dopaminergic cell number, accompanied by elevated levels
of striatal and nigral TNFα in offspring sacrificed at 21 days,
indicating that prenatal exposure to LPS not only creates a
neuroinflammatory response but also disrupts the normal
Parkinson’s Disease
development of dopaminergic neurons [101]. Dopaminergic
neuron loss is apparently permanent as it is still present
in 16 months old animals [102]. In utero LPS exposure
does not appear to affect dopaminergic neurons in the
ventral tegmental area (VTA) or nondopaminergic neurons
in the substantia nigra [101]. In contrast to TNFα, levels of
IL-1β are not affected by prenatal LPS treatment [101]. LPS
administration results in significant microglial activation
and sustained elevation of TNFα in both the SN and the
corpus striatum, even several weeks after the sole initial
exposure, suggesting a persisting effect [103].
However, endotoxin-induced dopaminergic cell loss does
not seem to progress as prenatal LPS reduces the baseline
number of dopaminergic neurons in offspring, but the
baseline remains stable once it has been established even
beyond 16 months of age (similarly 20%–30% reduction in
the number of SNpc dopaminergic neurons across studies
and across ages) [100, 101, 103, 104].
In utero LPS exposure may predispose the nigrostriatal
dopaminergic system of the pups to enhanced susceptibility
to neurotoxins such as rotenone and 6-OHDA [103, 104].
Using male offspring at 3 months of age, Ling et al.
has not been able to find any synergistic toxic effects of
prenatal LPS and postnatal 6-hydroxydopamine (6OHDA)
exposures [104]. In contrast, a subtoxic dose of neurotoxin
rotenone (1.25 mg/kg/day, 14 days, intrajugular) injected
at 18 months of age to female rats exposed prenatally to
LPS, exerted a synergistic effect on dopaminergic cell loss,
suggesting that a preexisting proinflammatory state can be
a risk factor for environmental toxins [103]. One subtoxic
rotenone dose did not directly lead to cell loss in these aged
female rats. However, against the background of prenatal LPS
exposure, cell loss was significant in the SNpc, displaying an
interaction of prenatal exposure and adulthood challenges,
which suggests that age and multiple environmental hits
play a role. Dopaminergic cell loss was associated with
decreased striatal DA and increased striatal dopaminergic
activity ([HVA]/[DA]). Animals prenatally exposed to LPS
exhibited a marked increase in the number of reactive
microglia that was further increased by rotenone exposure.
Prenatal LPS exposure also led to increased levels of oxidized
proteins and the formation of α-Syn and eosin positive
inclusions resembling Lewy bodies. These results suggest
that exposure to low doses of an environmental neurotoxin
like rotenone can produce synergistic dopaminergic neuron
losses in animals with a preexisting proinflammatory state
[103]. This supports the notion that PD may be caused
by multiple factors and the result of multiple hits from
environmental toxins. Yet, despite neuroinflammation, the
progressive loss of dopaminergic neurons that characterizes
PD is rarely seen in animals. In a recent study, 7-monthold male rats prenatally exposed to LPS were subjected to
supranigral infusion of LPS and sacrificed after 2 or 12
weeks [105]. LPS infusion into animals prenatally exposed
to LPS produced a neuroinflammatory response during
the 14 days of LPS infusion that subsequently reverted
to normal state over the next 70 days. In animals with
preexisting inflammation (i.e., prenatal LPS); however, the
acute changes seen were attenuated but the return to normal
Parkinson’s Disease
7
MD-2
TLR-4
CD14
LPS
NAPDH oxidase
enzyme system
MyD88
Healthy neuron
O2 −
IRAK
MAPK
iNOS
NFκB
TNFα
NFκB
Proinflammatory cytokine, iNOS
IL-1β
PGE2
COX-2
α-SYN
PGE2
α-SYN
Microglia
Microglial
activation
Damaged neuron
MMP-3
Figure 1: Simplified schematic representation of the link between LPS-induced microglial activation, inflammatory mediators, and
dopaminergic neurodegeneration. Microglia respond to pathogens, proinflammatory cytokines, neuronal dysfunction, and cellular debris
after injury or necrosis. These cells are at the forefront of the defence mechanisms that could set the conditions for repair or contribute to
neuronal damage. Such equilibrium might depend on the expression and function of specific TLRs and how they are activated by endogenous
and exogenous ligands and signals. Recognition of such signals lead to transcriptional activation of innate immune genes. Bacterial
endotoxin LPS is a potent stimulator of macrophages, monocytes, microglia, and astrocytes causing release of various immunoregulatory and
proinflammatory cytokines and free radicals. Neurons do not express functional TLR-4. Thus, LPS does not appear to have a direct effect on
neurons, making it an ideal activator to study indirect neuronal injury mediated by microglial activation [64]. LPS binds to its intermediate
receptor CD14 and in concert with TLR4 and accessory adaptor protein MD2 triggers the activation of kinases of various intracellular
signaling pathways. The MyD88-dependent cascade initiates NFκB activation through the IKKs and/or the MAPK pathway, leading to the
upregulated expression of proinflammatory cytokines (TNFα, IL-1β) and increased production of other inflammatory mediators (NO and
PGE2, synthesized by iNOS and COX-2, resp.). These soluble mediators collectively damage nigral dopaminergic neuron. MMP-3 and αSYN
released by stressed neurons aggravate microglial activation. Astrocyte, different activation states of microglia, peripheral immune cells, many
molecules involved in intracellular signaling pathways, and crosstalk between TLR signaling pathway and NADPH oxidase enzyme system
are not shown for the simplicity. Please see text for the abbreviations and the details of TLR signaling pathway.
state took much longer. Prenatal LPS exposure also causes
a disturbance in the glutathione homeostasis in offspring
brain, which renders dopaminergic neurons susceptible to
secondary endotoxin insults in adulthood [106].
When rats, prenatally exposed to LPS, were evaluated
at 4, 14, and 17 months, the progressive dopaminergic
neuron loss was parallel to that of the controls suggesting
that prenatal LPS exposure does not produce an accelerated rate of dopaminergic neuron loss [107]. Prenatal
LPS exposure disrupted the dopaminergic system involving
motor function, but this neurochemical effect was not
accompanied by behavioral impairment, which is probably due to adaptive plasticity processes [108]. Prenatal
LPS administration (100 µg/kg, i.p.) on gestational day 9.5
impairs the male offspring’s general activity and decreases
the striatal dopamine and metabolite levels in adulthood
after an additional immune challenge [108]. Following
prenatal LPS exposure, significant reductions in DA and
5-hydroxytryptamine (5-HT) levels were found in the frontal
cortex, nucleus accumbens, striatum, amygdala, hippocampus, and hypothalamus of male offspring at 4 months of
age [109]. The loss of DA and 5-HT were accompanied by
a significant increase in homovanillic acid over DA and 5hydroxyindoleacetic acid over 5-HT ratios in most tested
areas. These data further validate prenatal LPS exposure as
a model of PD, since DA and 5-HT changes are similar to
those seen in PD patients.
The neonatal period is developmentally distinct from the
gestational period, and exposures to endotoxin in either may
lead to different consequences. In an in vivo study using
a mouse model with nigrostriatal lesions, produced by the
administration of MPTP, microglia activated by systemic LPS
8
were neurotoxic toward dopamine neurons in aged mice but
unexpectedly neuroprotective in neonatal mice [110]. The
inflammatory process in the brain, which is accompanied
by changes in the levels of proinflammatory cytokines
and neurotrophins, along with the presence of activated
microglia, has recently gained much attention in the area
of neurodegenerative diseases. Activated microglia produce
either neuroprotective or neurotoxic factors. Many reports
indicate that activated microglia promote degeneration of
dopaminergic neurons in PD. On the other hand, there
are several lines of evidence that microglia also have a
neuroprotective function [111]. Microglia activated with LPS
in the nigrostriatum of neonatal mice protect dopaminergic
neurons against the neurotoxin MPTP whereas activated
microglia in aged mice promote death of dopaminergic
cells by MPTP. Recent findings suggest that the function of
activated microglia may change in vivo from neuroprotective
to neurotoxic during aging as neurodegeneration progresses
in the PD brain [111]. These results suggest that the activated
microglia in neonatal mice are different from those in aged
mice, with the former having neurotrophic potential toward
the dopamine neurons in the SN in contrast to the neurotoxic
effect of the latter [112].
As discussed above, recent studies have begun to identify
specific factors occurring as part of the in utero or perinatal
environment that may predispose or even cause damage
to the nigrostriatal system, suggesting that environmental
factors early in life of an individual cause a predisposition
to develop symptoms of PD. Interactions of prenatal environment, adulthood environment, gender, age, and genetic
background may also modify this risk [100]. Recently, animal
studies have been described that specifically consider the
role of gestational exposures in disrupting the nigrostriatal
system and each has implications for elaborating on our
current understanding of the etiology of PD.
5. Cellular and Molecular Mediators of
Endotoxin-Mediated Dopaminergic
Neurodegeneration
Unlike the direct death of dopaminergic neurons caused
by neurotoxins such as MPP+ or 6-OHDA, endotoxinmediated dopaminergic neurodegeneration seems to result
from indirect neuronal death due to inflammatory reactions. Bacterial endotoxin LPS is capable of activating glial
cells, predominantly microglia, to release a wide variety of
proinflammatory and neurotoxic factors that include reactive
oxygen and nitrogen species, proinflammatory cytokines,
and lipid mediators [113]. A number of mechanisms
by which inflammatory-activated microglia and astrocytes
kill neurons have been identified in cell-culture studies
[114]. Results from studies employing enzyme inhibitors,
neutralizing antibodies, specific inhibitors of inflammatory
signaling pathways, and knockout animals have identified
these soluble factors and signaling molecules involved in
microglial activation as major contributors to the endotoxinmediated dopaminergic neurodegeneration [64].
The toll encoding gene has first been identified in
Drosophila embryos, where it has a role in dorsoventral axis
Parkinson’s Disease
determination [115, 116]. Many organisms have multiple
homologues of the Drosophila toll gene, which is very conserved among species [117]. In vertebrates, TLR (Toll-like
receptors) recognize pathogen associated molecular patterns
of bacteria, fungi, and viruses and play roles in host defense
mechanism. TLR4 takes part in recognition of strongly
conserved patterns of gram-negative cell wall components,
LPS and discriminates indigenous from foreign molecules
[118]. In TLR4 signaling, TLR4 must first associate with
its extracellular binding partner, myeloid differentiation
factor 2 (MD-2), before ligands can bind to the TLR4-MD-2
complex [119, 120]. The TLR4-MD-2-Ligand complex forms
a heterodimer with another TLR4-MD-2 ligand complex
and the signal is transferred to the TLR4’s Toll/interleukin-1
receptor (TIR) domain. The signal is than further transduced
via an unknown mechanism [118, 121]. The signal is then
transmitted to two separate pathways which are the MyD88
path activating Nf-κB and Toll/IL-1 receptor also containing
adaptor inducing IFN-β (TRIF) path. In the MyD88 path,
MyD88 adaptor-like protein (Mal or TIRAP) mediates the
TIR-TIR association between TLR4 and MyD88 [122].
Next, an interaction occurs between IL-1 receptor-associated
kinase (IRAK) and MyD88. That interaction results in the
activation of a cascade leading to the phosphorylation of
Nf-κB transcription factors. This path results in activation
of Activator Protein-1, RelA and p50 heterodimers and
regulates expression of proinflammatory cytokines [123,
124]. In the other pathway, TRIF and TLR4 require an
adaptor molecule called TRAM for signal transduction,
which mediates endocytosis of the TLR4 receptor complex
[125, 126]. TRIF forwards the signal after incorporation of
TRAF3- or TRAF6-mediated adaptor molecules to either
TRIF-binding kinase- (TBK-) IKK or RIP, respectively
[127]. TBK-IKK terminates Interferon regulatory factor-3
dimerization and translocation into nucleus to induce IFNβ synthesis; in this way, TBK-IKK regulates cellular response
to inflammation [128]. On the other hand, TRAF6 interacts
with RIP and activates Nf-κB through TAK1, which operates
the same as in the MyD88 pathway, causing late phase Nf-κB
activation [127].
5.1. Nitric Oxide. Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a gas,
is produced from L-arginine by different isoforms of NOS
and takes part in many normal physiological functions, such
as promoting vasodilation of blood vessels and mediating
communication between cells of the nervous system. In
addition to its physiological actions, free radical activity
of NO can cause cellular damage through a phenomenon
known as nitrosative stress [129]. Although many in vitro
and in vivo studies support an involvement of NO in
microglial-mediated dopaminergic neuronal death due to
LPS-treatment, some studies suggested that NO is not
involved [113]. For instance, the first in vivo study of the
endotoxin-based PD model reported that the neurotoxic
effect of LPS was not mediated by NO [36]. However,
increasing evidence from recent studies supports for the
notion that excessive production and accumulation of NO
in the LPS-induced DA lead to neurodegeneration [64].
Parkinson’s Disease
Intracerebral administration of LPS causes increase in the
iNOS enzyme activity and NO production [130, 131].
Immunofluorescence and immunohistochemical analyses
have revealed that iNOS is located in fully activated microglia
having a characteristic amoeboid morphology [70, 132].
After intranigral LPS injection, iNOS mRNA levels and protein expression increase [132]. In Western blot analysis, iNOS
has been shown to be induced in the SN after injection of LPS
in a time- and dose-dependent manner [133]. The increase in
iNOS expression inversely correlates with the TH immunolabeling and animals pretreated with a selective inhibitor
of iNOS, N(G)-nitro-L-arginine methyl ester (L-NAME),
exhibited complete protection against behavioral deficits
induced by intrastriatal LPS injection [130]. Furthermore,
LPS-induced loss of dopaminergic neurons is significantly
inhibited by the administration of L-NAME [133]. Decrease
in DA level and increase in cytochrome-c release and caspase3 activation were significantly reversed with treatment of
L-NAME [131]. Thus, increased NO availability subsequent
to iNOS induction seems to play an important role in the initial phase of neurodegeneration. Hunter et al. have suggested
that permanent expression of the iNOS plays a role in the
progressive loss of dopaminergic neurons but not the initial
loss induced by LPS [75]. Although the mechanism of NOmediated neurodegeneration remains uncertain, it has been
suggested that NO contributes to LPS-induced dopaminergic
neurodegeneration through several mechanisms. NO has
been shown to modify protein function by nitrosylation
and nitrotyrosination, contribute to glutamate excitotoxicity,
inhibit mitochondrial respiratory complexes, participate in
organelle fragmentation, and mobilize zinc from internal
stores [129, 134]. NO can react with superoxide radicals
to form peroxynitrite radicals that are short-lived oxidants
and highly damaging to neurons [64, 135]. Mitochondrial
injury is prevented by treatment with L-N(6)-(l-iminoethyl)lysine, an iNOS inhibitor, suggesting that iNOS-derived
NO is also associated with the mitochondrial impairment
[72]. NO inhibits cytochrome oxidase in competition with
oxygen, resulting in glutamate release and excitotoxicity
[114].
The main cellular source of NO in the CNS are microglia
whereas astroglia constitute the main defense system against
oxidative stress. However, under pathological or chronic
inflammatory conditions, astroglial cells may also release
neurotoxic mediators. Although the PD-associated gene
DJ-1 mediates direct neuroprotection, the upregulation of
DJ-1 in reactive astrocytes also suggests a role in glia
[136]. The intracerebral LPS-based PD model is associated
with a moderate reactive astrogliosis [70]. DJ-1 acts as
a regulator of proinflammatory responses, and its loss
contributes to PD pathogenesis by deregulation of astrocytic
neuroinflammatory damage [137]. When treated with LPS,
DJ-1-knockout astrocytes generate significantly more NO
than littermate controls. The enhanced NO production
in DJ-1(−/−) astrocytes is mediated by a signaling pathway involving reactive oxygen species (ROS) leading to
specific hyperinduction of iNOS. These effects coincide
with significantly increased phosphorylation of the p38
mitogen-activated protein kinase (MAPK), p38 inhibition,
9
suppressed NO production, and iNOS mRNA as well as
protein induction. DJ-1(−/−) astrocytes also induce the
proinflammatory mediators COX-2 and IL-6 in high levels.
Primary neuron cultures grown on DJ-1(−/−) astrocytes
became apoptotic in response to LPS in an iNOS-dependent
manner suggesting the neurotoxic potential of astrocytic
DJ-1 deficiency [137]. These findings warrant in vivo confirmation.
5.2. Reactive Oxygen Species. A large body of evidence supports the involvement of oxidative stress in the pathogenesis
of PD [134]. Besides NO, ROS generated by activated
glia, especially microglia are major mediators of the DA
neurodegeneration cause by inflammation [64]. ROS can
cause lipid peroxidation, protein oxidation, DNA damage,
and mitochondrial dysfunction. LPS-induced ROS production in microglia is mediated by nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase, a multisubunit enzyme [114]. This complex is responsible for the
production of both extracellular and intracellular ROS
by microglia. Importantly, NADPH oxidase expression is
upregulated in PD and is an essential component of
microglia-mediated dopaminergic neurotoxicity. Activation
of microglial NADPH oxidase causes neurotoxicity through
two mechanisms. Firstly, extracellular ROS released from
activated microglia are directly toxic to neurons. Secondly,
intracellular ROS amplifies the production of several proinflammatory and neurotoxic cytokines and compounds such
as TNFα, prostaglandin E2 (PGE2), COX-2, and IL-1β [138].
The activation of the phagocyte NADPH oxidase (PHOX)
by cytokines, LPS, or arachidonic acid metabolites causes
microglial proliferation and inflammatory activation; thus,
PHOX is a key regulator of inflammation. Pharmacologic
inhibition of NADPH oxidase provides protection against
LPS-induced neurotoxicity and PHOX knockout mice are
resistant to LPS-induced loss of SNpc dopaminergic neurons
[139, 140]. Gene expression and release of tumor necrosis
factor alpha was much lower in PHOX−/− mice than in
control PHOX+/+ mice [140]. By injecting LPS into the
striatum of wild type and Nox1 knockout mice, it has
been shown that Nox1, a subunit of NADPH oxidase,
also enhances microglial production of cytotoxic nitrite
species and promotes loss of presynaptic proteins in striatal
neurons [141]. Activation of PHOX alone causes no cell
death, but when combined with expressed iNOS, it results
in extensive neuronal cell death via the production of
peroxynitrite [114]. The relationship between the signaling
pathway downstream of TLR4, after LPS stimulation, and the
activation of the oxidase remains elusive. Using mice lacking
a functional TLR4, it has been demonstrated that TLR4
and ROS work in concert to mediate microglia activation
[142]. Both TLR4(−/−) and TLR4(+/+) microglia display
a similar increase in extracellular superoxide production
when exposed to LPS. These data indicate that LPS-induced
superoxide production in microglia is independent of TLR4
and that ROS derived from the production of extracellular
superoxide in microglia mediates the LPS-induced TNF-α
response of both the TLR4-dependent and independent
pathway [142].
10
The integrin CD11b/CD18 (MAC1, macrophage antigen
complex-1) pattern recognition receptor mediates LPSinduced production of superoxide by microglia [143].
MAC1 is a TLR4-independent receptor for the endotoxin
LPS. MAC1 is essential for LPS-induction of superoxide in
microglia, implicating that MAC1 acts as a critical trigger
in microglial-derived oxidative stress during inflammationmediated neurodegeneration. Interestingly, MAC1 mediates
reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of PD, suggesting a
role for this receptor in neurodegeneration [144]. Activated
matrix metalloproteinase-3 (MMP-3) released from stressed
dopaminergic neurons is also responsible for microglial
activation and generation of NADPH oxidase-derived superoxide and eventually enhances nigrostriatal DA neuronal
degeneration [145].
5.3. Proinflammatory Cytokines. Of the variety of cytokines
that are released by LPS-activated glia, the proinflammatory
IL-1β and TNFα may be the major cytokines involved in
the LPS-induced dopaminergic neurodegeneration [64]. The
contribution of these cytokines to neurodegeneration is
supported by studies showing that neutralizing antibodies
against TNFα or IL-1 markedly reduce the LPS-induced loss
of nigral dopaminergic neurons [64]. Activated microglial
cells in the SN are found in all animal models of PD
and patients with the illness. Compared with astroglia or
microglia, they appear to possess a larger repertoire of
cytokine production [64, 113]. Elevated levels of TNFα in
the cerebrospinal fluid (CSF) and the postmortem brains
of PD patients as well as in animal models of PD implicate
that proinflammatory cytokines significantly influence the
pathophysiology of the disease [146]. TNFα has a pivotal
role in mediating the loss of DA neurons in PD, which
has been demonstrated using the endotoxin-based model.
A sustained elevation of TNFα has been observed in the
striatum and the mesencephalon of rats prenatally exposed to
LPS [104]. Furthermore, in the chronic LPS nigral infusion
model of PD, the loss of SNpc dopaminergic neurons,
and the activation of microglia are significantly reduced by
blockade of the soluble form of the TNFα receptor [146].
Systemic LPS administration results in rapid increase of
TNFα in the brain, which remains elevated for 10 months
[80]. Furthermore, LPS leads to microglial activation, to an
increase in the expression of proinflammatory factors such as
IL-1β, and NFκB p65, and to a progressive loss of nigral THimmunoreactive neurons in wild-type mice, but not in mice
lacking TNFα receptors [80]. Nontoxic doses of LPS also
induce secretion of cytokines and predispose dopaminergic
neurons to be more vulnerable to a subsequent low dose
of neurotoxins such as 6-OHDA. Alterations in cytokines,
prominently an increase in IL-1β, have been identified as
being potential mediators of this effect that is associated
with the activation of microglia [94, 95]. Administration
of an IL-1 receptor antagonist results in significant reductions in TNFα and interferon gamma and attenuates the
augmented loss of dopaminergic neurons caused by the
LPS-induced sensitization to dopaminergic degeneration.
Nigral injection of LPS in a degenerating SN exacerbates
Parkinson’s Disease
neurodegeneration and accelerates and increases motor signs
and shifts microglial activation towards a proinflammatory
phenotype with increased IL-1β secretion [95]. Importantly,
chronic systemic expression of IL-1 also exacerbates neurodegeneration and causes microglial activation in the SN.
It has been found by in vivo studies that NO is a downstream
molecule of IL-1 action and partially responsible for the
exacerbation of dopaminergic neurodegeneration, suggesting that IL-1 exerts its exacerbating effect on degenerating
dopaminergic neurons by direct and indirect mechanisms
[95].
Part of the challenge to sort out the contributions of
individual cytokines to neurodegeneration may be a result
of the complex interplay by various positive or negative
feedback and feedforward loops among various cytokines,
pro- and anti-inflammatory cytokines [64]. Microglial TNFα
not only upregulates its own production in an autocrine
fashion but also can further increase the surface expression
of the neuronal TNFα cell death receptor (TNF p55 receptor)
in a paracrine manner, thus exacerbating the LPS-induced
neurotoxicity [64]. On the other hand, anti-inflammatory
cytokines have been shown to reduce LPS-induced microglial
activation and loss of SNpc dopaminergic neurons [147,
148]. The transforming growth factor beta 1 (TGF-β1),
one of the most potent endogenous immune modulators
of inflammation, exerts significant neuroprotection against
LPS induction via its anti-inflammatory properties [147].
TGF-β1 inhibits the translocation of the cytosolic subunit
p47phox of the LPS-induced PHOX from the cytosol to
the membrane in cultured microglia. The molecular mechanisms of TGF-β1-mediated anti-inflammatory properties
works via the inhibition of PHOX activity by preventing
the ERK-dependent phosphorylation of Ser345 on PHOX’s
cytosolic subunit p47phox in microglia, thus reducing
oxidase activities induced by LPS [147]. Using the terminal
deoxynucleotidyl transferase biotin-dUTP nick end labeling
(TUNEL) assay and electron microscopy, Arimoto et al.
have shown that intranigral injection of LPS causes marked
microglial activation and a dose-dependent selective loss
of dopaminergic neurons, which is mediated by apoptosis
[148]. LPS injection leads to an increase in the mRNA
expression of the proapoptotic proteins Bax, Fas, and the
proinflammatory cytokines IL-1β, IL-6, and TNFα, while
expression of the antiapoptotic gene Bcl-2 is decreased. Infusion of interleukin-10 (IL-10) by osmotic minipump protects
against LPS-induced cell death of dopaminergic neurons. A
corresponding decrease in the number of activated microglia
suggests that the reduction in microglia-mediated release
of anti-inflammatory mediators may contribute to the antiinflammatory effect of IL-10 [148].
NFκB plays a key role in regulating neuroinflammation.
Activation of NFκB depends on the phosphorylation of its
inhibitor, IkappaB, by the specific IkappaB kinase (IKK) subunit IKK-beta. Compound A, a potent and selective inhibitor
of IKK-beta, inhibits the activation of microglia, induced
by nigral injection of LPS, and significantly attenuates LPSinduced loss of dopaminergic neurons in the SN [149]. Selective inhibition of NFκB activation affords neuroprotection
by suppressing the activity of microglial NADPH oxidase
Parkinson’s Disease
and by decreasing the production of ROS, and by inhibiting
gene transcription of various proinflammatory mediators
in microglia via IKK-beta suppression. Microglial activation
may involve kinase pathways controlled by mixed lineage
kinases (MLKs), a distinct family of mitogen-activated
protein kinases, which might contribute to the pathology of
PD. A potent MLK inhibitor, CEP-1347, inhibits brain TNFα
production induced by intracerebroventricular injection of
LPS in mice [150]. Coinjections of LPS with a p38 MAP
kinase inhibitor to SN reduces iNOS and caspase-11 mRNA
expression and rescues dopaminergic neurons in the SN
[132]. Thus, LPS-induced dopaminergic cellular death in SN
could be mediated, at least in part, by the p38 signal pathway
leading to activation of inducible nitric oxide synthase and
caspase-11.
5.4. Cyclo-Oxygenase-2 and Prostaglandin E2. Prostaglandins
are potent autocrine and paracrine oxygenated lipid
molecules that contribute appreciably to physiologic and
pathophysiologic responses in brain and other organs [151].
Emerging data indicate that PGE2 plays a central role in
neurodegenerative diseases. PGE2 signaling is mediated by
interactions with four distinct G protein-coupled receptors,
EP1-4, which are differentially expressed on neuronal and
glial cells throughout the CNS, (here something is missing
to make a sentence) [151]. EP2 activation has been shown to
mediate microglial-induced paracrine neurotoxicity as well
as to suppress the internalization of aggregated neurotoxic
peptides in microglia [152]. PGE2 is produced at high
levels in the injured CNS, where it is generally considered
a cytotoxic mediator of inflammation. LPS upregulates the
expression of COX-2 and increase the release of PGE2 in
cultured microglia [64]. Intracerebral injections of LPS result
in a significant upregulation of the striatal and nigral protein
expression of COX-2 as well as the activation of microglia
[153, 154]. Double labeling using immunohistochemistry
identified that activated microglia rather than intact resting
microglia are the main intracellular locations of COX-2
expression [64, 155]. In vivo pharmacological inhibition of
COX-2 activity protects nigral dopaminergic neuronal loss
and decreases microglial activation induced by intracerebral
LPS injection, supporting the role of COX-2 in the pathogenesis of neuroinflammation-mediated neurodegeneration
[153, 155, 156].
A local injection of LPS into the rat SN led to the induction of microsomal prostaglandin E2 synthase (mPGES)-1
in activated microglia [157]. Further in vitro and in vivo
experiments with mPGES-1 knockout mice indicate the
necessity of mPGES-1 for microglial PGE2 production. This
study has shown that the activation of microglia contributes
to PGE2 production through the concerted de novo synthesis
of mPGES-1 and COX-2 at the sites of inflammation in
the brain parenchyma. In contrast to that, a recent in
vitro study suggests that mPGES-1 expression is not strictly
coupled to the expression of COX-2 [158]. Activation of
cultured spinal microglia via TLR4 produces PGE2 and
causes NO release from these cells, showing that COXPGE2 pathway is regulated by p38 and iNOS [159]. These
findings emphasize that p38 in spinal microglia is a key
11
player among inflammatory mediators, such as PGE2 and
NO. In vitro experiments also indicate that microglial PGE2
plays an important role in astrocyte proliferation, identifying
PGE2 as a key neuroinflammatory molecule that triggers
the pathological response related to uncontrollable astrocyte
proliferation [160].
5.5. Matrix Metalloproteinase-3. As discussed above (Section
5.2), the release of MMP-3 from apoptotic neurons may
play a major role in degenerative human brain disorders,
such as PD. The catalytic domain of recombinant MMP-3
induces the generation of TNFα, IL-6, IL-1β, and IL-1
receptor antagonist but not of IL-12 and iNOS, which are
readily induced by LPS, in cultured microglia, suggesting
that there is a characteristic pattern of microglial cytokine
induction by apoptotic neurons [145]. MMP-3 activates the
nuclear factor-kappaB (NFκB) pathway, and these microglial
responses were totally abolished by preincubation with
an MMP-3 inhibitor. MMP-3-mediated microglial activation mostly depends on ERK (extracellular signal-regulated
kinase) phosphorylation but not on either JNK (c-Jun Nterminal protein kinase) or p38 activation. MMP-3-activated
microglial cells caused apoptosis of neuronal cells in in vitro
experiments. These results suggest that the distinctive signal
of neuronal apoptosis is the release of the active form of
MMP-3 that activates microglia and subsequently exacerbates neuronal degeneration [145]. The released active form
of MMP-3, as well as the catalytically active recombinant
from of MMP-3 leads to superoxide generation in cultured
microglia [161]. MMP-3 causes dopaminergic cell death in
mesencephalic neuron-glia mixed cultures of wild-type mice,
but this is attenuated in the culture of NADPH oxidase subunit null mice (gp91(phox−/−)), suggesting that NADPH
oxidase mediates the MMP-3-induced microglial production
of superoxide and the following dopaminergic cell death.
Moreover, in the MPTP model of PD, the nigrostriatal
dopaminergic neuronal degeneration, microglial activation,
and superoxide generation are largely attenuated in MMP3−/− mice. These results indicate that MMP-3 released
from stressed dopaminergic neurons is responsible for
microglial activation and generation of NADPH oxidasederived superoxide and in turn exacerbates the nigrostriatal
dopaminergic neuronal degeneration [161].
αSYN also induces the expression of MMP-3 in cultured microglia from rat [162]. The inhibition of MMP-3
significantly reduces NO and ROS levels and suppresses the
expression of TNFα and IL-1β. Inhibition of MMP-3 also
suppresses the activities of MAPK and transcription factors,
NFκB and AP-1. The specific inhibitor of the proteaseactivated receptor-1 (PAR-1) and a PAR-1 antagonist significantly suppress cytokine levels, NO, and ROS production
in αSYN-treated microglia, indicating that MMP-3 secreted
by αSYN-stimulated microglia activate PAR-1 and amplify
microglial inflammatory signals in an autocrine or paracrine
manner [162]. In vivo, LPS injection into the SN of
rats increases MMP-3 expression and activation suggesting
that MMP-3 may participate in neuroinflammation-induced
dopaminergic neurotoxicity [163]. These studies propose
that the in vivo modulation of MMP-3 expression and
12
activity may provide the neuroprotection for dopaminergic
neurons. Indeed, an antibiotic, doxycycline, shows neuroprotection for the dopaminergic system in a toxin-based model
of PD and this appears to derive from antiapoptotic and
anti-inflammatory mechanisms involving downregulation of
MMP-3 [164].
5.6. Microenvironmental Changes and Intercellular Interactions. The CNS microenvironment plays a significant role in
determining the phenotypes of both CNS-resident microglia
and CNS-infiltrating macrophages. In this section, we summarize the microenvironmental changes such as astroglial
responses, BBB alterations, and a wide range of intercellular
interactions in the context of the endotoxin-based PD model.
5.6.1. Reactive Astrocytes and Parkinson’s Disease. Astrocytes
are the most abundant cell types in the CNS and participate
in the local innate immune response triggered by a variety
of insults. The role of astrocytes in the pathogenesis of PD
is even less well understood than the one of microglia but
they are known to secrete both inflammatory and antiinflammatory molecules [165]. It has been proposed that
astrocytes may play dual roles in PD [166]. Similar to
microglial activation, star-shaped astrocytes transformed to
reactive form have enlarged and thick bodies and respond
to various stimuli, which coined the term reactive astrocytes
[167]. Reactive astrogliosis is generally mild or moderate
and rarely severely pronounced in autopsy specimens from
the SN of PD patients [166]. Classic reactive astrocytes are
observed in multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration, but not in PD
cases; the extent of reactivity correlates with indices of
neurodegeneration and disease stage [168]. Different subpopulations of astrocytes express disease-related proteins
such as αSYN, parkin, and p-tau at different levels and in
different combinations in different Parkinsonian syndromes
but the roles of astrocytes in these conditions are not yet well
defined [167, 168].
The role of astrocytes in the development of PD is still
unknown and controversial. Astrocytes provide the optimal
microenvironment for neuronal function by exerting active
control over the cerebral blood flow and by controlling the extracellular concentration of synaptically released
neurotransmitters [167]. Generally, astrocytes promote the
survival and maintenance of dopaminergic neurons through
secretion of various neurotrophic factors in the SN. The
decreased levels of astrocyte-derived neurotrophic factors
are at least in part responsible for DA neuronal death in
PD [167]. Astrocytes become activated and synthesize proand anti-inflammatory cytokines, chemokines, antioxidants,
neurotrophic factors, and prostanoids during neuroinflammation and neurodegeneration and interact with other
immune competent cells. These mediators act as doubleedged swords, exerting both detrimental and neuroprotective
effects. For example, myeloperoxidase (MPO), a key enzyme
in the generation of reactive nitrogen species (RNS), is
upregulated in the midbrains of PD patients and MPTP
treated mice [169]. This enzyme is localized within reactive
astrocytes in MPTP-treated mice, and MPTP neurotoxicity
Parkinson’s Disease
is attenuated by ablation of MPO from the nigrostriatal
pathway [167, 169].
5.6.2. Region-Specific Astroglial Responses in the Brain.
Degenerative disorders of the brain often occur in a region
specific fashion, suggesting differences in the activity and
reactivity of innate immune cells. This may make astrocytes
likely candidates to be responsible for region-specific incidence rates of neurological and neurodegenerative disorders.
Cultured astrocytes from the cortex and midbrain already
differ in their capacity and profile of cytokine expression
under unstimulated conditions [170]. In response to LPS,
both a region specific pattern of upregulation of distinct
cytokines, and differences in the extent and time course of
activation are observed. Thus, astrocytes reveal a regionspecific basal profile of cytokine expression and a selective
area specific regulation of cytokines upon LPS-induced
inflammation [170]. The densities of astrocytes are much
lower in the intact SNpc, compared with the cortex [171].
Furthermore, after LPS injection, damage to endothelial
cells and astrocytes and the blood-brain barrier (BBB)
permeability are more pronounced in the SNpc [171]. The
in vitro responses of microglia and astroglia to inflammatory
stimuli or environmental toxins also differ. Manganese
significantly potentiates LPS-induced release of TNF-α and
IL-1β in microglia, but not in astroglia [172]. These agents
are more effective in inducing the formation of ROS and NO
in microglia than in astroglia.
5.6.3. DJ-1, Oxidative Stress and Astrocytes. Recent findings
support the developing view that astrocytic dysfunction,
in addition to neuronal dysfunction, may contribute to
the progression of a variety of neurodegenerative disorders.
Thus, the treatments that support the beneficial aspects of
astrocyte function may represent novel approaches targeting
astrocytes to promote dopaminergic neurorescue. Although
aging enhances the neuroinflammatory response and the
alpha-synuclein nitration [73], the antioxidant capacity
and glutathione metabolism of astrocytes are preserved
from mature adulthood into senescence [173]. Thus, the
oxidative stress seen in aging brains is likely due to factors
extrinsic to astrocytes, rather than being caused by an
impairment of the antioxidative functions of astrocytes. The
PARK7 (DJ-1) gene, which has been implicated in some
forms of early-onset, autosomal recessive PD, is apparently
expressed mainly by the astrocytes in the human brain. Lossof-function mutations lead to the characteristic selective
neurodegeneration of nigrostriatal dopaminergic neurons.
In addition to cell-autonomous neuroprotective roles, DJ-1
may act in a transcellular manner, being upregulated in
reactive astrocytes in chronic neurodegenerative diseases, for
example. In sporadic PD, and many other neurodegenerative
diseases, reactive astrocytes overexpress DJ-1 whereas neurons maintain the expression at normal levels [136]. Since
DJ-1 has neuroprotective properties and since astrocytes are
known to support and protect neurons, DJ-1 overexpression
in reactive astrocytes may reflect an attempt to protect
themselves and the surrounding neurons against disease
progression. Knocking down DJ-1 in astrocytes impairs
Parkinson’s Disease
astrocyte mediated neuroprotection against rotenone [174].
DJ-1 is a ubiquitous redox responsive and cytoprotective
protein with diverse functions. DJ-1 regulates redox signaling
kinase pathways and acts as a transcriptional regulator
of antioxidative genes. DJ-1 scavenges H2 O2 by cysteine
oxidation in response to oxidative stress and, thus, confers
neuroprotection. Therefore, DJ-1 is an important redoxreactive signaling intermediate, controlling oxidative stress
upon neuroinflammation and during age-related neurodegenerative processes such as PD [136]. However, the functional basis of neuroprotection elicited by DJ-1 has remained
vague. DJ-1 stabilizes erythroid 2-related factor (Nrf2), a
master regulator of antioxidant transcriptional responses,
by preventing its association with the inhibitor protein
Keap1 and by blocking Nrf2’s subsequent ubiquitination
[175]. Without intact DJ-1, Nrf2 protein is unstable, and
transcriptional responses are thereby decreased both basally
and after induction [175] though a recent study suggests that
activation of the Nrf2 is independent of DJ-1 [176].
5.6.4. Nrf2/ARE Pathway and Parkinson’s Disease. The
expression of phase II detoxification and antioxidant
enzymes is governed by a cis-acting regulatory element
named the antioxidant response element (ARE). Nrf2 regulates genes containing the ARE element and is a member of
the Cap’n’Collar basic-leucine-zipper family of transcription
factors. Following activation, Nrf2 dissociates from Keap1,
translocates to the nucleus, and binds to the ARE promoter
sequences, as a part of the coordinated induction of a
battery of cytoprotective genes including antioxidants and
anti-inflammatory genes [177]. ARE-regulated genes are
preferentially activated in astrocytes, which consequently
have more efficient detoxification and antioxidant defense
mechanisms than neurons. Astrocytes closely interact with
neurons to provide structural, metabolic, and trophic
support, as well as actively participating in the modulation of neuronal excitability and neurotransmission [177].
Therefore, alterations in astroglial function can modulate
the interaction with surrounding cells such as neurons
and microglia. Activation of Nrf2 in astrocytes protects
neurons from a wide array of insults in different in vitro
and in vivo paradigms, confirming the role of astrocytes
in determining the vulnerability of neurons to deleterious
stimuli [177]. Nrf2 has been shown to be important for
protection against oxidative stress and cell death in toxinbased models of PD [177–181]. These findings remain
to be confirmed in endotoxin-based models. Genetic data
suggest that variation in Nrf2 gene NFE2L2 modifies the PD
process, which provides another link between oxidative stress
and neurodegeneration [182]. Nrf2 activating agents such
as synthetic triterpenoids and sulforaphane are potential
therapeutic targets for the prevention of neurodegeneration
in PD [183–185].
5.6.5. Nrf2/ARE Pathway and Microglial Activation. The
deficiency of Nrf2 results in an exacerbated inflammatory
response and in microglial activation of the expression of the
neurotoxin MPTP whereas inducers of Nrf2 downmodulate
neuroinflammation [181]. Nrf2-deficient mice exhibit more
13
astrogliosis and microgliosis, as determined by an increase in
mRNA and protein expression levels for GFAP and F4/80,
respectively, than wild-type mice. Inflammation markers,
characteristic of classical microglial activation like COX-2,
iNOS, IL-6, and TNF-alpha, are also increased. At the same
time, anti-inflammatory markers, attributable to alternative
microglial activation, such as FIZZ-1, YM-1, Arginase-1,
and IL-4 are decreased [181]. These results demonstrate a
role of Nrf2 in tuning the balance between classical and
alternative microglial activation. The restoration of the redox
balance may be a determinant in driving microglia back
to the resting state. ROS generated by microglia could
help to eliminate pathogens in the extracellular milieu and
also to act on the microglia itself, altering the intracellular
redox balance and functioning as a second messengers in
the induction of proinflammatory genes. The modulation
of microglial activation is a matter closely correlated with
control of oxidative stress in this cell type and is crucial to
restore its inactive state and modulate the inflammation in
neurologic diseases [186]. Nrf2 is essential for the regulation
of NADPH oxidase-dependent ROS-mediated TLR4 activation in macrophages [187]. Nrf2 activation by sulforaphane
inhibits the inflammatory response to LPS in cultured rodent
microglia [185]. These findings remain to be tested in the
context of in vivo endotoxin-based PD models. Interestingly,
LPS by itself is able to activate the cell’s defense against
oxidative and electrophilic stress, activating Nrf2 [185]. This
mechanism may be a mediator of LPS preconditioning or
endotoxin tolerance, a phenomenon which by prior exposure
of innate immune cells like monocytes/macrophages to
minute amounts of endotoxin causes them to become refractory to subsequent endotoxin challenges [188]. In contrast
to the well-known protective effect of this phenomenon,
in acute ischemic conditions, only one in vitro study has
reported this benefit in dopaminergic neurotoxicity [189].
Further understanding the underlying mechanism of LPS
preconditioning may open a new window for the treatment
of PD.
Astroglial cells are also involved in the microglial modulation by Nrf2 [177]. These cells are known to play an important role in antioxidant defense and in modulating microglial
activity in the CNS [165, 166]. Recently, astrocytes have been
found to regulate excessive inflammation via induction of
the microglial hemooxygenase-1 (HO-1) expression in vitro
[190]. While pharmacological or genetic intervention on
Nrf2 may provide a neuroprotective benefit, HO-1 does not
protect or enhance the sensitivity to neuronal death in the
MPTP model [191]. These results support the idea that the
modulation of a master transcription factor may be a better
strategy than targeting individual genes.
5.6.6. Blood-Brain Barrier Dysfunction and Peripheral
Immune Cell Infiltration. The brain demands an adequate
blood supply for the regulation of neuronal and synaptic
function. To maintain concentrations of ions within narrow
ranges as well as the adequate levels of metabolic substrates
in various brain regions, neural milieu are strictly separated
from circulatory spaces through BBB formation [167]. These
unique biological structures are comprised of neurovascular
14
units such as brain capillary endothelial cells, pericytes,
neurons, and astrocyte end-feet. Endothelial cells tightly
connect at junctional complexes such as adherens junctions,
tight junctions, and gap junctions confer low paracellular
permeability. Pericytes and astrocytes regulate hemodynamic
neurovascular coupling, microvascular permeability, matrix
interactions, neurotransmitter inactivation, neurotrophic
coupling, and angiogenic as well as neurogenic coupling
through close proximity with neurons [167, 192]. Although
there is no clear evidence as to whether these altered
neurovascular circumstances are responsible for the loss
of dopaminergic neurons in PD, several studies on PD
patients and animal models suggest a pathogenic linkage
between BBB disruption and dopaminergic neuronal death
[167]. PET and histological studies on PD patients revealed
BBB dysfunction in the midbrain of PD patients [193]. In
addition, increased BBB permeability has been observed in
the MPTP and the LPS models for PD [194]. These studies
suggest that the disruption of the BBB has a relationship
with neuronal cell death and neuroinflammation in PD
[167]. There is also a direct correlation between the location
of IgG immunoreactivity-a, a marker for disruption of
neurodegenerative processes, including the death of nigral
dopaminergic cells and reactive astrocytes. A precise spatial
correlation also exists between disruption of the BBB and
3-nitrotyrosine immunoreactivity [194]. LPS-activated
microglia can induce the dysfunction of the BBB in an
in vitro coculture system with rat brain microvascular
endothelial cells and microglia [195]. In the presence of LPSactivated microglia, tight junction proteins are fragmented,
and barrier disintegrity and dysfunction induced by LPSactivated microglia are blocked by an NADPH oxidase
inhibition, suggesting that LPS activates microglia to induce
dysfunction of the BBB by producing ROS through NADPH
oxidase.
Recent studies have shown that the dysfunction of the
BBB combined with the infiltration of peripheral immune
cells plays an important role in the degeneration of dopaminergic neurons [167]. However, these molecular and cellular
changes are not specific to the PD, since they are also
implicated in the pathogenesis of other neurodegenerative
diseases [196]. The neuroinflammation may contribute to
the infiltration of peripheral immune cells and leakage of
the BBB into the SN. Various peripheral immune cells, such
as T-cells, B-cells, microphages, and leukocytes infiltrate
into the SN region in the LPS and MPTP models [167,
171, 197]. CD11b and MPO double-positive neutrophils
infiltrate the SNpc following LPS injection [197]. MPO(+)
neutrophils observed in SNpc express iNOS, IL-1β, COX2, and monocyte chemoattractant protein-1 (MCP-1). In
intact rodent brain, the densities of microglia are similar
in SNpc and cortex [197]. In addition, the densities of
astrocytes are much lower in the intact SNpc, compared with
the cortex. However, LPS injection induces microgliosis and
causes neutrophil infiltration into the SNpc, but not into the
cortex [171]. The extent of neutrophil infiltration appears to
be correlated with neuronal damage. The loss of neurons in
the SNpc is significantly reduced in neutropenic rats versus
normal rats following LPS injection. Furthermore, after LPS
Parkinson’s Disease
injection, damage to endothelial cells and astrocytes and
increased BBB permeability are more pronounced in the
SNpc. Excessive neutrophil infiltration, lower astrocyte density, and higher BBB permeability following LPS exposure
contributes to severe inflammation and neuronal death in the
SNpc compared with the cortex [171].
The links between T-cell immunity and the nigrostriatal
neurodegeneration are supported by laboratory, animal
model, and human pathologic investigations [198]. The
presence of T-lymphocytes in the midbrain of PD patients
suggests that the potential role of infiltrated peripheral
cells is a factor of the PD pathogenesis [199]. Recently,
Brochard et al. have reported that numerous CD4 and CD8
positive cells are detectable in postmortem PD patients [200].
The infiltration of CD4+ lymphocytes into the brain also
contributes to the neurodegeneration in the MPTP model for
PD [200]. Specifically, invading T-lymphocytes contribute
to neuronal cell death via the Fas/FasL cell death pathway,
implicating the emerging role of the adaptive immune system
in the pathogenesis of PD [201].
The adoptive transfer of CD3-activated CD4+CD25+
regulatory T-cells (Tregs) is known to suppress immune activation and maintain immune homeostasis and tolerance. In
MPTP-treated mice, it protects the nigrostriatal system from
degeneration through suppression of microglial oxidative
stress and inflammation [202]. Tregs also attenuates Th17
cell-mediated nigrostriatal dopaminergic neurodegeneration
in the MPTP model [203]. In addition, these cells suppress
nitrated αSYN-induced microglial ROS production and
NFκB activation supporting the importance of adaptive
immunity in the regulation of PD-associated microglial
inflammation [204]. Taken together, these studies provide a
rationale for future immunization strategies in PD [198].
Accumulating evidence suggests that the penetration of
immune cells into the brain plays an important role in
the degeneration of dopaminergic neurons in PD. Further
understanding of the cellular and molecular mechanisms
responsible for trafficking of immune cells from the periphery into the diseased CNS may be the key to targeting these
cells for therapeutic intervention in PD [196].
In addition to glia-neuron crosstalk, multiple cell-to-cell
interactions and immune regulations, critical for neuronal
homeostasis, also influence immune responses [198, 205].
Microglia can be activated by MCP-1, which is expressed
by dopaminergic neurons and can interact with its receptor
CCR2 on microglial cells. The neuroimmune regulatory proteins CD47 and CD200 inhibit macrophage and microglia
activation through binding to their receptors SIRPalpha and
CD200R, expressed on phagocytes [206]. Upon stress, nigral
dopaminergic neurons secrete MMP-3 and α-SYN, which
activates microglial and astroglial cells [145, 207]. As disease progresses, secretions from α-SYN-activated microglia
can engage neighboring glia cells in a cycle of autocrine
and paracrine amplification of neurotoxic immune products. Astrocytes differentially regulate neutrophil functions
through direct or indirect interactions between the two cell
types [208]. Many of these established interactions between
different cell types involved in neuroinflammation have been
demonstrated in vitro and remain to be confirmed in vivo.
Parkinson’s Disease
Dissecting the molecular determinants of complex interplay
between CNS cells and immune cells in the context of the
endotoxin-based PD model will give the possibility to test
novel therapeutic strategies to promote restoration of injured
nigrostriatal dopaminergic neurons.
6. Therapeutic Approaches
The endotoxin-induced neuroinflammation model for PD is
a purely inflammation-driven model. However, all clinical
and pathological features of PD can be observed in this
model. Therefore, the LPS-induced model can be used to
search for novel treatment strategies for the therapy of
PD. In this section, we summarize known neuroprotective
molecules, which have been tested using the LPS-induced PD
models.
COX-2 is a rate-limiting enzyme in prostaglandin synthesis. Experimental and epidemiological evidence supports
the protective role of COX-2 inhibition in PD. COX-2
is upregulated in SN both in the PD and in the MPTP
model [209]. Pharmacological inhibition of COX-2 or the
knockout of the COX-2 gene provides resistance to MPTP
in vivo [209, 210] and to 6-OHDA-induced dopaminergic
toxicity in vitro [211]. There is epidemiological evidence
that the use of some NSAIDs lowers the incidence of PD
[212]. On the other hand, according to meta-analyses of
NSAID studies in PD, ibuprofen shows a slight protection
against PD whereas aspirin and acetaminophen did not show
any protective effects [213, 214]. Hunter et al. used the
COX-2 inhibitor Celecoxib (Celebrex) in LPS-induced PD
animal model for the first time. They were able to show
that Celecoxib protects dopaminergic neurons by decreasing
inflammation and by restoring mitochondrial function in
the intrastriatal LPS-induced PD model [153]. Using the
intranigral LPS rat model, Sui et al. [155] have shown
that another COX-2 inhibitor, meloxicam, diminishes the
activation of OX-42 positive microglia and reduces the loss of
dopaminergic neurons in the SNpc. Clinical studies suggest
that inhibition of COX-2 may cause side effects such as
trombogenic cardiovascular diseases [156, 215]. In order
to avoid potential side effects of COX-2 inhibition, new
drugs have been targeted for dual inhibition of COX-2 and
lipoxygenase (LOX) [156]. Dual inhibitor of COX-2 and 5LOX has been shown to lower gastrointestinal side effects.
Moreover, combination of the two inhibitors achieves a more
potent neuroprotection than usage of single inhibitors [216].
Li et al. tested the dopaminergic neuroprotective effect of
COX, LOX, and the combination of COX and LOX inhibitors
in the intrastriatal LPS-induced animal model for PD. They
found that the dual COX and LOX inhibitor, phenidone, is
better than COX or LOX inhibitors alone for suppressing
LPS-induced neurotoxicity [156].
Dexamethasone is a potent anti-inflammatory drug that
has been tested in the intranigral LPS-induced PD model
[67, 133]. These studies have shown that dopaminergic
degeneration and microglial activation induced by LPS can
be prevented by administration of dexamethasone [67, 133].
Dexamethasone also decreases the exacerbating effect of LPS
during neurodegeneration induced by 6-OHDA [95].
15
Experimental and epidemiological evidence supports the
protective role of nicotine in PD. Epidemiological studies
have confirmed that there is an inverse correlation between
cigarette smoking and the incidence of PD [217]. In vitro
nicotine pretreatment inhibits LPS-induced TNF-α release in
murine-derived microglial cells via the α-7 nicotinic receptor
[218]. These results suggest that nicotine could protect
dopaminergic neurons in the animal model of PD. Indeed,
Park et al. have shown that nicotine significantly decreases
the release of TNFα and the dopaminergic neuronal loss
induced by LPS stimulation. Both effects were blocked by α7nicotinic acetylcholine receptor blockers [219].
Peroxisome proliferators activated receptor (PPAR-γ) is a
nuclear receptor that regulates transcription of various genes.
It has been shown that the PPAR-γ agonist inhibits cytokine
secretion in microglia and macrophage-like cells [220].
Hunter et al. have shown that a PPAR-γ agonist, pioglitazone,
provides neuroprotection by decreasing inflammation and
restoring mitochondrial function. Pioglitazone administration partially reduces the LPS-induced striatal dopamine loss
and the TH-positive cell loss in the SN [153].
Minocycline is a semisynthetic tetracycline that exerts
anti-inflammatory activities [221]. Minocycline significantly
reduces the SN microglial activation induced by intranigral LPS administration [194]. Minocycline prevents the
LPS-induced increase of mRNA levels of proinflammatory
cytokines and diminishes the production of peroxynitrites
[194].
Naloxone, an opioid receptor competitive antagonist, has
been found to reduce microglial activation-mediated DA
neurodegeneration in mouse cortical neuron-glia cocultures
[64]. Systemic infusion of naloxone protects dopaminergic
neurons against inflammation-mediated degeneration and
decreases microglial activation in vivo through inactivation
of NADPH oxidase [139, 222].
The neuroprotective effects of statins in CNS disorders
such as experimental autoimmune encephalomyelitis, stroke,
and Alzheimer’s disease have been previously described
[223–225]. Selley has shown that oral administration of
simvastatin attenuates the depletion of dopamine DOPAC
and HVA inhibits the formation of 3-nitrotyrosine and the
production of TNFα in mice treated with MPTP [226].
Simvastatin has also been tested in the intranigral LPSinduced PD [227] and the LPS perfusion model [228].
Simvastatin prevents the loss of dopaminergic neurons and
astrocytes induced by LPS in both models [227, 228].
Simvastatin increases BDNF expression [228], which may
support neuronal and astroglial survival.
Osteopontin (OPN) is a glycosylated phosphoprotein
that has first been identified in 1986 in osteoblasts [229].
OPN is constitutively expressed in most tissues, including
the brain [208]. Iczkiewicz et al. have shown that OPN is
constitutively present in dopaminergic neurons, in the SN,
and that its expression is decreased in the MPTP model of
PD and in patients with PD [230]. It has been reported that
the intranigral injection of LPS enhances expression of OPN
[231]. These results suggest that OPN may have a regulatory
role in neuroinflammation. One peptide fragment of OPN
contains the arginine-glycine-aspartic acid (RGD) domain
16
that has been associated with the neuroprotective effects of
OPN [232]. Iczkiewicz et al. have tested RGD containing
peptide fragments of OPN in the LPS-induced PD model.
They found that the RGD containing peptide fragment of
OPN protects against LPS-induced TH positive cell loss and
alters gliosis in the rat SN [233].
Urocortin is a neuroprotective agent that is structurally
related to the corticotrophin releasing factor (CRF) [234–
236]. Abuirmeileh et al. have used urocortin for the treatment of the LPS-induced PD model. They have shown that
urocortin reduces nigrostriatal damage induced by LPS and
that this effect of urocortin is mediated by CRF1 receptors
[237–239].
7. Conclusion
Parkinson’s disease (PD) is the second most common neurodegenerative disease with increasing incidence worldwide.
Although the pathogenesis of PD remains elusive, accumulating evidence from many studies on animal models and
patients shows that the pivotal role of microglial activation
along with neuroinflammatory processes contribute to the
initiation and progression of the nigrostriatal dopaminergic
neurodegeneration in PD. In addition to that, recent studies
have proposed that the BBB dysfunction combined with the
infiltration of peripheral immune cells into the CNS plays
an essential role in the degeneration of nigral dopaminergic
neurons. Thus, using a purely inflammatory experimental
model induced by the administration of the bacterial
endotoxin, LPS, provides a valuable tool for the in vivo
modeling of the characteristics of progressive dopaminergic neurodegeneration associated with neuroinflammation.
Except for the acute direct administration of LPS to the nigral
region, other modified forms of the model, including the
prenatal one, realistically simulate the slow and progressive
dopaminergic neuronal loss and permanent neuroinflammation. Furthermore, the combination of endotoxin-based
PD models with genetic and toxin-based models is fruitful
for the delineation of the complex interactions among
the environmental and genetic factors and inflammatory
processes involved in PD. Many experimental variables
including sex, age, and strain of the animals have the potential to significantly perturb the functional and pathologic
outcomes. These methodological issues should be considered
in respect to the studies.
Several novel techniques, such as in vivo imaging of
microglial activation, are waiting to be applied in the
endotoxin-based model of PD. Molecular studies from the
domains of transcriptomics, proteomics, and microRNomics
will be valuable to gain in potential diagnostic markers
for the disease [240]. Since the inflammatory responses
precede the neurodegeneration and the motor dysfunctions,
alterations of the immune parameters, both in CSF and
blood, are likely to be useful as early diagnostic markers.
The major challenge in this area is the enhancement of the
specificity and sensitivity of the potential markers. Despite
intensive research, the mechanisms of neuroinflammationmediated nigral neurodegeneration are poorly understood.
Whether neuroinflammation is a consequence or a cause of
Parkinson’s Disease
nigral neuronal loss is still unknown. Neuroinflammation
seems to be a trigger of the initiation of neurodegeneration
and progressive neurodegeneration continuously aggravates
chronic neuroinflammatory processes. In this context, the
stimulation of TLR4 by endogenous ligands released by
injured dopaminergic neurons may contribute to this vicious
circle [241].
In vivo imaging and molecular studies will also extend
our understanding of the complex interplay between CNS
and immune cells. Especially, the novel links between neuroinflammatory processes, oxidative stress, and Nrf2/ARE
pathways that are mainly based on data from toxin-based
models of PD should be confirmed by the endotoxin based
model.
Based on the recent data, adaptive immune responses
along with innate immunity are important mediators of
neuroinflammation-mediated dopaminergic neurodegeneration. Recent evidence suggests that the importance of
nonautonomous pathological mechanisms are involved in
PD, which are mostly mediated by activated microglia
and peripheral immune cells. Thus, the harnessing of the
immune system by immunomodulating drugs or by immunisation aiming at the downregulation of immune responses
remains promising future therapeutic options. Immune
parameters will also be indispensable for the monitoring of
therapeutic responses.
Abbreviations
MPTP:
1-Methyl-4-Phenyl-1,2,3,6tetrahydropyridine
DOPAC: 3,4-dihydroxyphenylacetic acid
6-OHDA: 6-hydroxydopamine
ARE:
Antioxidant response element
BBB:
Blood-brain barrier
CNS:
Central nervous system
CSF:
Cerebrospinal fluid
COX-2: Cyclo-oxygenase-2
EGF:
Epidermal growth factor
ERK:
Extracellular signal-regulated kinase
DA:
Dopamine
GFAP:
Glial fibrillary acidic protein
HO-1:
Hemooxygenase-1
HPLC:
High-performance liquid chromatography
HVA:
Homovanillic acid
5-HT:
5-hydroxytryptamine
IKK:
IkappaB kinase
IRAK:
IL-1 receptor-associated kinase
iNOS:
Inducible nitric oxide synthase
IFN-β:
Interferon-beta
IL-2:
Interleukin-2
IL-6:
Interleukin-6
IL-10:
Interleukin-10
IL-1β:
Interleukin 1β
JNK:
c-Jun N-terminal protein kinase
LPS:
Lipopolysaccharide
MMP-3: Matrix metalloproteinase-3
1-methyl-4-phenylpyridinium
MPP+ :
MA:
Methamphetamine
Parkinson’s Disease
MLKs:
TFAM:
MD-2:
Mal or TIRAP:
PHOX:
L-NAME:
NADPH:
NO:
Nrf2:
NFκB:
PD:
PPAR-γ:
PGE2:
RNS:
ROS:
Tregs:
SN:
SNpc:
SNpr:
TUNEL:
TH+:
TLRs:
TIR:
TRIF:
TGFα:
TGF-β1:
TBK:
TNFα:
TH:
VTA:
Mixed lineage kinases
Mitochondrial transcription factor A
Myeloid differentiation factor 2
MyD88 adaptor-like protein
NADPH oxidase
N(G)-nitro-L-arginine methyl ester
Nicotinamide adenine dinucleotide
phosphate
Nitric oxide
Nuclear factor erythroid 2-related factor
Nuclear factor-kappaB
Parkinson’s disease
Peroxisome proliferator-activated receptor
Prostaglandin E2
Reactive nitrogen species
Reactive oxygen species
Regulatory T cells
Substantia nigra
Substantia nigra pars compacta
Substantia nigra pars reticulata
Terminal deoxynucleotidyl transferase
biotin-dUTP nick end labeling
Tyrosine hydroxylase-positive
Toll-like receptors
Toll/interleukin-1 receptor
Toll/IL-1 receptor containing adaptor
inducing IFN-β
Transforming growth factor-alpha
Transforming growth factor-beta 1
TRIF-binding kinase
Tumor necrosis factor-alpha
Tyrosine hydroxylase
Ventral tegmental area.
Conflict of Interest Disclosure
The authors declare no competing financial interests.
Acknowledgment
The authors thank Asst. Prof. Jens Allmer for critical reading
of the manuscript for English.
17
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
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