Urolithin A in Health and Diseases: Prospects for Parkinson’s Disease Management
<p>Catabolic pathway of ellagitannins and ellagic acid to urolithins. 5-OH, 4-OH, 3-OH, 2-OH, and 1-OH refer to the number of hydroxyl groups for each urolithin group—penta-, tetra-, tri-, di- and monohydroxy urolithins, respectively. The blue font refers to new urolithins generated by a bacterial 3-dehydroxylase. The purple and red circles designate the final urolithins produced in UM-A and UM-B, respectively. Uro-AR can be found in both metabotypes. Adapted from [<a href="#B7-antioxidants-12-01479" class="html-bibr">7</a>].</p> "> Figure 2
<p>Urolithin A mechanisms of action. Ellagitannins and ellagic acid are polyphenols that occur naturally in dietary products like pomegranates, berries, and nuts. The compounds are substrates of colonic bacteria transformed into urolithins. However, it is estimated that only 40% of individuals could naturally convert the polyphenolic precursors to UA. Thus, UA administration is proposed as an answer for urolithin non-producers. In vivo and in vitro experiments suggest the health-promoting activity of UA. The effects of the compound are related to different mechanisms of action, including engagement in mitochondrial function and the process of mitophagy, inflammation, oxidative stress, and the modulation of the apoptosis process. Created with BioRender.com.</p> "> Figure 3
<p>Urolithin A’s activity in Parkinson’s disease model studies. UA’s beneficial activity may include potential favorable effects of UA on brain health. The current research explores the potential neuroprotective effects of the compound in PD models. The beneficial role of the compound can be related to the reduction in neuroinflammation, loss of dopaminergic neurons, a-synuclein aggregation, and apoptosis, as well as improved mitochondrial, motor, and cognitive function. Created with BioRender.com.</p> ">
Abstract
:1. Introduction
2. Urolithin A Production and Mechanism of Action
2.1. Urolithins Metabolic Pathways
2.2. Mechanism of Action
2.2.1. Mitophagy and Mitochondrial Functions
2.2.2. Anti-Inflammatory Activity
2.2.3. Antioxidant Activity
2.2.4. Apoptosis-Modulating Activity
3. Urolithin A in Health and Diseases
4. Urolithin A and the CNS
4.1. Brain Health
4.2. AD and Brain Injury
4.3. Parkinson’s Disease
5. Summary and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Dose and Route of Administration | Experimental Model | Outcomes | References |
---|---|---|---|
Mitophagy and mitochondrial functions | |||
50 µM | SH-SY5Y cells | ↑ F-PINK-1, Parkin, Beclin-1, Bcl2L13, AMBRA1, and p-ULK1(Ser555) | [15] |
200 mg/kg/d, i.g., for 2 months | 6-month-old APP/PS1 mice | ↑ relative neuronal mitophagy level ↑ mitophagy events ↓ damaged mitochondria ↑ F-PINK-1 in brain tissue | [15] |
200 mg/kg/d, i.g., for 2 months | 13-month-old 3 × TgAD mice | ↑ relative neuronal mitophagy level ↑ mitophagy events in brain tissue | [15] |
50 µM, ad libitum, for 10 days | Caenorhabditis elegans | ↑ mRNA of the autophagy genes Bec-1, Sqst-1 and Vps-34 ↑ mRNA of the mitophagy genes Pink-1, Dct-1 ↑ mRNA of the mitophagy and biogenesis gene Skn-1 in muscle tissue GFP–LGG-1-positive punctae | [29] |
50 µM | C2C12 myoblasts Mode-K intestinal cells | ↑ LC3-II/LC3-I, p-AMPKα ↑ SQSTM-1, Ub in mitochonfrial fraction ↑ autophagosomes ↑ autolysosomes ↓ mt DNA/nDNA ↑ mt chain subunits ↑ CII-driven respiration | [29] |
50 mg/kg/d, p.o., for 34 weeks | 16-month-old C57BL/6J mice | ↑ LC3-II/LC3-I ↓ SQSTM-1 ↑ mRNA of autophagy genes Becn1, Ulk1, Pik3c3, Atg8l, p62, Atg5, Atg7, Atg12, Lc3b, LAMP2 ↑ mRNA of mitophagy gene Park2 ↑ p-AMPK ↑ Ub/SDHA, Ub/VDAC in muscle tissue | [29] |
50 mg/kg/d, p.o., for 10 weeks | Caenorhabditis elegans/DMD model | ↑ mRNA of mitophagy genes Pink1, Pdr-1, Dct-1 ↑mRNA of autophagy genes Bec-1, Vsp-34 ↑ mitochondrial network ↑ mitochondrial respiration ↑ citrate synthase activity ↑ mtDNA/nDNA in mucle tissue | [35] |
50 mg/kg/d, p.o., for 10 weeks | 13-week-old mdx mice/DMD model | ↑ mRNA of mitophagy genes Pink1, Park2, Park7, and Bnip3 ↑ mRNA of autophagy genes Sqstm-1 and Becn1 ↑ p-S65-Ub, BNIP3, PARKIN, VDAC ↑ mt LC3-II in mucle tissue | [35] |
25 µM | Primary myoblast cells derived from DMD patients | ↑ mRNA of mitophagy genes PINK1, PARK2, PARK7, and BNIP3 ↑ mRNA of autophagy genes SQSTM-1, BECN1 | [35] |
50 mg/kg/d, i.g., for 8 weeks | 10-week-old C57BL/6 mice/STZ-induced model of type 2 diabetes | ↑ LC3II/I, beclin1, ATG5, ↓ SQSTM-1 ↑ p-AKT, mTORC1 ↓ mitochondrial swelling in pancreatic tissue | [36] |
Anti-inflammatory activity | |||
20 mg/kg, p.o., 10-day post-treatment | C57BL/6 mice/DSS-induced acute colitis | ↓ IL-6, IL-1β, and TNF-α in serum ↓ MPO activity ↑ ZO-1, Ocln, Cldn4 ↓ F4/80+ CD11b+, CD4+ cells ↑ CD11c+, T-reg cells in the mesenteric lymph node | [10] |
200 mg/kg/d, i.g., for 2 months | 6-month-old APP/PS1 AD mice | ↓ TNF-α, IL-6 ↑ IL-10 in brain tissue ↓ TNF-α, IL-6 ↑ IL-10 in microglia | [15] |
300 mg/kg/d, p.o., for 14 days | 28-week-old APP/PS1 AD mice | ↓ mRNA of Tnfα, Il6 and Il1β ↓ TNF-α, IL-6 and IL-1β ↓ IBA1 and GFAP in brain tissue | [16] |
20 μg/d, i.p., for 12 weeks | C57BL/6 mice/HFD | ↓ Il1β mRNA ↓ p-eIF2α, p-ERK ↑ IκBα LC3I/II in liver tissue ↓ M1 polarization (mRNA of Cd11c, Tnfα, Il6, Il1β, and Mcp1) ↑ M2 polarization (mRNA of Ch3l3 and Mgl2) in peritoneal macrophages | [27] |
50 mg/kg/d, i.g., for 8 weeks | 10-week-old C57BL/6 mice/STZ-induced model of type 2 diabetes | ↓ IL-1β, TNF-α ↑ IL-10 in plasma | [36] |
100 mg/kg/d, i.p., for 5 days | C57BL/6 mice, cisplatin-induced nephrotoxicity model | ↓ CD11b positive monocyte/macrophage ↓ mRNA of Tnfα, Il23, Il18, Mip2 in kidney tissue | [37] |
20 mg/kg/d, p.o., on 4th and 6th day of DSS cycle | C57BL/6 mice/DSS-, TNBS-induced colitis | ↓ IL-6, IL-1β, and TNF-α in serum ↓ MPO activity ↓ Cldn4 in colon tissue | [38] |
150 and 250 μM | Caco-2 and HT-29/B6/TNFα-induced barrier loss models | ↑ TER ↓ claudin-2 | [39] |
25 mg/kg/d, p.o., 20 days | C57BL/6 mice/EAE model | ↓ GFP+ cells in the brain and spinal cord ↓ M1-type microglia ↓ CD11c+ cells infiltrated into CNS ↓ CD45high CD11b+, CD45low CD11b+, CD11b+ MHCII+, CD11b+ TNF-α+, CD11b+ CD16/32+ cells | [40] |
10, 40 μM, 2 h pretreatment | LPS-stimulated RAW264 macrophages | ↓ TNF-α, IL-6, NO−, iNOS ↓ intracellular peroxides ↓ NADPH oxidase activity ↓ DNA binding activity of NF-κB and AP-1 ↓ NF-κB (p65) ↑ IκBα ↓ c-Jun, p-c-Jun, p-Akt, p-JNK, p-p38 | [41] |
Antioxidant activity | |||
20 μg/d, i.p., for 12 weeks | C57BL/6 mice/HFD | ↑ mRNA of Sod1 and Sod2 in liver tissue | [27] |
50 mg/kg/d, i.g., for 8 weeks | 10-week-old C57BL/6 mice/STZ-induced model of type 2 diabetes | ↑ GSH ↓ MDA in pancreas tissue | [36] |
100 mg/kg/d, i.p., for 5 days | C57BL/6 mice, cisplatin-induced nephrotoxicity model | ↑ CAT, GPx, SOD activity ↑ GSH ↓ GSSG, HNE, protein nitration, DNA fragmentation, Nox2 mRNA in kidney tissue | [37] |
0.5, 1, 2, 4 μM | N2a cells/H2O2 | ↑ CAT, SOD, GR, GPx activity ↓ ROS production, TBARS | [42] |
Apoptosis-modulating activity | |||
300 mg/kg/d, i.g., for 14 days | 28-week-old APP/PS1 AD mice | ↑ NeuN+ cells ↓ TUNEL+ cells in brain tissue | [16] |
100 mg/kg/d, i.p., for 5 days | C57BL/6 mice, cisplatin-induced nephrotoxicity model | ↓ caspase 3 activity ↓ DNA fragmentation in kidney tissue | [37] |
50 mg/kg, i.g., 3 times/week up to 19 days | C57BL/6J mice/cisplatin-induced AKI | ↓ PARP1, TUNEL+ cells ↑ Bcl-2 in kidney tissue | [48] |
10 μM, 6 h pretreatment | SH-SY5Y cells/H2O2 | ↓ apoptotic cells ↓ caspase-3, -9 | [49] |
1.25, 2.5, 5 μM, 6 h pretreatment | SK-N-MC cells/H2O2 | ↓ Bax/Bcl-2 ↓ cytochrome c, caspase-3, -9 ↓ PARP | [50] |
25, 50, 100 μM | HT29, SW480, SW620 cells | ↑ apoptotic cells ↑ ytochrome c, caspase-3, -9 ↑ p53, p21, XIAP ↓ Bcl-2 G2/M phase arrest | [51] |
Treated with 40, 80 μM | LNCaP, 22RV1, PC3 cells | ↑ p53, p21, MDM2 ↑ PUMA and NOXA | [52] |
80 μM | HepG2.2.15 cells | ↑ caspase-3 ↓ Bax/Bcl-2 | [53] |
Dose and Route of Administration | Experimental Model | Outcomes | References |
---|---|---|---|
Longevity | |||
500 mg or 1000 mg/d, p.o. for 4 months | Middle-aged adults between 40 to 65 years old | ↑muscle strength, aerobic-endurance, physical performance ↓ acylcarnitines ↓ CRP, IL-1β, TNF-α, IFNγ in plasma | [11] |
50 µM, ad libitum, for 10 days | Caenorhabditis elegans | ↑ lifespan, mobility, ↑ pharyngeal pumping ↑ mitochondrial respiratory capacity ↓ dysfunctional mitochondria in muscle tissue | [29] |
50 mg/kg/d, p.o., for 10 weeks | 13-week-old mdx mice DMD model | ↑ improved muscle morphology ↑ motility ↓ muscle fiber degeneration ↑ eMyHC, dystrophin in muscle tissue | [35] |
10 mg/kg/d, p.o., for 16 weeks | C57BL/6 mice | ↑muscle strength, mobility, and exercise performance | [54] |
1000 mg/d, p.o., for 4 months | Adults aged 65 to 90 years | ↑ muscle endurance, physical performance ↓ acylcarnitines, ceramides ↓ CRP in plasma | [56] |
5 mg/kg/d, p.o., 10 months in alternate weeks (1 week on, 1 week off) | Female B6129SF2/J and male C57BL/6NJ/aging model | ↑ lifespan | [55] |
Cardiovascular health | |||
50 mg/kg/d, p.o., for 20 weeks | C57BL/6 mice/HFD | ↑ PINK1/Parkin-dependent mitophagy ↓ mitochondrial defects ↑ cardiac diastolic function | [57] |
3 mg/kg/d, p.o., for 3 weeks | Wistar rats/HFD + ballon injury in the aorta | ↓ TC, TG and LDL ↓ Ang II ↓ aortic edema | [58] |
1 mg/kg, i.p., 24 h and 1 h pretreatment | C57BL/6 mice/H/R | ↓ myocardial infarct sizes ↓ TUNEL+ cells ↑ ejection fraction, fractional shortening ↓ CK, LDH in serum | [59] |
10 mg/d for 12 weeks | Healthy volunteers 40–65 years old, UA non-producer or low producer | ↑ FMD score | [60] |
Metabolic dysfunctions | |||
20 μg/d, i.p., for 12 weeks | C57BL/6 mice/HFD | ↓ hepatic TG ↓ IR, adipocyte hypertrophy ↓ macrophage infiltration into the adipose tissue ↓ M1/M2 | [27] |
50 mg/kg/d, i.g., for 8 weeks | 10-week-old C57BL/6 mice/STZ-induced model of type 2 diabetes | ↓ BW ↓ FBG, GHb ↓ pancreatic histopathological damages ↑ HOMA-β | [36] |
30 mg/kg/d, i.g., for 10 weeks | C57BL/6 mice/HFD | ↓ BW, fat mass ↓ plasma glucose, insulin ↑ thermogenesis in brown adipose tissue ↑ browning of white adipose tissue | [61] |
13 mg/kg/d, p.o., for 8 weeks | DBA2J mice/HFD/HSD | ↓ FBG ↓ serum TG, FFA, adiponectin ↓ IR | [62] |
Cancer | |||
25–100 μM | PC-3 cells, C4-2B cells | ↓ cell proliferation ↑ apoptosis | [63] |
50 mg/kg, p.o.; 5 days/week, for 4–5 weeks | C4-2B xenografted mice PC-3 xenografted mice | ↓ tumor volume ↓ Ki67, AR, and pAKT in tumor samples | [63] |
50–200 μM | HepG2 cells | ↓ Cell survival ↓ Wnt/β-catenin signaling; β-catenin ↓ c-Myc, cyclin D1, p-c-Jun ↑ TP53, BAX, PUMA, NOXA, p53, p-p53 ↑ Caspase-3, p-p38 | [64] |
Pretreatment with 5–25 μM | A549, H460, H1299 cells | ↓ EMT ↓ Snail expression | [65] |
0.5–10 μM | HCT-116, Caco-2, and HT-29 cells | ↓ Colony formation G2/M arrest (Caco-2, HCT-116) ↑ Senescence-associated β–galactosidase activity (HCT-116) ↑ p53 and p21Cip1/Waf1 expression (HCT-116) | [66] |
30 μM | HCT116 cells | ↓ Cell growth ↑ p53, p21, TIGAR expression | [67] |
1.5 μM | SW620 cells | ↓ Proliferation, MMP-9 activity ↑ Autophagy, LC3 G2/M arrest ↑ Apoptosis, necrosis | [68] |
Alzheimer’s disease | |||
200 mg/kg/d, i.g., for 2 months | 6-month-old APP/PS1 AD mice | ↑ Cognitive behavior ↓ Aβ 1–40 and 1–42 | [15] |
300 mg/kg/d, p.o., for 14 days | 28-week-old APP/PS1 AD mice | ↓ learning and memory deficits ↓ Aβ 42 in the cerebral cortex and hippocampus | [16] |
5 mg/kg/d, p.o., 10 months in alternate weeks (1 week on, 1 week off) | 3xTg-AD mice | ↓ Aβ 42 in hippocampus ↑ learning and exploratory behavior | [55] |
30 μM | HT22 cells/Aβ oligomers | ↓ Aβ, SQSTM1, LC3 | [55] |
Intraperitoneal injection, 2.5 mg/kg, 3 times per week for 4 months | 7-month-old hAbKI mice | ↑ Cognitive behavior ↓ Aβ 1–40 and 1–42 ↓ mitochondria fission proteins Drp1, Fis1 ↑ mitochondria fusion proteins Mfn2, Opa1 ↑ mitochondrial biogenesis proteins PGC1α, Nrf1, Nrf2, TFAM ↑ mitophagy proteins PINK1, Parkin ↑ synaptic proteins synaptophysin PSD95 ↑ autophagy proteins ATG5, Beclin, BCL2, LC3B-I, LC3B-II ↓ microglia IBA-1, astrocytes GFAP, neuronal NeuN in brain tissue | [69] |
Brain injury | |||
2.5, 5 mg/kg, i.p., twice s1 h and 24 h before MCAO surgery | C57BL/6 mice/MCAO | ↓ infarct volume, NDS ↓ mRNA of autophagy genes Atf6 and Chop in the brain tissue | [14] |
30 μM | N2a cells, primary cultured neurons/OGD/R injury | ↑ cell viability ↓LDH ↑ LC3II, ↓p62 ↓ mRNA of autophagy genes Atf6 and Chop | [14] |
2.5 mg/kg, i.p., immediately after controlled injury and every 24 h for 3 days | C57BL/6J/CTI | ↓ NSS score, brain edema ↓ TUNEL+/NeuN+ cells ↓ caspase-3 ↑ bcl-2 ↑ LC3-II/LC3-I ↓ p62 ↓ p-Akt/Akt, p-mTOR/mTOR, p-IKKα/IKKα, p-NFκB/NFκB in the hippocampus | [70] |
1.5, 2 mg/kg, i.p., twice 1 h and 24 h before MCAO surgery | Mice/MCAO | ↓ infarct volume, NDS in hippocampus ↓ spatial memory deficits ↑ Nissl+ cells ↓ TUNEL+ cells ↓ Bax, caspase-3, ↑ Bcl-2 in the hippocampus | [71] |
Parkinson’s disease | |||
20 mg/kg/d, i.p., 7-day pretreatment | Mice/MPTP | ↑ Nissl+, TH+neurons ↓ motor deficits ↓ p62 ↑ LC3II/I ↓ NLRP3, caspase-1, IL-1β ↓ IBA1+, GFAP+ cells in the SN ↓ NLRP3 inflammasome activation ↓ neuroinflammation | [72] |
10 μM | BV2 cells/LPS | ↓ p62 ↑ LC3II/I ↑ PINK1 and Parkin ↓ Tim23 and Tom20 ↓ mRNA of Il1β, Tnfα, iNos, and Cox2 ↓ NO, NLRP3, caspase-1, IL-1β ↑ MMP, mitochondrial metabolism | [72] |
10 μM | PC12 cells/6-OHDA | ↑ cell viability ↓ apoptotic rate ↑ MMP, ↑ Tim23, Tom20 ↑ TFAM, PGC1α, SIRT1 | [73] |
10 mg/kg/d, i.p., 7-day pretreatment | C57BL/6J mice/6-OHDA | ↑ Nissl+, TH+neurons ↓ motor deficits ↑ TFAM, PGC1α, SIRT1 In the SN | [73] |
Diet exposition (exposure details not available) | 9-month-old Thy-1α-syn mice | ↑ Blood colonic γδ T cells ↑ novel object recognition | [74] |
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Wojciechowska, O.; Kujawska, M. Urolithin A in Health and Diseases: Prospects for Parkinson’s Disease Management. Antioxidants 2023, 12, 1479. https://doi.org/10.3390/antiox12071479
Wojciechowska O, Kujawska M. Urolithin A in Health and Diseases: Prospects for Parkinson’s Disease Management. Antioxidants. 2023; 12(7):1479. https://doi.org/10.3390/antiox12071479
Chicago/Turabian StyleWojciechowska, Olga, and Małgorzata Kujawska. 2023. "Urolithin A in Health and Diseases: Prospects for Parkinson’s Disease Management" Antioxidants 12, no. 7: 1479. https://doi.org/10.3390/antiox12071479