Donepezil

Donepezil is an indanone-benzyl piperidine derivative and the second generation of AChEIs and is
considered the leading drug for AD treatment. Donepezil is a drug that reversibly binds to
Acetylcholinesterase and inhibits acetylcholine hydrolysis. This results in a higher level of ACh at the
synapses. It is tolerated well with minor and transient cholinergic side effects that are related to the
nervous and gastrointestinal systems. Donepezil is used to treat AD symptoms such as cognitive and
behavioral improvements without altering the AD progression.
Rivastigmine
Rivastigmine is a pseudo-irreversible inhibitor of AChE and butyrylcholinesterase (BuChE) that acts by
binding to the two active sites of AChE (anionic and esoteric sites), which results in preventing ACh
metabolism. BuChE is most common in glial cells. In the normal brain, it is only 10% active. AChE
activity is greater in AD brains, where it is 40-90%. AChE activity is also reduced in both AD and normal
brains. This suggests that BuChE may be a sign of moderate to severe dementia. Rivastigmine is slower
than AChE in dissociating, which is why it's called a pseudo-irreversible. It undergoes metabolism at its
synapse via AChE or BuChE. It is recommended for mild to moderate AD. It enhances cognitive function
and daily activities. Negative side effects include nausea, vomiting, and dyspepsia. These side effects can
often be the reason why people stop taking the medication. However, they can be managed, and the drug
is more tolerable. Transdermal patches can deliver Rivastigmine to the skin in a controlled, continuous
manner. This provides increased tolerability and caregiver satisfaction. The patches may deliver lower
doses than pills. This reduces side effects. Many AD patients have difficulty swallowing and memory
loss, which can make it difficult to administer oral medication at regular times. Transdermal patches are
the best method to deliver the drug to AD patients.
Galantamine (GAL)
Galantamine, is a first-line treatment for mild to moderate AD cases. GAL, a selective tertiary alkaloid of
isoquinoline, has a dual mechanism. It acts as an AChE inhibitor and can also bind to the subunit of
nicotinic acid acetylcholine and activate them. GAL is like other AChE inhibitors in that it can improve
cognitive performance, behavioral symptoms, daily activities, and cognitive performance. Wahba and
colleagues developed several delivery systems to increase drug delivery to the brain. Attached GAL to
ceria-containing, hydroxyapatite particles to selectively deliver the drug to the brain's affected areas.
Misra et al. and Fornaguera et al. Fornaguera et al. used nano-emulsification and solid-lipid nanoparticles
to deliver GAL hydrobromide. These studies revealed a promising strategy to deliver the drug safely.
Hanafy et al. developed nasal GAL hydrobromide/chitosan complex nanoparticles which showed good
pharmacological efficacy, while Woo et al. The patch system was used as a carrier to control the release
of the drug.

1.6.2. N-methyl d-aspartate (NMDA) Antagonists

NMDAR is thought to play a major role in the pathophysiology and progression of AD. NMDAR
stimulation causes Ca 2+ influx, which activates signal transcription and, as a result, triggers gene
transcript essential for the formation of long-term potentiation. This is vital for synaptic
neurotransmission and plasticity, memory formation, and memory formation. Over-activation causes
abnormal levels of Ca 2+ signaling, which in turn triggers gene transcription essential for the formation of
long-term potentiation (LTP). This is important for synaptic neurotransmission, plasticity, memory
formation, and excitotoxicity. Although several NMDAR antagonists were developed and tested in
clinical trials, many failed because of low efficacy or side effects. Memantine is the only approved drug
in this category to treat moderate to severe AD; in addition, other NMDAR uncompetitive antagonist
compounds are being developed, such as RL-208 (3,4,8,9-tetramethyl tetra cyclo methylamine
hydrochloride), a polycyclic amine compound that may possess a promising therapeutic effect in age-
related cognitive problems and AD.
Memantine
Memantine is a low-affinity, uncompetitive antagonist for the NMDAR. This subtype of glutamine
receptor prevents overactivation of the glutaminergic systems that are involved in neurotoxicity in AD
cases. Memantine can be used alone or in combination with AChEI to treat moderate-severe AD.
Memantine is used to treat moderate to severe AD alone or in combination with AChEI. This drug is
associated with high side effects, particularly on memory and learning.
Future Therapies that Look Promising
DMT (disease-modifying therapy) can slow down the progression of AD. It works on multiple
pathophysiological mechanisms. This is different from symptomatic therapy, which works to improve
cognitive functions and decrease symptoms like depression or delusions but does not affect or modify the
disease. DMTs are both immunotherapies (or small molecules) that are administered orally. They are
designed to slow down or prevent AD. Several DMTs were developed and have entered clinical trials.
Among them was AN-1792, a synthetic Ab peptide (1-42 peptide) of 42-amino acid with the immune
adjuvant, QS-21. This first active immunotherapy against AD entered phase II clinical trials. However, it
was discontinued after a side effect of meningoencephalitis in 6%. Other drugs, such as the anti-Ab
antibody (solanezumab or bapineuzumab), the g-Secretase inhibitors (tarenflurbil 8, and semagacestat 6),
and the b-secretase inhibitions (BACE (Lanabecestat 9, verubecestat 10 and atabecestat 11, were also
tested but failed to work in clinical trials. Many factors can lead to DMT failures. These include starting
treatment too late, treating the wrong target, using inappropriate drug dosages, and misunderstanding the
pathophysiology. Many immunotherapies have been developed over the years, as shown in Table1. These
include CAD106, which induces Ab antibodies in animal models. It consists of multiple copies of the
Ab1-6 peptide combined with the Qb coat protein. This virus-like particle is still being tested in clinical
trials. CNP520 (umibecestat 12) a small compound that inhibits beta-secretase-1 and thus inhibits-1
(BACE-1 and inhibitase-1 (BACE-1 and therefore thereby reducing Ab production. CNP520, which has
been shown to decrease Ab plaque formation and Ab levels in the brain and CSF in dogs and healthy
adults over 60, is still in clinical trials. Furthermore, aducanumab, gantenerumab, and crenezumab are all
human Ab monoclonal antibodies that bind with high affinity to aggregated Ab, and they are still under
study in the clinical phases with other DMTs described below.
The second class of therapeutic agents was created that targets the a-secretase enzyme. A-secretase
activators and modulators stimulate the cleavage APP. Although little is known about the activation
pathway of APP, research suggests that it is mediated by the phosphatidylinositol 3kinase/Akt pathway or
by g–aminobutyric acids (GABA) receptor signaling. These pathways could be targeted to develop
therapeutic agents for AD.
The anti-amyloid drugs are not the only promising DMTs. Tau aggregation inhibitors are another
promising DMT. Tau is a biomarker of neurofibrillary Tangles (NFT), an AD-related disorder. It
naturally modifies microtubule stability and signaling pathways as well as axonal transportation. Toxic
aggregation is caused by a modification of tau conformation. To reduce AD progression, drug discovery
should consider ways to prevent tau aggregation. Study in mice has shown that tau oligomers can cause
mitochondrial damage, neuronal signaling disruption, synaptic loss, memory impairment, and disrupted
neuronal signaling. DMT (disease-modifying therapies) such as small molecules can be used to stop the
initial step of tau aggregation, and thus reduce its accumulation. Methylene blue,a blue dye that inhibits
tau aggregation, has entered phase II clinical trials for mild to moderate AD. The drug causes urine to turn
blue after administration. This indicates that there is no binding. This was strongly criticized. Another
approach suggests that inhibition of specific kinases, such as glycogen synthase 3b (GSK3b), can block
tau hyperphosphorylation. Examples of these entities include tideglusib (14, or NP-031112 (NP-12)a
thiazolidinedione-derived compound, lithium, pyrazolopyridines, pyrazolopyrazines, sodium valproate,
and others. AZD0530 ( is another protein kinase inhibitor. It acts by inhibiting tyrosine kinase. This drug
has been shown to improve memory in transgenic mice.