Unfolding Remedial Targets for Alzheimer’s Disease

 

Tamilselvan. M*, Tamilanban. T, V. Chitra

Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpet- 603203

 

ABSTRACT:

 

 

INTRODUCTION:

Alzheimer's disease is a developing neurodegenerative disorder. It determined dementia and neuronal cell death. AD is outlined by the development of extracellular amyloid plaques, intracellular neurofibrillary tangles, cholinergic deficiency and inflammation in the brain^[1]. The pathophysiology of disease interlinked with several cascade mechanism. Activation of brain microglial cells triggers the inflammatory mediators. Increased expression of AChE enzyme expression depletes the level of acetylcholine which tends to cognitive dysfunction.

 

Hyperactive monoamine oxidase enzymes degrade the substantial neurotransmitter like dopamine and serotonin leads to the motor incoordination and delay in the process of memory and learning. NMDA-Receptor antagonist such as memantine and reversible acetylcholinesterase such as Rivastigmine, Donepezil, Galantamine are the few drugs which only manage the symptoms of Alzheimer's disease with lesser effects on the complete cure of the disease^[2][3].

 

Hence the ideal characteristic of durg to treat AD should not only improve the symptoms of memory loss but also must reduce the from of neurofibrillary tangles and plaques. Thus preventing the neuronal degeneration for now many molecules which are under preclinical trail aims for the inhibition amyloid- agglomeration, degradation of already formed amyloid precursor protein or prevents the formation of hyperphosphorylated of tau protein^[4]. It is a complicated disease with multifactorial etiology. Age is the most common risk factor of Alzheimer's is aging where it is found as one in nine people at the age of 65 and older are in risk. Family history and genetics The risk increases if more than one family member has the illness. APOE genes increase the risk factors of AD. Other factors are sleep deprivation, oxidative stress, inflammatory response, and environmental factors these are the other risk factors of AD.

 

Pathophysiology of AD:

Cholinergic hypothesis:

It is a well known fact that acetylcholine, a neurotransmitter plays a vital role in memory and learning process an individual. Thus the cholinergic hypothesis of Alzheimer's is because of the deficiency of acetylcholine and choline acetyl transferase. Studies found that the decline in the cholinergic neuron which led to the decline in the neuronal cholinergic transmission was the main reason for the reduction in the non-cognotive and cognitive function^[5].

 

Amyloid- aggregation:

The early onset of autosomal dominant AD is due to the alteration in three genes. Amyloid β Precursor Protein, which encodes Amyloid Precursor Protein and PSEN1, PESN2 encodes persenilin1 and presenilin2 respectively. All three genes are involved in the formation of Amyloid-β. which is developed by the sequential proteolytic cleavage of amyloid precursor protein by two enzymes Which are β secretase and α secretase. Accumulation of amyloid precursor protein on neurons induces the neurotoxicity^[6],[7].

 

Hyperphosphorylated tau protein formation:

Every neuron has a cytoskeleton and its internal structure is made up of microtubule. On phosphorylation, the Tau, a protein stabilizes the microtubules. During Alzheimer's, the tau proteins undergo chemical changes and become hyperphosphorylated which then pairs with other threads and forms neurofibrillary tangles^[8].

 

CURRENT MANAGEMENT:

Cholinesterase Inhibitors and NMDA Antagonists:

Currently approved therapies are not directly target the AD pathology. Extent remedies are only symptomatic, which aims at lightening the cognitive function through two various modes of action which are an agonist of the cholinergic system and antagonism of the N-methyl-D-aspartate receptor (NMDA-receptor). Till date, cholinesterase inhibitors are the only drugs that have shown significant improvements in the cognitive process of patients with AD by reducing their symptoms and by improving the cholinergic function in neuronal synapses.(1) These drugs act as inhibitors of Acetylcholinesterase (AChE), and Butyrylcholinesterase (BChE), which are enzymes responsible for the degradation of the neurotransmitter Acetylcholine (ACh) in the synapses, after transmission of the nervous impulse. Overall, approximately one-half of patients show modest but significant cognitive and functional benefit from cholinesterase inhibition. Cholinesterase inhibitors vary in side effects and dosing profiles than in efficacy. Age, gender, and/or apoE genotype do not seem to determine the response to treatment. Drugs such as donepezil, rivastigmine, and galantamine which are acetylcholinesterase inhibitors (AChEIs) have UK marketing authorizations for the treatment of mild-to-moderately severe AD. Whereas the fourth drug, memantine hydrochloride,  has a UK marketing authorization for the treatment of moderate-to-severe AD. It is a voltage-dependent, moderate-affinity, uncompetitive N-methyl-d-aspartate receptor antagonist.

 

DONEPEZIL:

Donepezil is designated for the symptomatic treatment of mild to moderate AD. It is a specific and reversible inhibitor of acetylcholine, thus inhibiting acetylcholine hydrolysis.  maintaining the level of acetylcholine donepezil may help compensate for the loss of function cholinergic neurons in AD^[10]. It is piperidine-based, inhibitors of acetylcholine and a pharmacological agent prescribed most widely for the treatment of AD. The primary mechanism of donepezil is enzyme inhibitation, where it promotes central cholinergic neurotransmission activity.  The other actions of donepezil are opposing glutamate-induced excitotoxicity thus influencing amyloid processing and deposition^[11]. Besides, cholinesterase inhibitors such as donepezil may be effective in vascular dementia associated with Parkinson's disease and other conditions. The pharmacokinetic profile of donepezil was found to be linear and dose-proportional following the administration of single doses to healthy volunteers^[12]. A direct correlation was also observed between plasma donepezil concentration and AChE inhibition. The extended half-life of donepezil makes it suitable for once-daily dosing. It is administered orally at a dose of 5mg or 10mg per day. Due to its long half-life, it is administered once daily. Initially, the dose is started from 5mg/kg for a period of 4 - 6 weeks and slowly increased to a dose of 10mg/kg on the seventh week. If any form of adverse effects shows up the dose can be withdrawn and the initial dose of 5mg/kg can be given^[13],[14]. Nausea, diarrhea, vomiting is common. When taken before bedtime it might cause sleep disturbances and its long term administration eventually causes bradycardia, heart attack, and behavioral disturbance^[15].

 

RIVASTIGMINE:

The continuous inhibition of AchE and BuchE is done by Rivastigmine which was the first authorised for the management of memory loss and Parkinson's disease. All the AchE inhibitors except Rivastigmine are available as oral formulation where Rivastigmine now developed as transdermal patches which is also authenticated many countries across the globe for the management of AD^[16]. This transdermal method of drug delivery is given a consideration as a successful method due to the presents of mainute hydrophilic and liphophilic molecule which readyly passes through the dermal and systamic circulation^[17]. The starting dose of Rivastigmine patch has a dimension of 5*2.5cm with a dose of 4.6mg/24hrs where as the target dose of Rivastigmine patch which is 9.5mg/24hrs measures about 10*3.5cm surface area^[18].

 

GALANTAMINE:

Galantamine hydrobromide which is a tertiary alkaloid drug that has been developed and approved in several countries for the treatment of mild to moderate AD. Galantamine has a unique dual mechanism of action. This drug has a particular dual mechanism of action, this is the only drug which has been broken modulate the nicotinic acetylcholine receptor in allostric manner as it is a reversible combetative inhibitor of AchE. Galantamine is administered via oral, iv or sc routes. Galantamine rapidly absorbed in oral administration^[19].  A short half-life and linear plasma concentration were observed in a daily dose range of 8-24mg/kg. Galantamine is metabolized by cytochrome P450 isoenzyme in the liver. Main metabolites include norgalantamine O-desmethyl-galantamine, o-desmethyl-norgalantamine, epigalantamine and galantaminone. The renal Clearance of galantamine was approximately 20% lower in women than in men. The safety and tolerability profile of galantamine reminded favorably during extended periods of treatment^[20]. Galantamine as the good tolerability profile and there appear any serious safety concerns associated with its use. The most frequent adverse events of galantamine are nausea, vomiting, and diarrhea.

 

MEMANTINE:

Memantine is used to treat the severe to moderate dementia approved by the US and EU market. It inhibits the excessive calcium influx which causes chronic over stimulation of the NMDA receptor and on/off the NMDA receptor antagonist activity in a fast ratememantine as a the less voltage dependency then magnesium although it blocks the NMDA receptor channel in higher affinity with non competitive manner^[21]. Memantine is compared with other NMDA receptor by invivo method it acts moderately inhibiting the excitatory activity by retaining the learning behaviors. Memantine as an absolute bioavailability 100%(approx) when administer orally. Memantine forms NMDA inactive metabolites with the help of metabolites such as glucuronidation, hydroxylation, and N-oxidation. Then it is excreted through urine unchanged^[22]. Memantine acts like magnesium to block the NMDA receptor and it is the derivative of amantidine it binds the magnesium site or near and as a longer duration of action in the channel then magnesium inhibits the calcium influx.

 

 

Targeting therapies for Amyloid-β:

Amyloid cascade hypothesis says the pathology of alzheimer’s comments several years before the out break of AD’S notable clinical symptoms with amyloidsis of cerebral region which is usually without any symptoms ^[23]. The amyloid-β plaques aggregation begins with the formation of monomeric units of amyloid-β leaving it’s source in the cerebro spinal fluid which later from toxic agglomerates which gets deposit on the surface of neurons and the synaptic terminals^[24]. Hence the management of AD till date had been focusing either on the β-amyloid cascade for on controlling the amyloid-β formation past 25 years.

 

Secretase inhibitors:

Stimulating the clearance of amyloid-β via active and passive immunotherapies and their by preventing the agglomeration of the toxic amyloid aggregates was achieved through the up bring of β and γ secretase inhibitors^[25].

 

Inhibitors of  β-secretase (BACE1):

The initiation of amyloidogenic pathway which is responsible for the processing of APP is compassed by the β-secretase but their lyes a major difficulty in the development of β-secretase inhibitors due to the presence of many it’s substrase such as neuregulin-1 ,which myclinates the nerves in the peripheral region. Hence the risk of adverse effect is high on the inhibition of enzyme^[26],[27].

 

Inhibitors and modulators of  γ-secretase:

The final stage of amyloidogenic pathway which is the processing of APP is compassed by the γ-secretase which produces Aβ42 and Aβ40 peptides^[28]. The function of γ-secretase is the processing of protein such as APP Notch protein which involves in the development, proliferation, differentiation, communication and survival of the cell. Hence the risk of adverse effect is high on the inhibition of the enzyme^[29].

 

Activation of  α-secretase:

α-secretase enzyme activation is found to have a neuroprotector and stimulator of synaptogensis action due to solubilisation of amyloidβ peptide processed by the non-amyloidogenesis pathway. This shows the activation of α-secretase enzyme contributes a fair approach for the management of AD^[30].          

 

Anti-amyloid aggregates: inhibition of A β peptide aggregation:

This drug was designed in such a way it either inhibits the interaction between amyloid-β and endogenous glycosaminoglycans or the interaction of the same. The agglomeration by the formation of amyloid fibrils and the establishment of deposition of plaques is due to the glycosaminoglycan^[31]. Many compounds are available in anti amyloid aggregate effects, which are PBT1(clioquinol) and PBT2. Ciloquinol is a potential compound for the management of AD. The mechanism of action of this molecule is the inhibition of interaction between the Aβ peptide and the metals in the brain^[32].This molecule sugged oncourse og aging where there occurs an increase in the levels of bioactive metals in the brain which causes the formation of amyloid plaques as well as neuro toxic oxidative process which leads to the progression of AD^[33].

 

Enzyme activation for the secretion of amyloid plaques:

Neprilysin, Insulin-degrading enzyme, Plasmin, Endothelin converting enzyme, Angiotensin-converting enzyme, and Metalloproteinase9 these enzymes are responsible for the breakdown of Amyloid agglomeration and plaques formation^[34]. Drug development process focusing this strategy because of this molecule is donating the Amyloid agglomeration and plaques formation and it provide an attractive amyloid-fighting. Currently protease activator not available because of molecule has the lack efficacy ^[35].

 

Amyloid-β transport modulation from the CNS to periphery:

The following factors regulate the transportation of amyloid-β from the brain to periphery:

1)Low density lipoprotein receptor-related proteins (LRP)that increase transfer of Amyloid-β from the brain to the blood-stream; 2)The penetration of amyloid-β in the CNS by receptor (RAGE), and 3) APOE4 kind of apolipoproteins^[36],[37].

 

Specific anti-amyloid immunotherapy:

Most of the studies reveals that the reduction density of amyloid in Alzheimer’s affected brain is can be done by a method called active immunotherapy. This method immunotherapy holds the strategy to listen the clearance of amyloid-β in CNS^[38]. Active immunization is the process of vaccination either with amyloid-β42 which is the predominant amyloid-β responsible for the formation of amyliod plaques (or with any other fragments produced) synthetically was found to gain access in transgenic model of rodent with Alzheimer’s disease. Further when this immunization was cared out in human trails by vaccinating patients with amyloid-β peptide consisting of 42 amino acids resulted in neuro inflammation like Aseptic meningoencephalitis due to the anti-immune response anti-AN1792 which has medicated by T-cells^[39],[40].

 

Targeting therapies for Tau:

Another neuropathological property of AD is neurofibrillary tangles (NFTs), which is formed by the Tau it is a microtubule-binding protein. Tau shows the toxic effect it causes hyper-phosphorylation of the protein^[40]. Now drug development field is focusing the therapies for targeting the Tau because of targeting the amyloid-β it induced many failure and ADR to the patients in the clinical trail ^[41]. Inhibition of Tau agglomeration, reducing the hyper-phosphorylation, toxic post-translational modifications of Tau and increasing the clearance and preventing spread of the tau these is classified therapeutic ways to drop the AD in patients^[42].

 

Stabilizers of Tau protein and inhibitors of agglomeration:

Most of the Tau stabilizing molecules such as paclitaxel and epothilone D produce un expected toxic effect. Also many new molecules of the same kind have failed in multicentric Phase II and Phase III clinical trail which enrolled patients with AD due to it’s less efficacy and safety profile^[43].

 

Therapies targeting post-translation modification of Tau:

Focusing on the toxic effect of the post-translation modification of Tau is one of the way in the Tau targeted therapy. This can be done by the ways: 1) inhibiting tau hyper-phosphorylation kinases such as glycogen synthase kinase 3 beta (GSK3) and cyclin-dependent kinase 5 (CDK5); 2) promoting the activity of tau dephosphorylation enzyme protein phosphate 2A (PP2A); 3) modulating tau acetylation and cis-transformation. Another strategy is to inhibit O-GlcNAcase, an enzyme that strips sugars from tau. It is believed that O-GlcNAcylation either competes with phosphorylation for the same serine/threonine residues or simply prevents tau molecules from cozying up to one another. In animal studies, O-GlcNAcase inhibitors suppress tau phosphorylation, prevent tangles, and boost neuronal survival. Further studies are needed to determine the clinical efficacy of these strategies^[44],[45].

 

Anti-tau Immunotherapy:

The development of transcellular Tau lid the foundation for Anti-Tau immunotherapy which was duly supported both preclinical and clinical trails many researches active-immnunization by modulating the phosphorylated tou peptide which simultaneously showed alteration in pathology of tau yielded good result in animal models at present AATvax vac1 and ACI-35 are two vaccines which are used actively to test in AD affected patients in clinical trails^[46]. The interrelationship between the pathology of tau and cognitive impairment gives above that the declined in the cognitive function can either slow down are prevented by treatment targeting tau removed^[47].

 

OTHER TARGETING SITES:

Gene therapy:

Apoptosis of cholinergic neurons are protected by nerve growth factor which is discorved in 1986. Presently various experiments and clinical trails are focusing the way of nerve growing factor (NGF), glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and neprilysin in gene therapy for the management of AD and related neurodegenerative disorders^[48],[49]. Result of this therapy it show not only the effect of preventing cholinergic neurons also improving the behavioral activity and memory impairment of Alzheimer’s in animal model.

 

Hence a one-time therapy with CERE-110 provides adequate safety and efficacy of InGf protein which in turn guard and maintains the cholinergic in the CNS of patients affected by and slow down the progression of the disease^[50],[51].

 

Stem cell therapy:

Stem cells of neuronal region have advancing potential to develop major cells like astrocytes, neurons and oligodendrocytes also they neural stem cells found to be combitent and self-reinvegorating^[52]. The single cell suspension ways of the brain of featus is develop and this is used for the production of primary-neuronal cells and mixed gilal cultures which facilitated the advanced discovery of isolation of neural stem cells (NSCs) from adult or fetal neuronal tissue of rodents and augmented as neurospheres (free floating cells speroids)^[53]. In the presence of growth factors like epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) on the multiplication of stem cells which becomes as a neural stem cells enriched culture in a course of time^[54].

 

Antioxidant and Anti-inflammatory therapies:

The typical feature of the pathology of an Alzheimer’s affected brain is the neuro inflammation associated with over expression of cytokines. It is been suspected that the association of tumor necrosis alpha A pro-inflammatory mediator for a long time in the pathophysiology of AD^[55].

 

The reduction in the synthesis of cytokines, iNOS, agglomeration of platelets, activation of microglial cells, beta-secretase brought about by the action oh NSAIDS which inhibits the enzyme, among NASIDS only Indomethacin and Ibuprofen where found to exhibit clinical efficacy in the management of Alzheimer’s^[56]. many researchers has incistated upon the intake of antioxidant such as vitamin A, C, B₆, E, green tea (flavonoids), Ginko Biolba, Curcumin (turmeric), extract of garlic which were found to have a decreased incidence of Alzheimer’s Disease^[57].

 

CONCLUSION:

Alzheimer’s is an incurable and most complicated disease. Currently available treatments only give a symptomatic relief to the patients. The drugs do not interact directly the on the AD pathway and hence does not cures the disease. As research in AD progresses, knowledge of underlying AD pathogenesis will guide future drug development effort. In the past two decades or so, we have learned that amyloid may not be the only critical step or the only mechanism of action to be targeted in AD. There is no proper cure for AD till date due to irreversible degeneration of neurons. We need a new modification, safe and effective treatment for AD. Many researchers are focusing a multi-target site of Alzheimer’s pathway. They are targeting on the Amyloid plaques formation and agglomeration, Tau hyperphosphorylation, Neuroprotective and oxidative stress sites. The lack of success in targeting sites are Secretase inhibitors, Anti-amyliod plaques formation, enzymes activation, inhibitors of Tau formation, stabilization of Tau formation, Anti-oxidant andamp; Anti-inflammatory, stem cell therapy, gene therapy because of the toxicity of these drugs and being less efficacious to the patients. We need more effort to discover newer molecules to cure the Alzheimer’s disease in a safe and effective manner.

 

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Accepted on 20.12.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(6): 3021-3027.