1. ACETYLCHOLINESTERASE (AChE) INHIBITORS:

AD is characterized by progressive deterioration in learning and memory ability. Several hypotheses exist to explain the origin of AD; these include the cholinergic, tau, and amyloid theories.^7,8. Among these hypotheses, the cholinergic one is the most studied, and the majority of the drugs on the market are AChE inhibitors.⁹ There are many lines of evidences suggesting profound losses in the cholinergic system of the AD brain. This includes the dramatic loss of cholinacetyltransferase level, choline uptake, and Ach level in the neocortex and hippocampus. Also, the reduced number of cholinergic neurons in the basal forebrain and the nucleus basalis of Meynert is closely associated with cognitive deficits observed in the disease.¹⁰

Acetylcholine (Ach), a neurotransmitter in the brain plays a critical role in the function of learning and memory. ACh is synthesized from acetyl- CoA and choline by cholineacetyltransferase, and is released into the synaptic cleft which then is hydrolyzed by AChE to become choline and acetic acid. Choline is taken up again into the presynaptic neurons for use in ACh synthesis. AChE, which is widely distributed in the central nervous system (CNS) and the peripheral nervous system, has been the focus of much attention because of the relationship to ACh hydrolysis and cognitive impairment in AD.⁹

To date, the only drugs with proven efficacy in the treatment of patients with AD are acetylcholinesterase inhibitors.¹¹ The first of these medications was tacrine (Cognex, approved in 1993).¹² However, this drug is limited by its q.i.d. dosing and titration, side effects (especially nausea, vomiting, diarrhea, and hepatotoxicity), and requirement for serum alanine aminotransferase (ALT) monitoring and is no longer used in practice.⁹

Newer acetylcholinesterase inhibitors without hepatotoxicity— donepezil (Aricept, approved in 1996,¹³ rivastigmine (Exelon, approved in 2000), and galantamine (Reminyl, approved in 2001)—have eclipsed tacrine (Cognex).

Compared to Tacrine, the hepatotoxicity is substantially lower with Donepezil and daily dosing of 5 and 10 mg/day has proved convenient for most patients. Side effects, which are generally mild and transient, include nausea, diarrhea, vomiting, constipation, headache, dizziness and sleep disturbance.¹⁴ Rivastigmine and Galantamine have also shown beneficial results in AD but side effect profile of both drugs is almost similar. Rivastigmine has been approved in at least 40 countries around the world and Rivastigmine's adverse effects are gastrointestinal disturbances, including nausea, vomiting, anorexia, and weight loss.⁹ Although their main use has been in the stabilisation of cognitive decline, there is evidence linking them with improvement in behavioural and psychological symptoms of dementia.¹⁵ Prevailing view has been that efficacy of these agents is through acetylcholine-mediated neuron-to-neuron transmission and they also protect against free radical’s toxicity and amyloid-induced injury and attenuate cytokine release from microglia. Increasing evidence support an additional anti-inflammatory role for acetylcholinesterase inhibitors.¹⁶

2. NMDA antagonist:

It is the first molecule to demonstrate a clinical benefit in the treatment of patients with moderately-severe to severe AD.^17,18 NMDA receptor antagonists have also shown beneficial effects to alleviate the motor dysfunction in Parkinson’s disease, relieve pain in animal models and beneficial in Alzheimer’s experimental models.^19,20

Persistent activation of central nervous system NMDA receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of AD. Thus inhibiting this receptor might improve symptoms in AD patients.¹⁹ Memantine is a voltage-dependent, moderate affinity, uncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, which blocks the effect of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.²¹

Memantine appears to work by regulating the activity of glutamate, a chemical involved in information processing, storage and retrieval. Glutamate plays an essential role in learning and memory by triggering NMDA receptors to let a controlled amount of calcium into a nerve cell. The calcium helps creates the chemical environment required for information storage. Excess glutamate, on the other hand, over stimulates NMDA receptors so that they allow too much calcium into nerve cells. That leads to disruption and death of cells. Memantine may protect cells against excess glutamate by partially blocking NMDA receptors. It is approved for moderate to severe AD and associated side effects are headache, constipation, confusion and dizziness²².

3. STATINS:

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. These are the most common agents used in the treatment of hyperlipidemias since 1987 when lovastatin, the first discovered statin got its FDA approval. Currently available statins include atorvastatin, simvastatin, fluvastatin, lovastatin, pravastatin and rosuvastatin. Statins are generally well tolerated and have a safe side effect profile, except for rare cases of hepatotoxicity and myotoxicity.^6,23

Cholesterol in the CNS is reported to be synthesized locally and to a greater extent is independent of the nutritional intake.²⁴ However, it has been shown that feeding cholesterol and raising the plasma lipid level is associated with metabolic changes in the brain.⁶

The link between cholesterol and AD is not surprising because the brain is the most cholesterol-rich organ, and disturbances in cholesterol homeostasis have been found associated with all major neuropathological features of AD.²⁵ A reduction in the risk of AD was observed in patients treated with statins compared with those receiving other medications typically used in cardiovascular disease,²⁶ suggesting that statins in particular, rather than low cholesterol levels or lipid-lowering agents in general, are responsible for the reduction in the risk of AD.²⁷

A number of nonlipid-dependent or pleiotropic effects of statins have been reported²⁸ and they include anti-inflammatory properties as well as antiproliferative and proapoptotic effects,²⁹ all of these potentially are relevant in treating AD. Growing evidence suggests that neuronal cell cycle regulatory failure, leading to apoptosis, may be a significant component of the AD pathogenesis.^30,31 Literature support the ability of some statins to exert direct antiproliferative and proapoptotic effects and their potential to interfere with cell cycle machinery²⁷ and thus exerting a beneficial role in AD.

Although observational studies have found a strong signal of lower rates of prevalent dementia in statin users, prospective studies have failed to show benefit of statin use on incident dementia or the rate of progression of dementia consistently.⁶

4. ANTIOXIDANT THERAPY:

Oxidative stress occurs due to an imbalance in the prooxidant and antioxidant levels. The free radical hypothesis of aging, which was proposed many years ago, posits that the age-related accumulation of reactive oxygen species (ROS) results in damage to major components of cells: nucleus, mitochondrial DNA, membranes, and cytoplasmic proteins. The imbalance between the generation of free radicals and ROS may be involved in the pathogenesis of most of the neurodegenerative disorders, including AD.^32,33

Free radicals are in fact potent deleterious agents causing cell death or other forms of irreversible damage, eg, free radicals appear to modify <10000 DNA base pairs every day. ³⁴ Neurons appear to be particularly vulnerable to attack by free radicals because their glutathione content, an important natural antioxidant, is low,³⁵ their membranes contain a high proportion of polyunsaturated fatty acids,³⁶ and brain metabolism requires substantial quantities of oxygen.³⁷

As oxidative damage to neurons play an important role in the AD pathogenesis. . Thus, antioxidant approach may prove beneficial in retarding or preventing the onset and progression of AD in patients.

Free radical–scavenging drugs used for therapeutic purposes in different fields are also scrutinized in preclinical as well as clinical studies of AD and produced beneficial results: vitamin E (a-tocopherol), selegiline (also a monoamine oxidase B inhibitor), and Ginkgo biloba extract EGb 76.

EGb 761 has been studied in clinical investigations and the studies concluded that it had a positive effect on cognitive indexes, similar to the results obtained with tetrahydroaminoacridine. It has small but significant effect of on cognitive function in AD.³⁸ Interestingly, this result differs from the findings for a-tocopherol and selegiline because neither of these 2 drugs had any significant effect on cognition.³⁹ Melatonin can reduce neuronal damage induced by oxygen-based reactive species in experimental models of AD. Melatonin also has antiamyloidogenic activities.⁴⁰

Withania somnifera Dunal (ashwagandha, WS) is widely used in Ayurvedic medicine, the traditional medical system of India and has shown potent antioxidant activity has shown memory enhancing property in several animal models and withanaloid, an active constituent of WS has been continuosly explored for treatment for AD.⁴¹

Vitamin E, a widely used early intervention for Alzheimer's disease, had no effect on patients with mild cognitive impairment clinical studies.⁴²

5. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS):

Inflammation plays an integral role in Alzheimer’s disease development and may precede plaque and tangle formation.⁴³ Inflammatory components related to AD neuroinflammation include brain cells such as microglia and astrocytes,⁴⁴ neuronal-type nicotinic acetylcholine receptors (AChRs), peroxisomal proliferator-activated receptors (PPARs), as well as cytokines and chemokines.⁴⁵

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed drugs for the treatment of painful joint conditions like osteoarthritis, rheumatoid arthritis, arthritis of systemic lupus erythematosus, psoriasis, and other seronegative spondyloarthropathies.⁴⁶ Recent observational studies, however, have shown that non-steroidal anti-inflammatory drugs may protect against the development of the disease.⁴⁷

NSAIDs work by interfering with the cyclooxygenase pathway, which involves the conversion of arachidonic acid, by the enzyme cyclooxygenase(COX) to prostaglandins (PGs) in presence of an enzyme, cyclooxygenase (COX).⁴⁸

COX is available in two forms i.e. COX-1 and COX-2. The COX- 1 enzyme is constitutive, and present in most tissues and controls normal body functions, such as stomach mucus production and kidney water excretion, as well as platelet formation⁴⁹.

In contrast, the COX-2 enzyme is induced dramatically by the action of macrophages, the scavenger cells of the immune system and is involved in producing prostaglandins for an inflammatory response.⁵⁰

NSAID’s may influence inflammation by inhibiting COX-1 and COX-2 and by activating the peroxisome proliferators-γ (PPAR-γ) nuclear transcription factor.^51,52 In addition, COX mediated oxidation is important in the calcium-dependent glutamate signaling pathway that involves N-methyl CD aspartate. Thus, COX-2 inhibitors may be able to protect neurons directly by reducing cellular response to glutamate and have potential to reduce the risk of Alzheimer’s disease.⁵³

Unfortunately, new evidence regarding some NSAIDs suggests that they may cause cardiovascular problems, which will slow their development for AD treatment⁵⁴.

6. MAO INHIBITORS:

Monoamine oxidase is a flavoprotein located at the outer membrane of mitochondria in neuronal, glial and other cells. It catalyzes oxidative deamination of monoamine neurotransmitters such as serotonin, norepinephrine and dopamine and hence is a target enzyme for neurological and specifically antidepressant drugs.⁵⁵ MAO exists in two forms, namely MAO-A and MAO-B. Specific substrates and inhibitors characterize both MAO subtypes. MAO-A has a higher affinity for serotonin and norepinephrine, while; MAO-B preferentially deaminates phenylethylamine and benzylamine. These properties determine the clinical importance of MAO inhibitors. Selective MAOA inhibitors are used in the treatment of neurological disorders such as depression, whereas the MAOB inhibitors are useful in the treatment of Parkinson’s and Alzheimer’s disease.

Selegeline, Rasagiline and Ladostigil and their structurally modified moieties are being explored in different animal models of Alzheimer’s disease and they have shown encouraging results although success in clinical trials is still debated.^9,56

7. ANTIAMYLOID DRUGS:

One of the major histopathological characteristics of Alzheimer’s disease (AD) is the presence of senile plaques (SP), composed mainly of Amyloid β peptide⁵⁷and the amyloid hypothesis of Alzheimer disease states that the accumulation and deposition of fibrillar β-amyloid is the primary driver of neurodegeneration and cognitive decline leading to dementia.

Aβ (first described by Glenner and Wong (1984) is derived from the amyloidβ protein precursor (APP) via complex proteolytic pathway catalyzed by a number of secretases.⁵⁸

Two enzymes, β secretase and the gamma secretase complex, appear to be essential for cleavage of the amyloidogenic Aβ fragment from its transmembrane amyloid precursor protein (APP); inhibition of one or both is expected to reduce amyloid accumulation.⁵⁹ But despite the proliferation of clinical development programs, early results have been quite disappointing. The first two antiamyloid drugs to reach the pivotal stage of development, tramiprosate and tarenflurbil, failed in phase III.⁶⁰

Bapineuzumab, a monoclonal amino terminusspecific anti-amyloid antibody showed encouraging cognitive data from a small phase I trial hinting at a symptomatic effect, particularly in the apolipoprotein E ε4 negative subgroup, the primary cognitive efficacy analysis was negative.^60,61

Beside these, nutritional therapy, vitamin B12, Folic acid, DHEA, phospahtidylcholine, Nutritional Therapy and life style modifications are recommended and have shown partial success in different preclinical and clinical studies.

CONCLUSION:

This review has examined the major drug molecules commercially available, as well as those that are in clinical or experimental trials. From commercially available drugs, herbs, synthetic compounds and to experimental compounds in the laboratory, tremendous efforts have been put into discovering more potent and successful drug candidates for AD. Different theories explaining pathology of AD have been put forwarded and different causative targets are being identified and targeted. Research community all over the world has put their best of efforts to find possible cure. But one question still haunts scientific community-when will we get a drug without any side effect that will slow the progression of AD?.

After 100 years of discovery of Alzheimer’s disease and claiming that much has been understood regarding AD, we have five FDA approved drugs (in fact four, Tacrine is already withdrawn) that too associated with life threatening side effects and complications. Various countries and Govt. agencies in the world have spent and is spending enormous amount, and research community has left no stone unturned for development of drugs for AD. Current scenario as reviewed in the present article do not show a very positive picture. Many Molecules are discovered, developed shows positive results in preclinical studies some reach phase 1, few phase 2 one or two in phase3 then, a heartbreaking failure? And we again have to start form scratch. Do we lack direction or a sufficient scientific depth in understanding pathobiology of the disease or are we ignoring something important? These question need to be answered. The creation of effective therapeutic agents for AD would be a major medical milestone. Furthermore, new avenues of approaches for AD drug development will have to be discovered and hopes need to be kept alive.

ACKNOWLEDGEMENT:

Author would like to acknowledge Sh.SN Singh (Asst. Prof.) and Sh. Rajendra Guleria (Asst. Prof.) Govt. College of Pharmacy, Rohru, for their blessings. Mr. Vinay Thakur (Lecturer, Pharmacognosy) and Mr. BB Sharma (Lecturer, IT) are also to be thanked for their encouragement.

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Received on 15.01.2010

Accepted on 24.03.2010

Research J. Pharmacology and Pharmacodynamics. 2(3): May-June 2010, 215-220