Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists As Potential Disease-Modifying Agents for Alzheimer’S Disease
Total Page:16
File Type:pdf, Size:1020Kb
Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer’s Disease Abraham Fisher Israel Institute for Biological Research, P. O. Box 19, Ness-Ziona 74100, Israel Summary: The only prescribed drugs for treatment of Alzhei- formation of -amyloid plaques, and tangles containing hyper- mer’s disease (AD) are acetylcholinesterase inhibitors (e.g., phosphorylated tau proteins) are apparently linked. Such link- donepezil, rivastigmine, galantamine, and tacrine) and meman- ages may have therapeutic implications, and this review is an tine, an NMDA antagonist. These drugs ameliorate mainly the attempt to analyze these versus the advantages and drawbacks symptoms of AD, such as cognitive impairments, rather than of some cholinergic compounds, such as acetylcholinesterase halting or preventing the causal neuropathology. There is cur- inhibitors, M1 muscarinic agonists, M2 antagonists, and nico- rently no cure for AD and there is no way to stop its progres- tinic agonists. Among the reviewed treatments, M1 selective sion, yet there are numerous therapeutic approaches directed agonists emerge, in particular, as potential disease modifiers. against various pathological hallmarks of AD that are exten- Key Words: Alzheimer’s, cholinergic, -amyloid, tau, acetyl- sively being pursued. In this context, the three major hallmark cholinesterase inhibitors, M1 muscarinic, nicotinic, agonists, characteristics of AD (i.e., the CNS cholinergic hypofunction, M2 muscarinic antagonists. INTRODUCTION (␣-APPs) that is neurotrophic and neuroprotective. In an alternate pathway, -secretase (BACE1) cleaves APP Alzheimer’s disease (AD) is a progressive, neurode- releasing a large secreted derivative sAPP andaC- generative disease that is a major health problem in terminal fragment C99 that can be further cleaved by modern societies. AD is characterized by memory and ␥-secretase to form A, which is released into the extra- cognitive loss, synaptic loss, amyloid plaques containing the -amyloid peptide (A), degeneration of cholinergic cellular milieu. The predominant peptide secreted is   neurons that ascend from the basal forebrain to cortical A 40 with approximately 10 to 15% being A 42, the   and hippocampal areas, and neurofibrillary tangles more toxic specie. The A peptide, in particular A 42, (NFT).1 In spite of extensive research performed in the aggregates and is part of the plaque core. The “amyloid last decades there is no clear proof as to the etiology of cascade hypothesis,” and variations thereof, postulate  AD. that generation of A , its oligomers, and their accumu- One of the major hallmarks of AD is the amyloid lation in the brain, and finally their deposits in plaques is 8,9 plaque. The key component of the amyloid plaque core is the major culprit that leads to AD, ; also see further 10,11 the deposited A, which is derived from the amyloid references on this. In this context, the current notion precursor protein (APP). The APP is cleaved by at least is that blocking A formation and/or deposition into three sites, ␣-, -, and ␥-secretase cleavage.1–8 The APP plaques should prevent the progression of AD, but it does 12 through an enzymatic activity termed ␣-secretase, pre- not, however, reverse the damage already caused. cludes formation of A and generates a cell-associated Another major hallmark of AD is a cholinergic hypo- C-terminus (C83) fragment and a longer secreted form function evidenced by a reduction in acetylcholine (ACh) synthesis due to reduced choline acetyltransferase (ChAT) and choline uptake, cholinergic neuronal, and axonal abnormalities, with degeneration of cholinergic Address correspondence to: Abraham Fisher, Ph.D., Israel Institute for Biological Research, P. O. Box 19, Ness-Ziona 74100, Israel. neurons projecting to the cortex and hippocampus, and E-mail: fi[email protected]; fi[email protected]. significant depletion of the nicotinic receptors.1,12,13–18 Vol. 5, 433–442, July 2008 © The American Society for Experimental NeuroTherapeutics, Inc. 433 434 FISHER Central cholinergic deficits have a major role in the address the question of how the three major hallmarks progressive cognitive dysfunction, as well as some be- that characterize AD (e.g., cholinergic hypofunction, A, havioral impairment associated with AD. In this context, and neurofibrillary tangles) may relate to each other, and the loss of presynaptic cholinergic markers correlates how these findings can be translated into comprehensive with the number of plaques, NFT, and clinical severity of and viable modern therapies. dementia.17 The rationale for cholinergic treatment in AD is based on the “cholinergic hypothesis,” which sug- SELECT TREATMENT STRATEGIES BASED gests that cholinergic hypofunction contributes to many ON THE CHOLINERGIC HYPOTHESIS of the cognitive and behavioral deficits in patients with AD.2,14,15 This hypothesis prompted the development of AChE-Is treatment strategies aimed to restore lost cholinergic The AChE-Is act on the ACh pathway by inhibiting the function and to ameliorate cognitive and behavioral im- enzyme AChE, which is normally responsible for hydro- pairments in AD patients. The increase in A formation lysis of ACh. These AChE-Is, in spite of some limita- and cholinergic dysfunction may occur long before overt tions (see as follows), still represent the primary treat- cognitive or behavioral symptoms of AD are detectable, ment available for AD and related forms of and both may be implicated as causal factors in AD. dementia.13,27–32 However, it is beyond the scope of this review to debate The effects of the four prescribed AChE-Is on im- which culprit is the earliest causal factor for inducing provement of cognition in AD patients is similar, yet the AD. compounds differ to a certain extent in mechanism of A third major hallmark of AD is the NFT comprised of action, in terms of side effects (SE) and treatment sched- hyperphosphorylated tau proteins. Tau proteins are nor- ules. Notably, while donepezil is mainly selective for mally expressed in axons as microtubule associated tau AChE, rivastigmine and tacrine inhibit both AChE and proteins, which stabilize microtubules, allowing fast ax- butyrylcholinesterase (BuChE) and galantamine, in ad- onal transport.7,17,19,20 The “tau hypothesis” is based on dition to its inhibitory effect on AChE, is a putative the abnormal state of tau proteins in AD that is both allosteric activator of the nicotinic receptor (e.g., ␣42 highly phosphorylated and aggregated into paired helical subtype).13,27–31 In general, these drugs have demon- filaments in NFTs.17,19,21 When tau proteins are hyper- strated a statistically significant effect versus placebo on phosphorylated, there is a breakdown in the system; pre- cognitive, global, and functional performance of patients venting tau hyperphosphorylation and aggregation can with AD, but tacrine is rarely used because it can cause decrease formation of NFTs. The formation of NFT con- liver problems. Notably, the drugs (and their most fre- tributes to AD, but it is debatable whether it is the earliest quent SE) observed include: tacrine (hepatotoxicity and causal factor underlying AD pathogenesis as A plaques gastrointestinal effects); donepezil (nausea, vomiting and typically occur before NFTs. diarrhea); rivastigmine (nausea, vomiting, diarrhea, and Notably, a relationship between three of the major anorexia); and galantamine (nausea, vomiting, diarrhea, hallmarks that are characteristic of AD have been re- and anorexia). It is beyond the scope of this review to ported: 1) the CNS cholinergic hypofunction, 2) forma- elaborate on these treatments because numerous reviews tion of A plaques, and 3) tangles containing hyperphos- have been written on this subject.13,27–32 phorylated tau proteins.17,20,22–26 The use of AChE-Is in AD patients is regarded mainly The existing drug therapy mainly targets the symp- as a symptomatic treatment without significant effect on toms of AD, such as cognitive impairments, rather than disease progression. In this context, the progression of also halting or preventing the causal neuropathology. the disease associated with loss of the cholinergic neu- The only approved drugs for the treatment of AD by rons and decreases in ACh may limit the therapeutic many national regulatory authorities, including the Food potential of this treatment strategy to only part of the AD and Drug Administration in the United States, are ace- patients. AChE-Is may also appear to stabilize the course tylcholinesterase (AChE) inhibitors (AChE-Is) (e.g., of AD progression to a certain extent.28 Several long- donepezil, rivastigmine, galantamine and tacrine),13,27–32 term clinical trials with AChE-Is have reported that these and memantine, which is an NMDA antagonist.14 drugs actually decrease the rate of cognitive decline, and This review will present some of the published cho- may delay the disease progression by 1 to 2 years,28,31 linergic therapeutic strategies vis-a-vis the major hypoth- but the benefits are modest.31 It was also recently re- eses as to the causes of AD. However, due to the plethora ported that AChE-Is are unable to slow progression from of treatments advocated in the last few years (several of mild cognitive impairment to dementia.33 them at an early stage of drug discovery), the review can In addition to the Food and Drug Administration-ap- not cover all the published cholinergic treatments. Some proved AChE-Is, several other such inhibitors at various potential advantages and possible challenges in the re- stages of research and development have been reported. viewed therapies are discussed. This review will also These include compounds such as: phenserine,34,35 Neurotherapeutics, Vol. 5, No. 3, 2008 DISEASE-MODIFYING CHOLINERGICS FOR ALZHEIMER’S 435 CHF2819,36 TAK147,37 TV3326,38 huperzine A and an- lation of M1 mAChR, if continuously stimulated by ago- alogs,39 NP-61,40 and Memoquin.41 Preclinical studies nists. Such a disadvantage may be evident with full, but showed that some of these newer AChE-Is may have not partial, agonists.