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Activities of Nicotinic Acetylcholine Receptors Modulate Neurotransmission and Synaptic Architecture

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Activities of Nicotinic Acetylcholine Receptors Modulate Neurotransmission and Synaptic Architecture NEURAL REGENERATION RESEARCH December 2014,Volume 9,Issue 24 www.nrronline.org INVITED REVIEW Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture Akira Oda1, Hidekazu Tanaka2 1 CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan 2 Laboratory of Pharmacology, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan Abstract Corresponding author: The cholinergic system is involved in a broad spectrum of brain function, and its failure has Hidekazu Tanaka, M.D., Ph.D., been implicated in Alzheimer’s disease. Acetylcholine transduces signals through muscarinic Laboratory of Pharmacology, Department and nicotinic acetylcholine receptors, both of which influence synaptic plasticity and cognition. of Biomedical Sciences, College of Life However, the mechanisms that relate the rapid gating of nicotinic acetylcholine receptors to per- Sciences, Ritsumeikan University, sistent changes in brain function have remained elusive. Recent evidence indicates that nicotinic [email protected]. acetylcholine receptors activities affect synaptic morphology and density, which result in per- sistent rearrangements of neural connectivity. Further investigations of the relationships between doi:10.4103/1673-5374.147943 nicotinic acetylcholine receptors and rearrangements of neural circuitry in the central nervous http://www.nrronline.org/ system may help understand the pathogenesis of Alzheimer’s disease. Accepted: 2014-11-03 Key Words: cholinergic system; nicotinic acetylcholine receptors (nAChRs); Alzheimer’s disease (AD); synaptic transmission; synaptic plasticity; synaptic morphology; dendritic spine remodeling; cognition Funding: Tanaka H is supported by the Takeda Science Foundation and JSPS KAKENHI Grant Number 19590247. Oda A, Tanaka H. Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture. Neural Regen Res. 2014;9(24):2128-2131. Nicotinic receptors in the central nervous junctive use of acetylcholinesterase inhibitors alleviates visual hallucinations (Patel et al., 2010). In contrast, acetylcholine system (CNS) are candidate targets for the receptor antagonism ameliorates depressive symptoms in ma- treatment of dementia jor depression and bipolar disorders (Drevets et al., 2013). Dementia is one of the biggest global public health challeng- The neurotransmitter acetylcholine transduces signals es. Accordingly, over 40 million people suffer from dementia through muscarinic and nicotinic acetylcholine receptors. globally, and this number is expected to double by 2030 and Nicotinic acetylcholine receptor (nAChR) comprises five more than triple by 2050 (Alzheimer’s disease International, subunit polypeptides. Brain-type nAChRs consist of hetero- World Alzheimer Report 2014). Alzheimer’s disease (AD) meric combinations of α2–10 and β2–4 subunits, as well as α7 * is the most common type of dementia, and accounts for an homopentamers; α4β2 and α7 nAChRs are predominantly estimated 60 to 80% of cases. expressed in the brain (an asterisk indicates that the receptor Loss of cholinergic neurons is a pathological hallmark of may include other subunits than the described ones). In the AD, and is also assessed in human imaging studies (Nordberg pathophysiology of AD, amyloid β (Aβ), the peptide in senile et al., 2010). Cholinergic neurons of the nucleus basalis of plaques characteristic of AD, binds with high affinity to α7 Meynert and the medial septum innervate the cerebral cortex nAChRs, and impairs their channel functions. The selective and the hippocampus, respectively, and are involved in cog- vulnerability of nAChR-expressing neurons to Aβ toxicity nition. Hence enhancement of cholinergic transmission with may lead to the failure of cholinergic neurotransmission and acetylcholinesterase inhibitors ameliorates cognitive deficits cognitive dysfunctions in AD (Dineley, 2007). in AD patients (Rogers et al., 1998). Consistently, deprivation Several nAChR-targeting compounds have been developed of cholinergic transmission by either genetic disruption of to relieve neuropsychiatric symptoms in AD patients. However, * acetylcholine receptors or denervation of cholinergic nerve clinical trials of compounds that target α4β2 and α7 nAChRs fibers severely impairs learning and memory in animal exper- (Table 1) have produced discouraging results (see review, iments (Champtiaux and Changeux, 2004; Wess, 2004). Hurst et al., 2013). For example, varenicline, a partial agonist * The cholinergic system also plays pivotal roles in other of α4β2 nAChR, is the only clinically available nAChR-target- psychiatric disorders (Scarr et al., 2013). For example, an ing drug, and was approved for smoking cessation, but failed imbalance between cholinergic and dopaminergic systems to improve cognition in AD patients (Kim et al., 2014). contributes to the pathophysiology of schizophrenia, and ad- The failure of nAChR-targeting therapy for AD may be at- 2128 Oda A, et al. / Neural Regeneration Research. 2014;9(24):2128-2131. Table 1 Development of nicotinic acetylcholine receptor (nAChR) ligands for the treatment of Alzheimer’s disease and cognitive disorders Molecular Development Code name Generic name Company mechanism Indication status Notes EVP-6124, Encenicline FORUM α7 nAChR Alzheimer's disease Phase 3 A phase 3 program called cognitive MT-4666 hydrochloride Pharmaceuticals agonist Alzheimer's disease is set to run through 2016. ABT-126 AbbVie α7 nAChR Alzheimer's disease Phase 2 ABT-126 is also in phase 3 development agonist for cognitive impairment associated with schizophrenia. AZD-3480, Ispronicline Targacept α7 nAChR Alzheimer's disease Phase 2 Phase 2b clinical trial in Alzheimer’s disease TC-1734 agonist does not show superiority of TC-1734 over donepezil in July, 2014. DMXBA, DMXB- CoMentis α7 nAChR Alzheimer's disease Phase 2 GTS-21 anabaseine partial agonist AQW051 Novartis α7 nAChR Cognitive impairment Phase 2 Phase 2 trial in mild Alzheimer's disease was partial agonist associated with discontinued. schizophrenia ABT-560, Abbott, α4β2 nAChR Cognitive disorders Phase 1 ABT-PR2 NeuroSearch agonist CP-526555- Varenicline Pfizer α4β2 partial Alzheimer's disease Discontinued Development of varenicline for Alzheimer's 18 tartrate nAChR therapy was discontinued in 2011, based on agonist negative results from phase 2 trial conducted in South Korea. TC-5619 Bradanicline Targacept α7 nAChR Alzheimer's disease Discontinued In 2013, Targacept announced negative agonist results for phase 2b clinical trials of schizophrenia, and decided not to pursue further development for the treatment of either schizophrenia or Alzheimer’s disease. MEM 3454, Facinicline Roche α7 nAChR Alzheimer's disease Discontinued R3487, hydrochloride partial agonist RG3487, 5-HT3 RO5313534 antagonist SSR 180711 Sanofi α7 nAChR Alzheimer's disease Discontinued partial agonist AZD-1446, AstraZeneca α4β2 nAChR Alzheimer's disease Discontinued TC-6683 agonist A-87089, Pozanicline Abbott nAChR partial Alzheimer's disease Discontinued ABT-089 hydrochloride agonist A-81418, Abbott nAChR Alzheimer's disease Discontinued ABT-418 agonist ABT-107, Abbott, α7 nAChR Cognitive disorders Discontinued In 2009, development of ABT-107 was ABT-PR1 NeuroSearch agonist discontinued in phase 1 trials. AR- AstraZeneca α7 nAChR Alzheimer's disease Discontinued In 2009, AstraZeneca discontinued the R23465XX, agonist development of AZD-0328 as a potential AZD-0328 treatment option for Alzheimer’s disease in phase 2 trials in Europe. Drug information was sourced from Alzforum, the Schizophrenia Research Forum, and a recent review article (Hurst et al., 2013). This source was amended upon availability of more accurate information on company websites. 5-HT3: 5-Hydroxytryptamine 3. tributed to several reasons. First, the expression of nAChRs Third, adverse effects of nAChR-targeting compounds, such is down-regulated in the brains of AD patients (Nordberg as gastrointestinal and CNS-related side effects (Hurst et al., * et al., 2010). Moreover, the expression of α4β2 nAChRs 2013), may limit therapeutic doses of compounds. To cir- is decreased in these patients, especially in affected brain cumvent these side effects, partial agonists for nAChRs have areas, and appears to be correlated with the severity of cog- been developed with the expectation of broader therapeutic nitive impairment and the amount of amyloid deposition windows than full agonists (Table 1). Nonetheless, a better (Sabri et al., 2008; Okada et al., 2013). Conditions relating understanding of the relationships between nAChRs and to α7 nAChRs have been more controversial, with reports plasticity or rearrangements of neural circuitry may be re- of decreased (Burghaus et al., 2000), stable (Ikonomovic et quired for the successful treatment of AD. al., 2009), and increased (Nordberg, 2001) α7 nAChR ex- pression in AD patients. Second, tested compounds have insufficient potencies, and under conditions of decreased Nicotinic activity modulates plasticity and nAChR subunit expression, these reportedly activate only a various synaptic transmissions small fraction (about 10%) of nAChRs (Kim et al., 2014). In addition to acetylcholine, major neurotransmitters in 2129 Oda A, et al. / Neural Regeneration Research. 2014;9(24):2128-2131. Table 2 Nicotinic acetylcholine receptors modulate synaptic
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