烟碱型乙酰胆碱受体在神经传递中对突触结构的调制作用

胆碱能神经元丧失是阿尔茨海默病的主要病理特征,人类影像学检查同样可以证实这一点。基底核和内侧隔核胆碱能神经可支配大脑皮质和海马,并分别与参与认知任务。因此,增强胆碱能传递与乙酰胆碱酯酶抑制剂可改善阿尔兹海默病患者的认知功能障碍。同理,剥夺胆碱能传递乙酰胆碱受体或胆碱能神经纤维去神经支配遗传性就会严重损害实验动物的学习和记忆能力。然而针对α4β2和α7烟碱型乙酰胆碱受体化合物的临床试验结果却令人沮丧。

烟碱型乙酰胆碱受体在神经传递中对突触结构的调制作用

胆碱能神经元丧失是阿尔茨海默病的主要病理特征，人类影像学检查同样可以证实这一点。基底核和内侧隔核胆碱能神经可支配大脑皮质和海马，并分别与参与认知任务。因此，增强胆碱能传递与乙酰胆碱酯酶抑制剂可改善阿尔兹海默病患者的认知功能障碍。同理，剥夺胆碱能传递乙酰胆碱受体或胆碱能神经纤维去神经支配遗传性就会严重损害实验动物的学习和记忆能力。然而，针对α4β2和α7烟碱型乙酰胆碱受体化合物的临床试验结果却令人沮丧。例如伐尼克兰片，是唯一可用的临床胆碱受体靶向药物，被批准用于戒烟，但未能改善阿尔茨海默病患者的认知能力。

日本立命馆大学的Hidekazu Tanaka教授指出胆碱受体靶向治疗阿尔茨海默病失败可能有以下几个原因：首先，阿尔茨海默病患者大脑中的烟碱型乙酰胆碱受体表达下调；第二，测试化合物效力不足：在胆碱受体亚基表达降低的条件下，只能激活烟碱型乙酰胆碱受体一小部分（约10％）的胆碱受体靶向化合物；第三，副作用：如胃肠道和与中枢神经系统相关的副作用会限制化合物治疗剂量。为了规避这些副作用，现已开发出比完全激动剂具有更广泛治疗窗的烟碱型乙酰胆碱受体部分激动剂。不过，要成功治疗阿尔茨海默病可能需要更好地了解烟碱型乙酰胆碱受体可塑性和神经回路重组之间的关系。目前针对阿尔茨海默病的治疗仅限于缓解症状，并不能阻止病情恶化。因此，阿尔茨海默病治疗产生的神经连接持久性重排是非常必需的，并且可以基本上改善阿尔茨海默病的发病机制。胆碱受体和中枢神经系统神经环路重组之间的关系还需要进一步研究，并且其可能有助于阐明胆碱能神经系统中的治疗靶点。相关研究内容发表在2014年12月第24期《中国神经再生研究（英文版）》杂志上。

Article: "Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture " by 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)

Oda A, Tanaka H. Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture. Neural Regen Res. 2014;9(24):2128-2131.

胆碱能神经元丧失是阿尔茨海默病的主要病理特征,人类影像学检查同样可以证实这一点。基底核和内侧隔核胆碱能神经可支配大脑皮质和海马,并分别与参与认知任务。因此,增强胆碱能传递与乙酰胆碱酯酶抑制剂可改善阿尔兹海默病患者的认知功能障碍。同理,剥夺胆碱能传递乙酰胆碱受体或胆碱能神经纤维去神经支配遗传性就会严重损害实验动物的学习和记忆能力。然而针对α4β2和α7烟碱型乙酰胆碱受体化合物的临床试验结果却令人沮丧。

Nicotinic receptors in the central nervous system are candidate targets for the treatment of dementia

Loss of cholinergic neurons is a pathological hallmark of Alzheimer’s disease (AD), and is also assessed in human imaging studies. Cholinergic neurons of the nucleus basalis of Meynert and the medial septum innervate the cerebral cortex and the hippocampus, respectively, and are involved in cognition. Hence enhancement of cholinergic transmission with acetylcholinesterase inhibitors ameliorates cognitive deficits in AD patients. Consistently, deprivation of cholinergic transmission by either genetic disruption of acetylcholine receptors or denervation of cholinergic nerve fibers severely impairs learning and memory in animal experiments. The neurotransmitter acetylcholine transduces signals through muscarinic and nicotinic acetylcholine receptors. Several nAChR-targeting compounds have been developed to relieve neuropsychiatric symptoms in AD patients. However, clinical trials of compounds that target α4β2* and α7 nAChRs have produced discouraging results. For example, varenicline, a partial agonist of α4β2* nAChR, is the only clinically available nAChR-targeting drug, and was approved for smoking cessation, but failed to improve cognition in AD patients.

Prof. Hidekazu Tanaka, comes from Ritsumeikan University, Japan considers that the failure of nAChR-targeting therapy for AD may be attributed to several reasons. First, the expression of nAChRs is down-regulated in the brains of AD patients. Second, tested compounds have insufficient potencies, and under conditions of decreased nAChR subunit expression, these reportedly activate only a small fraction (about 10%) of nAChRs. Third, adverse effects of nAChR-targeting compounds, such as gastrointestinal and CNS-related side effects, may limit therapeutic doses of compounds. To circumvent these side effects, partial agonists for nAChRs have been developed with the expectation of broader therapeutic windows than full agonists. Nonetheless, a better understanding of the relationships between nAChRs and plasticity or rearrangements of neural circuitry may be required for the successful treatment of AD. The relevant study has been published in the Neural Regeneration Research (Vol. 9, No. 24, 2014)

Article: "Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture " by 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)

Oda A, Tanaka H. Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture. Neural Regen Res. 2014;9(24):2128-2131.