M1胆碱受体激动剂治疗阿尔茨海默病的研究进展

阿尔茨海默病(Alzheimer disease，AD)是一种以胆碱能神经元进行性退变、老年斑和神经元缠结为病理特征的神经退行性疾病。尽管AD发病机制尚未阐明，但β淀粉样肽沉积和tau蛋白磷酸化与胆碱能神经退变的恶性循环(vicious cycle)无疑是造成AD的重要病理机制之一。大量研究表明胆碱能神经突触后膜的M1受体的数目在整个病程中变化不大，M1受体选择性激动剂不但可以直接补偿胆碱能的功能，而且可以调节β淀粉样前体蛋白代谢和降低tau蛋白的过度磷酸化，有助于打破这一恶性循环，改善AD的学习记忆功能并延缓病情的发展。因此M1胆碱受体激动剂被认为是最有前途的治疗AD药物之一。目前Xanomeline、Sabcomeline等具有相对选择性M1受体激动剂业已进入新药临床试验阶段。

Pharmacological and clinical studies on M1 muscarinic receptor agonist in treatment of Alzheimerdisease

Alzheimer disease(AD) is characterized by the progressive deterioration of the cholinergic neurons, senile plaques and neurofibrillary tangles. Cholinergic hypofunction in AD may enhance the beta amyloid production and deposition, and tau hyperphosphorylation, leading to a vicious cycle which can potentially accelerate the pathological process. A number of studies strongly suggest that there are no changes in the number of muscarinic receptors in AD. M 1 muscarinic receptor agonists could directly activate muscarinic receptors to ameliorate cognition dysfunction and modulate beta amyloid together with tau phosphorylation. This unique property of M 1 agonists to alter different aspects of AD pathogenesis could represent the most remarkable clinical value of such compounds. Recently, several M 1 muscarinic receptor agonists such as xanomeline, sabcomeline are under the clinical trial for the treatment of AD. This review focuses on some pharmacological and clinical studies concerning M 1 muscarinic receptor agonists for AD therapy.