将中枢胆碱能受体作为阿尔茨海默病治疗靶点的最新进展。

Kushagra Nagori, Madhulika Pradhan, Mukesh Sharma, Ajazuddin, Hemant R Badwaik, Kartik T Nakhate
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引用次数: 0

摘要

乙酰胆碱(ACh)普遍存在于神经系统中,参与调节各种大脑功能。通过调节突触传递和促进突触可塑性(尤其是在海马和大脑皮层),乙酰胆碱在调节学习和记忆方面发挥着关键作用。神经元的毒蕈碱和烟碱胆碱能受体介导了 ACh 的这些认知作用。胆碱能传递受损会导致与衰老和痴呆相关的认知能力下降。因此,胆碱能系统一直是阿尔茨海默病(AD)--最常见的痴呆症病因--的首要关注点。在阿尔茨海默病中,淀粉样β斑块和富含tau蛋白的神经纤维缠结会对胆碱能神经元造成广泛破坏。淀粉样蛋白-β还会阻断胆碱能受体,阻碍神经元信号传导。这使得中枢胆碱能系统成为开发治疗注意力缺失症药物的重要靶点。事实上,多奈哌齐(donepezil)和利伐斯的明(rivastigmine)等中枢作用胆碱酯酶抑制剂已被批准用于治疗 AD,但疗效并不理想。因此,确定参与 AD 发病机制的胆碱能受体的特定亚型对于开发未来的药物至关重要。此外,确定胆碱能系统的内源性拯救机制也能为新药开发铺平道路。在本文中,我们讨论了中枢胆碱能系统的神经解剖学。此外,还详细介绍了与认知和 AD 病理生理学有关的各种毒蕈碱受体和烟碱受体亚型。文章还回顾了通过调节基底前脑胆碱能投射神经元来调节认知过程的主要神经递质。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Current Progress on Central Cholinergic Receptors as Therapeutic Targets for Alzheimer's Disease.

Acetylcholine (ACh) is ubiquitously present in the nervous system and has been involved in the regulation of various brain functions. By modulating synaptic transmission and promoting synaptic plasticity, particularly in the hippocampus and cortex, ACh plays a pivotal role in the regulation of learning and memory. These procognitive actions of ACh are mediated by the neuronal muscarinic and nicotinic cholinergic receptors. The impairment of cholinergic transmission leads to cognitive decline associated with aging and dementia. Therefore, the cholinergic system has been of prime focus when concerned with Alzheimer's disease (AD), the most common cause of dementia. In AD, the extensive destruction of cholinergic neurons occurs by amyloid-β plaques and tau protein-rich neurofibrillary tangles. Amyloid-β also blocks cholinergic receptors and obstructs neuronal signaling. This makes the central cholinergic system an important target for the development of drugs for AD. In fact, centrally acting cholinesterase inhibitors like donepezil and rivastigmine are approved for the treatment of AD, although the outcome is not satisfactory. Therefore, identification of specific subtypes of cholinergic receptors involved in the pathogenesis of AD is essential to develop future drugs. Also, the identification of endogenous rescue mechanisms to the cholinergic system can pave the way for new drug development. In this article, we discussed the neuroanatomy of the central cholinergic system. Further, various subtypes of muscarinic and nicotinic receptors involved in the cognition and pathophysiology of AD are described in detail. The article also reviewed primary neurotransmitters that regulate cognitive processes by modulating basal forebrain cholinergic projection neurons.

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