Nagori Kushagra, Pradhan Madhulika, Sharma Mukesh, Badwaik Hemant R, Nakhate Kartik T
Department of Pharmaceutical Chemistry, Rungta College of Pharmaceutical Sciences and Research, Kurud Road, Kohka, Bhilai 490024, Chhattisgarh, India.
Department of Pharmaceutical Technology, Gracious College of Pharmacy, Abhanpur 493661, Chhattisgarh, India.
Curr Alzheimer Res. 2024;21(1):50-68. doi: 10.2174/0115672050306008240321034006.
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.
乙酰胆碱（ACh）广泛存在于神经系统中，并参与多种脑功能的调节。通过调节突触传递和促进突触可塑性，尤其是在海马体和皮层中，乙酰胆碱在学习和记忆的调节中起着关键作用。乙酰胆碱的这些促认知作用是由神经元毒蕈碱型和烟碱型胆碱能受体介导的。胆碱能传递受损会导致与衰老和痴呆相关的认知衰退。因此，当涉及到最常见的痴呆病因——阿尔茨海默病（AD）时，胆碱能系统一直是主要关注的焦点。在AD中，胆碱能神经元会因淀粉样β斑块和富含tau蛋白的神经原纤维缠结而广泛受损。淀粉样β还会阻断胆碱能受体并阻碍神经元信号传导。这使得中枢胆碱能系统成为开发AD药物的重要靶点。事实上，像多奈哌齐和卡巴拉汀这样的中枢性胆碱酯酶抑制剂已被批准用于治疗AD，尽管效果并不令人满意。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挽救机制可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，还详细描述了参与AD认知和病理生理学的各种毒蕈碱型和烟碱型受体亚型。本文还综述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。
