Pittaluga Anna, Torre Veronica, Olivero Guendalina, Rosenwasser Nicole, Taddeucci Alice
Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, Centre of Excellence for Biomedical Research, 3Rs Center, University of Genoa, viale Cembrano 4, Genoa, 16148, Italy.
IRCCS Ospedale Policlinico San Martino, Genova, 16145, Italy.
Curr Neuropharmacol. 2025;23(7):820-834. doi: 10.2174/011570159X327960240823065729.
The central nervous system (CNS) is not an immune-privileged compartment, but it is intimately intertwined with the immune system. Among the components shared by the two compartments is the complement, a main constituent of innate immunity, which is also produced centrally and controls the development and organization of synaptic connections. Complement is considered a doubled-faced system that, besides controlling the physiological development of the central network, also subserves synaptic engulfment pivotal to the progression of neurodegenerative diseases. Quite interestingly, besides these "" roles, evidence in the last two decades highlighted other "" role(s), thereby complementing modulates chemical transmission at central synapsis. It emerged that glutamate is the preferential target of these "" complementinduced effects, which include i) the control of the release of glutamate from neurons and astrocytes and ii) the control of the number and the functions of central glutamatergic receptor subtypes (i.e., the NMDA receptors, the AMPA/kainate receptors, and the metabotropic glutamate receptors) in plasma membranes. This review summarizes some of the available results supporting the role of complement as a "" of central glutamate transmission, paying particular attention to those events that occur presynaptically. Taking into consideration the enormous progress in complement pharmacology and the increasing number of therapeutics in clinical trials, deepening our knowledge of these" " role(s) could pave the road to new therapeutic approaches for the management of central neurological diseases.
中枢神经系统（CNS）并非免疫豁免区，而是与免疫系统紧密相连。这两个系统共有的组成部分之一是补体，它是先天免疫的主要成分，也在中枢产生并控制突触连接的发育和组织。补体被认为是一个双面系统，除了控制中枢网络的生理发育外，还在神经退行性疾病进展中对突触吞噬起关键作用。非常有趣的是，除了这些“作用”外，过去二十年的证据还突出了其他“作用”，从而表明补体可调节中枢突触处的化学传递。结果发现，谷氨酸是这些“补体诱导效应”的优先靶点，这些效应包括：（i）控制神经元和星形胶质细胞释放谷氨酸，以及（ii）控制质膜上中枢谷氨酸能受体亚型（即N-甲基-D-天冬氨酸受体、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/海人藻酸受体和代谢型谷氨酸受体）的数量和功能。本综述总结了一些现有结果，这些结果支持补体作为中枢谷氨酸传递“调节因子”的作用，尤其关注突触前发生的那些事件。考虑到补体药理学的巨大进展以及临床试验中治疗药物数量的不断增加，加深我们对这些“作用”的了解可能为中枢神经系统疾病的管理开辟新的治疗途径。
