Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.
Front Neural Circuits. 2021 Aug 17;15:711564. doi: 10.3389/fncir.2021.711564. eCollection 2021.
Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca influx-triggered excitotoxicity through Ca-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.
兴奋性毒性是中枢和周围神经系统多种疾病中细胞丢失的主要机制之一。除了先前确定的依赖于谷氨酸从轴突末梢过度释放或 NMDA 受体（NMDAR）过度激活的兴奋性毒性信号通路之外，在多种疾病模型中还检测到 Ca 流入触发的通过 Ca 通透性（CP）-AMPA 受体（AMPAR）的兴奋性毒性。在这篇综述中，讨论了急性脑损伤（例如脑创伤或脊髓损伤、缺血）和慢性神经疾病，包括癫痫/发作、亨廷顿病（HD）、帕金森病（PD）、阿尔茨海默病（AD）、肌萎缩侧索硬化症（ALS）、慢性疼痛和青光眼，关于 CP-AMPAR 介导的兴奋性毒性。考虑到 CP-AMPAR 在大多数细胞中的低表达或不存在，特异性操纵 CP-AMPAR 可能是一种比阻断 NMDAR 更合理的策略，以延迟病理改变的发生和进展，副作用更少。
