Savolainen K, Hirvonen M R, Naarala J
Department of Toxicology, National Public Health Institute, Kuopio, Finland.
Neurotoxicology. 1994 Fall;15(3):493-502.
Acetylcholine (ACh) is a powerful excitotoxic neurotransmitter in the brain. By stimulating Ca(2+)-mobilizing receptors, ACh, through G-protein(s), stimulates phospholipase C and causes the hydrolysis of a membrane phospholipid, phosphatidylinositol-4,5-bisphosphate to two second messengers, inositol-1,4,5-trisphosphate (ins-(1,4,5)-P3), and diacylglycerol. Ins-(1,4,5)-P3 is important in cholinergic neuronal stimulation, and injury. Cholinergic agonists cause tonic-clonic convulsions which may be either transient or persistent. Even short-term cholinergic convulsions may be associated with neuronal injury, especially in the basal forebrain and the hippocampus. Cholinergic-induced convulsions also elevate levels of brain Ca2+ which precede neuronal injury. Female sex and senescence increase the sensitivity of rats to cholinergic excitotoxicity. Even if cholinergic-induced brain phosphoinositide signalling is likely to trigger cholinergic excitotoxicity, several other processes may be involved in the ensuing neuronal injury. Once initiated, cholinergic convulsions cannot be stopped with cholinergic antagonists such as atropine even though they are effective when given prior to a cholinergic agonist. However, glutaminergic antagonists, and GABAergic agonists, are effective in the attenuation of ongoing cholinergic status epilepticus. Cholinergic brain stimulation may be, in fact, under a partial control of brain GABAergic tonus, but also cause the release of glutamate. Glutamate stimulates inositol lipid signalling in several neuronal cells and, therefore, underlines the significance of inositol lipid signalling in cholinergic-induced excitotoxicity. Moreover, the anatomical distribution of cholinergic brain damage correlates well with that of glutaminergic neurons. Furthermore, glutamate increases neuronal oxidative stress, i.e. it increases the levels of free intracellular calcium, the production of reactive oxygen species, and causes the depletion of neuronal glutathione. The role of excitatory amino acids as common mediators of cholinergic excitotoxicity may offer new insights into the neurotoxic consequences of cholinergic neuronal stimulation.
乙酰胆碱（ACh）是大脑中一种强大的兴奋性毒性神经递质。通过刺激钙动员受体，ACh通过G蛋白刺激磷脂酶C，并导致膜磷脂磷脂酰肌醇-4,5-二磷酸水解为两种第二信使，即肌醇-1,4,5-三磷酸（Ins-(1,4,5)-P3）和二酰基甘油。Ins-(1,4,5)-P3在胆碱能神经元刺激和损伤中起重要作用。胆碱能激动剂会引起强直性阵挛性惊厥，惊厥可能是短暂的或持续的。即使是短期的胆碱能惊厥也可能与神经元损伤有关，尤其是在基底前脑和海马体中。胆碱能诱导的惊厥还会升高大脑Ca2+水平，这在神经元损伤之前就会出现。雌性和衰老会增加大鼠对胆碱能兴奋性毒性的敏感性。即使胆碱能诱导的脑磷酸肌醇信号可能触发胆碱能兴奋性毒性，但随后的神经元损伤可能还涉及其他几个过程。一旦开始，胆碱能惊厥即使使用阿托品等胆碱能拮抗剂也无法停止，尽管它们在胆碱能激动剂给药前有效。然而，谷氨酰胺能拮抗剂和GABA能激动剂在减轻正在进行的胆碱能癫痫持续状态方面是有效的。事实上，胆碱能脑刺激可能部分受脑GABA能张力的控制，但也会导致谷氨酸的释放。谷氨酸在几种神经元细胞中刺激肌醇脂质信号，因此强调了肌醇脂质信号在胆碱能诱导的兴奋性毒性中的重要性。此外，胆碱能脑损伤的解剖分布与谷氨酰胺能神经元的分布密切相关。此外，谷氨酸会增加神经元氧化应激，即它会增加细胞内游离钙水平、活性氧的产生，并导致神经元谷胱甘肽的消耗。兴奋性氨基酸作为胆碱能兴奋性毒性的常见介质的作用可能为胆碱能神经元刺激的神经毒性后果提供新的见解。
