Rodríguez-Ithurralde D, Olivera S, La Paz A, Vincent O, Rondeau A
Laboratory of Molecular Neuroscience, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay.
J Neurol Sci. 1996 Aug;139 Suppl:76-82. doi: 10.1016/0022-510x(96)00095-0.
To study the mechanisms by which glutamate-elicited acetylcholinesterase release (GEAR) might play a part in the pathogenesis of excitotoxically triggered motor neurone disease, and to investigate the interaction of GEAR with spinal glycinergic mechanisms, we measured acetylcholinesterase (AChE) and cholinergic markers, after stimulating ventral horn slices and synaptosomes from the mouse spinal cord, with both glutamate- and glycine-receptor agonists. Glutamate (GLU), kainate and AMPA, as well as glycine (GLY) evoked dose-related, calcium-dependent liberation of soluble forms of AChE from both slices and synaptosomes. GLY-evoked AChE release showed remarkable age-related postnatal changes. In the immature slice of the ventral horn. GLY potentiated the GEAR response in the presence of strychnine, suggesting N-methyl-D-aspartate (NMDA) receptor involvement, and was also able to evoke a strychnine-sensitive AChE release in the absence of exogenous GLU. After the 28th postnatal day, nearly all the AChE secreted was released either after the activation of non-NMDA glutamate receptors or by strychnine-sensitive GLY-evoked AChE release mechanisms. Both GEAR and GLY-evoked AChE release might impair the negative feedback loop which modulates the overactivation of motor neurones, and cause prolonged extracellular rises of soluble AChE. These effects might augment the vulnerability of motor neurones to excitotoxic stress, promote fiber outgrowth, and eventually accelerate the metabolic exhaustion of lower motor neurones. It is possible that the mechanisms described are operative at the spinal cord of ALS/MND patients.
为研究谷氨酸诱发的乙酰胆碱酯酶释放（GEAR）可能在兴奋性毒性引发的运动神经元疾病发病机制中所起的作用，并探究GEAR与脊髓甘氨酸能机制的相互作用，我们在用谷氨酸和甘氨酸受体激动剂刺激小鼠脊髓腹角切片和突触体后，测量了乙酰胆碱酯酶（AChE）及胆碱能标志物。谷氨酸（GLU）、 kainate和AMPA，以及甘氨酸（GLY）均可诱发剂量相关的、依赖钙的可溶性AChE从切片和突触体中的释放。GLY诱发的AChE释放呈现出显著的出生后年龄相关变化。在未成熟的腹角切片中，GLY在士的宁存在的情况下增强了GEAR反应，提示N-甲基-D-天冬氨酸（NMDA）受体参与其中，并且在没有外源性GLU的情况下也能够诱发士的宁敏感的AChE释放。出生后第28天之后，几乎所有分泌的AChE都是在非NMDA谷氨酸受体激活后或通过士的宁敏感的GLY诱发的AChE释放机制释放的。GEAR和GLY诱发的AChE释放均可能损害调节运动神经元过度激活的负反馈回路，并导致可溶性AChE细胞外水平长时间升高。这些效应可能会增加运动神经元对兴奋性毒性应激的易感性，促进纤维生长，并最终加速下运动神经元的代谢耗竭。所述机制有可能在肌萎缩侧索硬化症/运动神经元病（ALS/MND）患者的脊髓中起作用。
