UCD School of Biomolecular and Biomedical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
J Neuroinflammation. 2011 Aug 2;8:87. doi: 10.1186/1742-2094-8-87.
During cerebral ischemia, elevation of TNF-α and glutamate to pathophysiological levels may induce dysregulation of normal synaptic processes, leading ultimately to cell death. Previous studies have shown that patients subjected to a mild transient ischemic attack within a critical time window prior to a more severe ischemic episode may show attenuation in the clinical severity of the stroke and result in a more positive functional outcome. Studies with organotypic hippocampal cultures and mixed primary hippocampal cultures have shown that prior incubation with low concentrations of glutamate and TNF-α increase the resistance of neurones to a subsequent insult from glutamate, AMPA and NMDA, while co-exposure of TNF-α and for example AMPA may have neuroprotective effects compared to cultures exposed to excitotoxic agents alone. In addition our work has shown that although glutamate and TNF-α pretreatment induces analogous levels of desensitisation of the intracellular calcium dynamics of neurons under resting conditions and in response to acute glutamate stimulation, their downstream signalling pathways involved in this response do not converge. Glutamate and TNF-α would appear to have opposing effects on resting Ca2+ levels which supports the proposal that they have distinct modes of preconditioning.
在脑缺血期间，TNF-α 和谷氨酸升高到病理生理水平可能会导致正常突触过程的失调，最终导致细胞死亡。先前的研究表明，在更严重的缺血发作之前，在关键时间窗内经历轻度短暂性缺血发作的患者，其中风的临床严重程度可能会减轻，并导致更积极的功能结果。使用器官型海马培养物和混合原代海马培养物的研究表明，先前用低浓度的谷氨酸和 TNF-α孵育可增加神经元对随后谷氨酸、AMPA 和 NMDA 损伤的抵抗力，而 TNF-α与例如 AMPA 的共同暴露与单独暴露于兴奋性毒性剂的培养物相比可能具有神经保护作用。此外，我们的工作表明，尽管谷氨酸和 TNF-α预处理诱导神经元在静息状态下和响应急性谷氨酸刺激时细胞内钙动力学的类似脱敏水平，但它们参与该反应的下游信号通路并不收敛。谷氨酸和 TNF-α似乎对静息 Ca2+水平有相反的影响，这支持了它们具有不同的预处理模式的观点。
