Liu X H, Xu H, Barks J D
Department of Pediatrics, University of Michigan Medical Center, Ann Arbor 48109-0646, USA.
Brain Res. 1999 Dec 18;851(1-2):94-104. doi: 10.1016/s0006-8993(99)02126-5.
Tumor necrosis factor-a TNFa. has been implicated in the pathophysiology of acute neonatal brain injury. We hypothesized that acute brain injury would induce TNFa expression and that exogenous TNFa would influence the severity of N-methyl-D-aspartate-induced tissue damage. We performed two complementary groups of experiments to evaluate the potential role s. of TNFa in a neonatal rodent model of excitotoxic injury, elicited by intracerebral injection of N-methyl-D-aspartate. We used immunohistochemistry and ELISA to evaluate N-methyl-D-aspartate-induced changes in TNFa expression, and we co-injected TNFa with N-methyl-D-aspartate, to evaluate the effect of this cytokine on the severity of tissue injury. Both intra-hippocampal and intra-striatal injection of N-methyl-D-aspartate 5 nmol. stimulated TNFa expression. Increased TNFa expression was detected 3-12 h after lesioning; TNFa was localized both in glial cells in the corpus callosum, and in cells with the morphology of interneurons in the ipsilateral hippocampus, striatum, cortex and thalamus. Intra-hippocampal or intra-striatal administration of TNFa 50 ng. alone did not elicit neuropathologic damage. In the hippocampus, when co-injected with N-methyl-D-aspartate 5 or 10 nmol., TNFa 50 ng. attenuated excitotoxic injury by 35%-57%, compared to controls co-injected with heat-treated TNFa. In contrast, in the striatum, co-injection of TNFa with N-methyl-D-aspartate had no effect on the severity of the ensuing damage. The data indicate that TNFa is rapidly produced in glial cells and neurons after an excitotoxic insult in the neonatal rat brain, and that administration of exogenous TNFa results in region-specific attenuation of excitotoxic damage. We speculate that endogenous TNFa may modulate the tissue response to excitotoxic injury in the developing brain.
肿瘤坏死因子-α（TNFα）与急性新生儿脑损伤的病理生理学有关。我们假设急性脑损伤会诱导TNFα表达，并且外源性TNFα会影响N-甲基-D-天冬氨酸诱导的组织损伤的严重程度。我们进行了两组互补实验，以评估TNFα在新生啮齿动物兴奋性毒性损伤模型中的潜在作用，该损伤由脑内注射N-甲基-D-天冬氨酸引起。我们使用免疫组织化学和酶联免疫吸附测定法来评估N-甲基-D-天冬氨酸诱导的TNFα表达变化，并将TNFα与N-甲基-D-天冬氨酸共同注射，以评估这种细胞因子对组织损伤严重程度的影响。海马内和纹状体内注射5 nmol的N-甲基-D-天冬氨酸均刺激了TNFα表达。损伤后3 - 12小时检测到TNFα表达增加；TNFα定位于胼胝体的胶质细胞以及同侧海马、纹状体、皮质和丘脑的中间神经元形态的细胞中。单独海马内或纹状体内给予50 ng的TNFα不会引起神经病理损伤。在海马中，当与5或10 nmol的N-甲基-D-天冬氨酸共同注射时，与共同注射热处理TNFα的对照组相比，50 ng的TNFα将兴奋性毒性损伤减轻了35% - 57%。相反，在纹状体中，TNFα与N-甲基-D-天冬氨酸共同注射对随后损伤的严重程度没有影响。数据表明，在新生大鼠脑兴奋性毒性损伤后，胶质细胞和神经元中会迅速产生TNFα，并且外源性TNFα的给药导致兴奋性毒性损伤的区域特异性减轻。我们推测内源性TNFα可能调节发育中脑对兴奋性毒性损伤的组织反应。
