Shuaib A, Ijaz S, Miyashita H, Mainprize T, Kanthan R
Department of Medicine (Neurology), Royal University Hospital, Saskatoon, Sask, Canada.
Brain Res. 1994 Dec 12;666(1):99-103. doi: 10.1016/0006-8993(94)90287-9.
Repetitive cerebral ischemia in gerbils produces delayed neuronal damage in the substantia nigra reticulata (SNr). This damage begins 4 to 5 days after the insult and is severe by day 7. The damage can be attenuated by GABA agonists. There is a prominent GABAergic striatal pathway to the SNr. Damage to this pathway leads to progressive loss of SNr neurons. This loss can be prevented by GABA agonists. We postulate that, ischemia-induced lack of GABAergic inhibitory input from the striatum to the SNr, may be responsible for this delayed neuronal damage. In the present experiment, we have measured striatal extracellular GABA concentrations with or without nipecotic acid, a GABA-reuptake inhibitor, in gerbils exposed to repetitive ischemia. GABA levels were measured on days 1, 3, 5, and 7 after the ischemic insult. Five control animals and a similar number of ischemic animals were monitored on each day. Extracellular fluid was collected using in vivo microdialysis and GABA levels were measured by electrochemical detection with HPLC. The extracellular striatal GABA levels were very low in the initial three specimens collected, both in the control and in the ischemic animals. However, addition of nipecotic acid resulted in an immediate increase of GABA in measurable range. In comparison to the controls, the increase in GABA on day 1 and 3 were significantly higher in animals with repetitive ischemia (two-way ANOVA with repeated measures). Subsequent measurements showed a gradual decrease in GABA levels when compared to controls. The increase in GABA with nipecotic acid was significantly lower on day 7 after the ischemic insults when compared to the controls. The increased GABA responsiveness immediately after the ischemic insults may reflect a protective effect against excitotoxicity. The subsequent decline in GABA levels after the insult may be secondary to progressive loss of striatal GABAergic neurons. This may contribute to the production of delayed neural damage in the SNr by a decrease in the inhibitory striatal input.
沙土鼠反复脑缺血会导致黑质网状部（SNr）出现迟发性神经元损伤。这种损伤在缺血后4至5天开始，到第7天会很严重。GABA激动剂可减轻这种损伤。存在一条从纹状体到SNr的重要GABA能通路。该通路受损会导致SNr神经元逐渐丧失。GABA激动剂可预防这种丧失。我们推测，缺血诱导的从纹状体到SNr的GABA能抑制性输入缺失，可能是这种迟发性神经元损伤的原因。在本实验中，我们在暴露于反复缺血的沙土鼠中，测量了有无GABA再摄取抑制剂尼克酸情况下的纹状体细胞外GABA浓度。在缺血损伤后的第1、3、5和7天测量GABA水平。每天监测5只对照动物和数量相似的缺血动物。使用体内微透析收集细胞外液，并通过HPLC电化学检测测量GABA水平。在最初收集的三个样本中，对照动物和缺血动物的纹状体细胞外GABA水平都非常低。然而，添加尼克酸会使GABA立即增加到可测量范围内。与对照组相比，反复缺血动物在第1天和第3天的GABA增加量显著更高（重复测量的双向方差分析）。后续测量显示，与对照组相比，GABA水平逐渐下降。缺血损伤后第7天，与对照组相比，尼克酸引起的GABA增加量显著更低。缺血损伤后立即出现的GABA反应性增加可能反映了对兴奋性毒性的保护作用。损伤后GABA水平的后续下降可能继发于纹状体GABA能神经元的逐渐丧失。这可能通过减少纹状体抑制性输入，导致SNr中迟发性神经损伤的产生。
