Kuhmonen J, Pokorný J, Miettinen R, Haapalinna A, Jolkkonen J, Riekkinen P, Sivenius J
Department of Neurology, University of Kuopio, Finland.
Anesthesiology. 1997 Aug;87(2):371-7. doi: 10.1097/00000542-199708000-00025.
Cerebral ischemia induces a massive release of norepinephrine associated with neuronal death in the brain. It has been demonstrated that alpha2-adrenoceptor agonists decrease the release and turnover of noradrenaline, and this might prove advantageous in counteracting the neurodegeneration in ischemic brain. Therefore, in the present study, the authors tested whether dexmedetomidine, a selective alpha2-receptor agonist, has neuroprotective effects in a gerbil transient global ischemia model.
Ischemia was induced by bilateral carotid occlusion for 5 min in diethylether-anesthetized normothermic gerbils. Dexmedetomidine was administered subcutaneously in four different treatment paradigms (6-8 animals/group): 3 or 30 microg/kg 30 min before and thereafter at 3, 12, 24, and 48 h after the occlusion, or 3 or 30 microg/kg at 3, 12, 24, and 48 h after the occlusion. Control animals were subjected to forebrain ischemia but received only saline injections. One week after occlusion, animals were transcardially perfused for histochemistry. Neuronal death in the CA1 and CA3 regions of the hippocampus and in the hilus of the dentate gyrus was evaluated in silver-stained 60-microm coronal sections.
Compared with saline-treated ischemic animals, dexmedetomidine at a dose of 3 microg/kg given before and continued after the induction of ischemia reduced the number of damaged neurons in the CA3 area (2 +/- 3 vs. 17 +/- 20 degenerated neurons/mm2; P < 0.05). Also in the dentate hilus, the number of damaged neurons was reduced by dexmedetomidine (3 microg/kg) given before and continued after ischemia (5 +/- 7 vs. 56 +/- 42 degenerated neurons/mm2; P < 0.01).
The present data demonstrate that dexmedetomidine effectively prevents delayed neuronal death in CA3 area and in the dentate hilus in gerbil hippocampus when the management is started before the onset of ischemia and continued for 48 h after reperfusion. Inhibition of ischemia-induced norepinephrine release may be associated with neuroprotection by dexmedetomidine.
脑缺血会导致去甲肾上腺素大量释放，这与大脑中的神经元死亡有关。已经证明，α2-肾上腺素能受体激动剂可减少去甲肾上腺素的释放和周转，这可能在对抗缺血性脑损伤中的神经退行性变方面具有优势。因此，在本研究中，作者测试了选择性α2受体激动剂右美托咪定在沙土鼠短暂性全脑缺血模型中是否具有神经保护作用。
在乙醚麻醉的常温沙土鼠中，通过双侧颈动脉闭塞5分钟诱导缺血。右美托咪定以四种不同的治疗方案皮下给药（每组6-8只动物）：闭塞前30分钟给予3或30微克/千克，此后在闭塞后3、12、24和48小时给予；或在闭塞后3、12、24和48小时给予3或30微克/千克。对照动物接受前脑缺血，但仅注射生理盐水。闭塞一周后，对动物进行经心灌注以进行组织化学分析。在60微米冠状银染切片中评估海马CA1和CA3区域以及齿状回门区的神经元死亡情况。
与生理盐水处理的缺血动物相比，缺血诱导前给予3微克/千克并在缺血后持续给药的右美托咪定减少了CA3区域受损神经元的数量（2±3 vs. 17±20个变性神经元/平方毫米；P<0.05）。在齿状回门区，缺血前给予并在缺血后持续给药的右美托咪定（3微克/千克）也减少了受损神经元的数量（5±7 vs. 56±42个变性神经元/平方毫米；P<0.01）。
本研究数据表明，当在缺血发作前开始处理并在再灌注后持续48小时时，右美托咪定可有效预防沙土鼠海马CA3区域和齿状回门区的迟发性神经元死亡。右美托咪定对缺血诱导的去甲肾上腺素释放的抑制作用可能与其神经保护作用有关。
