PROTECTION AGAINST ISCHEMIA-INDUCED NEURONAL DAMAGE BY THE ALPHA-2-ADRENOCEPTOR ANTAGONIST IDAZOXAN - INFLUENCE OF TIME OF ADMINISTRATION AND POSSIBLE MECHANISMS OF ACTION
PROTECTION AGAINST ISCHEMIA-INDUCED NEURONAL DAMAGE BY THE ALPHA-2-ADRENOCEPTOR ANTAGONIST IDAZOXAN - INFLUENCE OF TIME OF ADMINISTRATION AND POSSIBLE MECHANISMS OF ACTION
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DOI：
10.1038/jcbfm.1990.145
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发表时间：
1990-11-01
影响因子：
6.3
通讯作者：
WIELOCH, T
中科院分区：
文献类型：
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作者：
GUSTAFSON, I;WESTERBERG, E;WIELOCH, T
在暴露于10分钟不完全前脑缺血的大鼠中研究了α2受体拮抗剂咪唑克生对新皮质和海马CA1区神经元损伤的保护作用。静脉注射时缺血后立即（0.1 mg/kg）和随后的 6 小时（10 μg/kg/min），idazoxan 显着减少海马体（从 84% 至 26%）和新皮质脆弱部分（从 15% 至 1%）的神经元损伤。单独的推注剂量不能提供显着的保护。当咪唑克生给药延迟30分钟时，在新皮质中没有观察到明显的保护作用，并且在海马中的作用不明确。缺血期间诱导血浆皮质酮水平短暂升高。与输注生理盐水相比，给予伊达唑克 2 小时不影响缺血后皮质酮水平的变化。 Idazoxan (10-7-10-4 M) 不影响体外与脑切片中谷氨酸受体的结合。 因此，咪唑克生的保护作用不能通过抑制血浆皮质类固醇水平或通过对谷氨酸受体的拮抗作用来解释。在缺血再灌注后的最初几个小时内给予艾达唑生显然可以保护神经元，而神经元的组织病理学坏死在缺血后 48-72 小时变得可见。导致迟发性神经元死亡的有害过程发生在缺血后早期，并且可能受到肾上腺素受体配体的影响。咪唑克生可能通过多种机制发挥保护作用，但可能主要通过增加去甲肾上腺素能神经元活动和提高大脑中细胞外去甲肾上腺素 (NA) 水平来发挥其保护性缺血后作用。 NA 的有利作用可能是由于抑制兴奋性毒性神经传递或激活促进生存和营养过程。
The protective effect of the .alpha.2-receptor antagonist idazoxan against neuronal damage in the neocortex and in the hippocampal CA1 region was studied in rats exposed to 10 min of incomplete forebrain ischemia. When administered i.v. immediately after ischemia (0.1 mg/kg) and subsequently for 6 h (10 .mu.g/kg/min), idazoxan significantly reduced neuronal damage in the hippocampus (from 84 to 26%) and in the vulnerable parts of the neocortex (from 15 to 1%). The bolus dose alone provided no significant protection. When idazoxan administration was delayed for 30 min, no significant protection was noticed in the neocortex, and the effect in the hippocampus was ambiguous. A transient elevation of plasma corticosterone levels was induced during ischemia. Idazoxan administration for 2 h did not affect postischemic changes in corticosterone levels compared with saline infusion. Idazoxan (10-7-10-4 M) did not influence the in vitro binding to glutamate receptors in brain slices. Thus, the protective effect of idazoxan cannot be explained by suppression of the plasma corticosteroid levels or via an antagonistic effect on glutamate receptors. Idazoxan apparently protects neurons when given during the first hours of postischemic reperfusion, while histopathological necrosis of neurons becomes visible 48-72 h after ischemia. Detrimental processes causing delayed neuronal death occur in the early postischemic phase and can be influenced by adrenoceptor ligands. Idazoxan may protect by several mechanisms but probably exerts its protective postischemic effect mainly through an increased noradrenergic neuronal activity and an elevation of extracellular noradrenaline (NA) levels in the brain. The favorable effects of NA may either be due to inhibition of excitotoxic neurotransmission or activation of survival-promoting and trophic processes.