Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl
Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl
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DOI：
10.1038/sj.bjp.0702940
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发表时间：
1999-12-01
影响因子：
7.3
通讯作者：
Stone, TW
中科院分区：
文献类型：
--
作者：
Behan, WMH;McDonald, M;Stone, TW
1喹啉酸和N-甲基-D-天冬氨酸（NMDA）的兴奋性毒性作用存在差异，提示喹啉酸可能通过激活NMDA受体以外的机制发挥作用。本研究旨在研究一种有效的抗氧化剂，褪黑激素，和潜在的神经保护剂，丙炔苯丙胺，作为喹啉酸诱导的脑损伤的抑制剂的效果。向麻醉大鼠的海马体注射药物，使其恢复，然后取脑进行组织学检查和存活神经元计数。2喹啉酸（120 nmol）诱导锥体细胞层损伤，这可以通过共同给予褪黑激素（5 nmol局部加2 x 20 mg kg（-1）i. p.）来预防。褪黑激素受体阻断剂luzindole不能阻止这种保护作用。NMDA引起的神经元损伤3喹啉酸增加了海马组织脂质过氧化产物的形成，这种作用被褪黑素阻止。4丙炔苯丙胺在50 nmol的剂量下也能阻止喹啉酸诱导的损伤，但不能在10 nmol的剂量下加上2 x 1.0 mg kg（-1）i. p.（10和50 nmol加2 x 25 mg kg（-1））没有提供保护。5结果表明，喹啉酸诱导的神经元损伤可以通过褪黑素和丙炔苯丙胺的受体非依赖性作用来预防，这两种药物分别可以作为有效的自由基清除剂和增加内源性抗氧化酶的活性。这表明自由基的形成对喹啉酸诱导的体内损伤有显著贡献。
1 There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones.2 Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2 x 20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin.3 Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin.4 Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2 x 1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide(10 and 50 nmols plus 2 x 25 mg kg(-1)) did not afford protection.5 The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.