Methamphetamine potentiates ischemia/reperfusion insults after transient middle cerebral artery ligation
Methamphetamine potentiates ischemia/reperfusion insults after transient middle cerebral artery ligation
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DOI：
10.1161/01.str.32.3.775
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发表时间：
2001-03-01
期刊：
影响因子：
8.3
通讯作者：
Lin, SZ
中科院分区：
文献类型：
--
作者：
Wang, Y;Hayashi, T;Lin, SZ
背景和目的-以往的研究表明，甲基苯丙胺(MA)和缺血/再灌注损伤都涉及活性氧的形成和细胞凋亡机制的激活。MA对中风引起的脑损伤可能具有协同或相加作用。本研究旨在探讨体内给予MA是否会加重脑缺血损伤。方法成年CD-1小鼠分别给予MA或生理盐水预处理。随后，每只动物都被水合氯醛麻醉，并放置在立体定位框架中。一组动物接受了脑内注射胶质细胞系衍生神经营养因子(GDNF)。右侧大脑中动脉和双侧颈总动脉短暂闭塞45min。激光多谱勒测定局部脑血流量。再灌流24小时后处死动物，进行氯化三苯四氮唑染色和P53 mRNA Northern印迹分析，用ELISA法检测皮质和纹状体GDNF的表达。结果：MA可增加脑缺血后脑梗塞的发生率。缺血或单用MA可增强P53基因的表达。此外，MA还能增强缺血小鼠脑内P53基因的表达。MA预处理可降低缺血区纹状体内GDNF水平。结论：我们的数据表明MA加重脑缺血损伤，可能是通过抑制GDNF介导的通路，并提示MA可能拮抗内源性神经保护通路：作为其作用机制的一部分。
Background and Purpose-Previous studies have indicated that both methamphetamine (MA) and ischemia/reperfusion injuries involve reactive oxygen species formation and activation of apoptotic mechanism. That MA could have a synergistic or additive effect with stroke-induced brain damage is possible. The purpose of the present study was to investigate whether administration of MA in vivo would potentiate ischemic brain injury.Methods-Adult CD-1 mice were pretreated with MA or saline. Each animal later was anesthetized with chloral hydrate and placed in a stereotaxic frame. A subset of animals received intracerebral administration of glial cell line-derived neurotrophic factor (GDNF). The right middle cerebral artery and bilateral carotids were transiently occluded for 45 minutes. Regional cerebral blood flow was measured by laser Doppler. Animals were sacrificed for triphenyltetrazolium chloride staining and p53 mRNA Northern blot assay after 24 hours of reperfusion, Cortical and striatal GDNF levels were assayed by ELISA.Results-We Found that pretreatment with MA increased ischemia-induced cerebral infarction. Ischemia or MA alone enhanced p53 mRNA expression. Moreover, MA potentiated expression of p53 mRNA in the ischemic mouse brain. MA pretreatment decreased GDNF levels in ischemic striatum. Intracerebral administration of GDNF before ischemia reduced MA-facilitated infarction,Conclusions-Our data indicate that MA exacerbates ischemic insults in brain, perhaps through the inhibition of GDNF-mediated pathways and suggest that MA may antagonize endogenous neuroprotective pathways: as part of its mechanism of action.