Wang Y, Hayashi T, Chang C F, Chiang Y H, Tsao L I, Su T P, Borlongan C, Lin S Z
National Institute on Drug Abuse, I.R.P., 5500 Nathan Shock Dr, Baltimore, MD 21224, USA.
Stroke. 2001 Mar;32(3):775-82. doi: 10.1161/01.str.32.3.775.
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.
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.
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.
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.
先前的研究表明，甲基苯丙胺（MA）和缺血/再灌注损伤均涉及活性氧的形成和凋亡机制的激活。MA可能与中风引起的脑损伤产生协同或累加效应。本研究的目的是调查体内给予MA是否会加重缺血性脑损伤。
成年CD-1小鼠预先接受MA或生理盐水处理。随后，每只动物用氯水合醛麻醉并置于立体定位框架中。一部分动物接受脑内注射胶质细胞源性神经营养因子（GDNF）。右侧大脑中动脉和双侧颈动脉短暂闭塞45分钟。用激光多普勒测量局部脑血流量。再灌注24小时后，处死动物进行氯化三苯基四氮唑染色和p53 mRNA Northern印迹分析。通过酶联免疫吸附测定法检测皮质和纹状体中的GDNF水平。
我们发现，MA预处理增加了缺血诱导的脑梗死。单独的缺血或MA均可增强p53 mRNA表达。此外，MA增强了缺血小鼠脑中p53 mRNA的表达。MA预处理降低了缺血纹状体中的GDNF水平。缺血前脑内注射GDNF可减少MA促进的梗死。
我们的数据表明，MA可能通过抑制GDNF介导的途径加重脑缺血损伤，并提示MA可能拮抗内源性神经保护途径作为其作用机制的一部分。
