Methamphetamine potentiates ischemia/reperfusion insults after transient middle cerebral artery ligation.
OBJECTIVE
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.
National Institute on Drug Abuse, I.R.P., 5500 Nathan Shock Dr, Baltimore, MD 21224, USA. ywang@intra.nida.nih.gov
Y
Y
Wang
T
T
Hayashi
C F
CF
Chang
Y H
YH
Chiang
L I
LI
Tsao
T P
TP
Su
C
C
Borlongan
S Z
SZ
Lin
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006339:Heart Rate / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D007276:Injections, Intraventricular; D008026:Ligation; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D008694:Methamphetamine; D002118:Calcium