Methamphetamine Potentiates Ischemia/Reperfusion Insults After Transient Middle Cerebral Artery Ligation

Abstract

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.

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

“…Activation of oxidative/ inflammatory stress signaling cascades by drugs of abuse is the primary mechanism for increased endothelial activation and leukocyte migration across the BBB into the brain. Recent studies from our group (Sajja et al, 46 Naik et al, 115 and Prasad et al 146 ) and other groups (Alfieri et al 147 and Sandberg et al…”

“…2,6,16 Importantly, these pathological manifestations are strongly associated with various cerebrovascular abnormalities such as ischemia or hypoxia in METH abusers. 17,18,46 For instance, METH abuse, independent of the route of administration, is strongly associated with stroke pathogenesis and hypoxia in humans 47,48 and rats. 46,49 Notably, binge use of METH in humans elicits a sustained reduction in global and regional cerebral blood flow that is prominent even after 2 years of abstinence (Chung et al 2010).…”

Development of an allogeneic adherent stem cell therapy for treatment of ischemic stroke

“…Only animals who successfully achieved >80% occlusion and >50% reperfusion were utilized in the study. This surgical model has been used successfully in previously published rat stroke studies (Chiang et al 1999;Wang et al 2001).…”

Amphetamine increases blood pressure and heart rate but has no effect on motor recovery or cerebral haemodynamics in ischaemic stroke: a randomized controlled trial (ISRCTN 36285333)

“…5,9,10 However, timing and dose of administration appears important; high doses and early administration being associated with a poor outcome, 5,11 whereas pretreatment with amphetamine led to increased ischaemic insult. 12 The evidence in normal subjects [13][14][15] and in clinical stroke is less clear, [16][17][18][19][20][21][22][23][24][25][26][27] numerous small trials, utilising varying dosage and timing of treatment, showing conflicting results, overall demonstrating no evidence of benefit on motor recovery. Although treatment appears feasible and well tolerated, a trend towards increased death in the treatment group exists on meta-anlaysis.…”