dextrorphan and Cerebral-Infarction

Previous studies have implicated both excitotoxicity and apoptosis in the pathogenesis of cerebral infarction induced by focal ischemic insults. Here we tested the possibility that the NMDA antagonist, dextrorphan, and the protein synthesis inhibitor, cycloheximide, would produce additive protective effects in a rodent model of focal ischemia-reperfusion. Transient focal cerebral ischemia was induced by a 90 min period of ligation of the right middle cerebral artery and both common carotid arteries. Administration of either 30 mg/kg dextrorphan or 0.5 mg/kg cycloheximide, given i.p. 15 min before ischemia, reduced infarct volume by about 65%. When optimal concentrations of each drug were given together, infarct volume was reduced by 87% as measured 14 days later. These observations support the idea that both excitotoxicity, and apoptosis dependent on new protein synthesis, contribute to cerebral infarction after transient focal ischemia in the rat.

Topics: Animals; Blood Glucose; Cerebral Arteries; Cerebral Infarction; Cycloheximide; Dextrorphan; Ischemic Attack, Transient; Male; Neuroprotective Agents; Protein Synthesis Inhibitors; Rats

Focal cerebral ischemia confined to the cerebral cortex in the right middle cerebral artery (MCA) territory was induced by temporary ligation of the MCA and both common carotid arteries (CCAs). Reperfusion was initiated by releasing all three arterial occlusions after 90 min of ischemia. Infarct volume was morphometrically measured after triphenyltetrazolium chloride staining 24 h postischemia. Blood-brain barrier breakdown was assessed 4 h postischemia by measuring vascular permeability to fluorescein isothiocyanate-conjugated dextran (FITC-D), a macromolecule tracer. Ischemic brain edema was measured based on percent water content, 24 h postischemia. Dextrorphan (DX) 20-10 mg/kg given ip 15 min before ischemia reduced infarct volume in a dose-dependent manner with an apparent U-shaped dose-response curve; best protection was observed at 30 mg/kg. Posttreatment at 30 min, but not 60 min, was still effective. DX (30 mg/kg, given 15 min before ischemia) also reduced the postischemic increase in vascular permeability and brain edema in the right MCA cortex. Results from this study support the idea that NMDA receptor activation contributes to blood-brain barrier breakdown and brain edema after ischemic insults

Topics: Analysis of Variance; Animals; Blood Glucose; Blood Pressure; Blood-Brain Barrier; Brain Edema; Carbon Dioxide; Carotid Artery, Common; Cerebral Infarction; Cerebrovascular Circulation; Dextrorphan; Heart Rate; Ischemic Attack, Transient; Male; Neuroprotective Agents; Oxygen; Rats; Reperfusion; Time Factors

The dose-response curve and time window of efficacy for dextrorphan in permanent focal brain ischemia leading to infarction was studied in the rat. With pretreatment, the maximum effective dose of 20 mg/kg reduced the eventual infarct volume by greater than 50%. Delayed drug administration, up to 45 min following permanent middle cerebral artery occlusion, significantly reduced infarct size.

Topics: Analysis of Variance; Animals; Basal Ganglia; Blood Gas Analysis; Blood Pressure; Brain Ischemia; Cerebral Arteries; Cerebral Infarction; Dextrorphan; Dose-Response Relationship, Drug; N-Methylaspartate; Rats