1. ¹Department of Radiology, Unversity of Manitoba, Winnipeg, Canada
2. ²Department of Basic Medical Sciences, Memorial University, St.John's, Newfoundland, Canada
3. ³Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada

We demonstrated previously that minocycline is neuroprotective in a rat model of collagenase-induced intrastriatal hemorrhage through depression of inflammation. Minocycline treatment significantly reduced necrotic damage and apoptic cell death, suppressed monocyte activation, and downregulated MMP-12 (matrix metalloproteinase) expression. The present study examined the effect of minocycline treatment in an intrastriatal ischemia (ISI) model in rat. Twenty-four male SD rats received an intrastriatal injection of enothelin-1 (ET-1, 400 pmol in 1L saline) under halothane anesthesia. Minocycline was given intraperitoneally at a dose of 45 mg/kg 1 h before or 3 hours after ISI, and on days 1, 2, and 3, and 22.5 mg/kg on day 4 and 5. Control rats received equivalent injections of saline at the same times. Behavioral tests (forelimb postural reflex, spontaneous circling, and beam walking) were conducted before and 2, 4, 7, and 21 days after ISI. Rats in both treatment groups showed a significant improvement in behavioral scores (p<0.05) as early as day 2 after ISI, and this was maintained until day 21 (p<0.01). The cylinder test, which measures any asymmetrical usage of the forelimbs during postural support, was conducted before and at 1 and 3 weeks after ISI. Rats in the control group displayed more reliance on the ipsilateral limb, while those in both treatment groups showed a nearly normal pattern (p<0.05-0.01), after ISI. Delaying the initiation of minocycline treatment to 3 hr after ISI was as effective as starting treatment before ISI. All rats underwent MRI examination for brain perfusion 1 h after ISI, and T2-MRI 2 days and 21 days after ISI. The size of the ischemic lesion at 2 days was not different significantly between groups, nor was there a difference in blood flow in the lesion region of interest. The final volume of histological injury was correlated with MRI estimates of damage. The results showed that the neurobehavioral outcome was significantly improved with minocycline treatment after ISI, even though there was no marked difference in the size of the ischemic lesion, and that there appears to be a clinically useful window for minocycline treatment.