This report compares the effects of progesterone and its metabolite, allopregnanolone, on the early injury cascade (apoptosis) and long-term functional deficits after TBI. Progesterone (16 mg/kg) or allopregnanolone (4, 8, or 16 mg/kg) were injected at 1 h, 6 h, and then for 5 consecutive days after bilateral contusions of the frontal cortex in adult male rats. Within one day after injury, progesterone and allopregnanolone reduced both the expression of pro-apoptotic proteins caspase-3 and Bax, and apoptotic DNA fragmentation. Progesterone and allopregnanolone also reduced the size of glial fibrillary acid protein (GFAP)-positive astrocytes at the lesion site 24 h after injury. Compared to sham-operated controls at 19 days after injury, injured rats given either progesterone or any of three doses of allopregnanolone had equivalent numbers of ChAT-positive cells in the nucleus basalis magnocellularis. At 19 days post-injury, rats given progesterone or allopregnanolone (8 mg/kg) showed improved performance in a spatial learning task compared to injured rats given only the vehicle. These results provide evidence of the anti-apoptotic and anti-astrogliotic effects of progesterone and allopregnanolone and help to explain why better cognitive performance is observed after injury when animals are given either neurosteroid.

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Background and Purpose-Filamentous middle cerebral artery occlusion (fMCAO) is the most frequently used focal cerebral ischemia model in rodents. The proximity of the ophthalmic artery to the middle cerebral artery suggests that fMCAO induces retinal ischemia. We therefore tested whether fMCAO induces ischemia/reperfusion damage in retina in mice. Methods-SV129EV mice were subjected to transient (30 or 60 minutes) fMCAO followed by reperfusion under isoflurane anesthesia. Retinal perfusion was evaluated by intravenous injection of fluorescent microspheres combined with fluorescent microscopy using flat-mounted retinas. The fluorescent density of ipsilateral retina relative to contralateral retina was determined in each animal. Retinal injury was assessed by cresyl violet staining and in situ TUNEL. Results-Microsphere analysis demonstrated perfusion defect in the ipsilateral retina after 60 minutes fMCAO and effective restoration after reperfusion. Thirty minutes fMCAO did not produce evident histological changes, even after 2 days of reperfusion. Sixty minutes fMCAO followed by 2 hours reperfusion resulted in extensive cell damage in the inner nuclear (Ͼ30%) and ganglion cell (Ͼ50%) layers. TUNEL demonstrated very few positive cells, suggesting that damaged cells were mainly undergoing nonapoptotic cell death. Conclusions-Sixty minutes fMCAO produces retinal injury in SV129EV mice. Potential visual dysfunction should be considered when a particular occlusion period is selected for studying neurological outcomes after fMCAO. Because visual disturbance is often associated with thrombotic/embolic stroke in humans, fMCAO represents an appropriate model for future studies aimed at understanding and ameliorating the changes that lead to retinal damage in these patients.