Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion

Study objective: We compare the effects of postinjury administration of allopregnanolone, a metabolite of progesterone, to progesterone in an animal model of transient middle cerebral artery occlusion. Methods: Focal cerebral ischemia was induced in age-matched, adult, male, Sprague-Dawley rats by using an intraluminal filament and suture method to occlude the right middle cerebral artery. After 120 minutes of middle cerebral artery occlusion, the occluding filament was withdrawn to allow reperfusion. Laser-Doppler flowmetry was used to monitor cerebral blood flow for the entire 2-hour period of occlusion and for 5 minutes after reperfusion. Animals subjected to middle cerebral artery occlusion received injections of allopregnanolone (8 mg/kg, n=6), progesterone (8 mg/kg, n=6) and vehicle (2-hydroxypropyl-beta-cyclodextrin, n=7) at 2 hours (intraperitoneally 5 minutes before reperfusion) and 6 hours (subcutaneously) postocclusion. Brains were removed at 72 hours post-middle cerebral artery occlusion, sectioned into coronal slices, and stained with 2,3,5-triphenyltetrazolium chloride (TTC). In a blinded analysis, infarct volume was calculated by using computer-aided morphometry to measure brain areas not stained with TTC. Results: After progesterone or allopregnanolone treatment, stained sections revealed a significant reduction in cortical, caudate-putamen, and hemispheric infarct volumes (percentage of contralateral structure) compared with vehicle-injected controls. Cortical infarction (percentage of contralateral cortex) was 37.47%+/- 10.57% (vehicle), 25.49%+/- 7.38% (progesterone; P <.05 from vehicle), and 11.40%+/- 7.09% (allopregnanolone; P <.05 from vehicle; P <.05 from progesterone). Caudate-putamen infarction (percentage of contralateral caudate-putamen) was 78.02%+/- 22.81% (vehicle), 48.41%+/- 22.44% (progesterone; P <.05 from vehicle), and 50.44%+/- 10.90% (allopregnanolone; P <.05 from vehicle). Total hemispheric infarction (percentage of contralateral hemisphere) was 24.37%+/- 6.69% (vehicle), 15.95%+/- 3.59% (progesterone; P <.05 from vehicle), and 11.54%+/- 3.71% (allopregnanolone; P <.05 from vehicle). No significant differences in cerebral blood flow between groups and time points during ischemia and early reperfusion were observed, suggesting that the relative ischemic insult was equivalent among all groups. Conclusion: Although progesterone and allopregnanolone are effective in reducing infarct pathology, allopregnanolone is more potent than progesterone in attenuating cortical damage. Our results suggest that both neurosteroids should be examined for safety and efficacy in a clinical trial for ischemic stroke.