Delayed progesterone treatment reduces brain infarction and improves functional outcomes after ischemic stroke: a time-window study in middle-aged rats

We evaluated the neuroprotective effects of delayed progesterone (PROG) treatment against ischemic stroke-induced neuronal death, inflammation, and functional deficits. We induced transient focal cerebral ischemia in male rats and administered PROG (8 mg/kg) or vehicle intraperitoneally at 3, 6, or 24 hours post occlusion, subcutaneously 5 hours later and then every 24 hours for 7 days. Behavioral outcomes were evaluated over 22 days. Infarct size and other biomarkers of injury were evaluated by cresyl violet staining, and matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP), and vascular endothelial growth factor (VEGF) by immunofluorescence. Progesterone treatment started at 3 and 6 hours post occlusion significantly (P<0.05) improved behavioral performance at all time points (74.01%) and reduced infarction volume (61.68%) compared with vehicle. No significant difference was observed between the 3 and 6 hour PROG treatment groups. Matrix metalloproteinase-9 and VEGF were upregulated in the PROG groups compared with vehicle. Glial fibrillary acidic protein expression was increased in the vehicle group but markedly lower in the PROG groups. Treatment delayed for 24 hours did not significantly improve functional outcomes or reduce infarction volume. We conclude that, under the right treatment conditions, PROG treatment delayed up to 6 hours can improve functional deficits and reduce brain infarction, possibly by modulating GFAP, VEGF, and MMP-9 expression.