Neuronal protection of progesterone against ischemic brain injury and underlying molecular mechanisms

Objective To investigate the effect of progesterone pretreatment of focal cerebral ischemic and reperfusion injury (fCIRI) and underlying molecular mechanisms. Methods A single intraperitoneal injection of progesterone (8 mg/kg) given 1 h，48 h and 96 h before fCIRI was established in male Sprague-Dawley rats.The number of survival of neurons in hippocampal CA1region of the ischemia-side，as well as spatial memory function，was detected on days 3-8 after fCIRI.Extracellular-signal-regulated kinase 1/2 phosphorylation (p-ERK1/2) and nuclear translocation of p-ERK1/2 in hippocampal CA1region were examined using western blot. Results The number of survival of neuronal cells was significantly increased in ischemic groups treated with progesterone at 1 h and 48 h pre-fCIRI (164.3±11.0，218.5±9.1 and 142.7±12.1，F=29.4，P<0.01) compared with fCIRI group treated with vehicle.Likewise，the escape-latency to reach the hidden-platform recorded in day 5 of Morris water maze test was reduced markedly in fCIRI-treatment groups compared with the vehicle group (10.3±11.1，19.2±9.6 and 32.4±14.3; F=35.8，P<0.01).The level of p-ERK1/2 was elevated notably during 24 h to 48 h post-progesterone by western blot，while restored to the baseline at 96 h post-progesterone.Improved nuclear translocation of p-ERK1/2 was observed from 2 h to 48 h post-progesterone.The progesterone receptor antagonist RU486 blocked the exaltation of either intracellular level or nuclear translocation of p-ERK1/2，which was induced by progesterone. Conclusions The pretreatment with progesterone exerts a neuroprotective effect against the ischemia-induced neuronal death and ameliorates the deficits in spatial memory through enhancing the activation of ERK1/2. The neuroprotection derived from pretreatment with progesterone achieves a time window of not less than 48 h，which is progesterone receptor-mediated ERK1/2 signaling pathway-dependent. Key words: Progesterone; Brain ischemia; Reperfusion injury; Extracellular signalregulated MAP kinases