Time-Window of Progesterone Neuroprotection After Stroke and Its Underlying Molecular Mechanisms

Evidence exists for a gender difference in the vulnerability to either stroke or traumatic brain injury (TBI) in humans. For example, pre-menopausal women with the high serum levels of ovarian hormones estrogen (E2) and progesterone (P4) have a lower risk of stroke (Kannel et al., 1994; Sacco et al., 1997) and a better outcome following stroke (Thorvaldsen et al., 1995) or TBI (Groswasser et al., 1998) relative to men of the same age. After menopause, incidence of stroke in women increases abruptly (Wenger et al., 1993) coincident with decreases in the circulating levels of the ovarian steroid hormones, estrogen (E2) and progesterone (P4). Although clinical trial for TBI with P4 treatment has been well tolerated and giving improved outcomes (Wright et al., 2007; Stein et al., 2008), clinical trial with P4 treatment after cerebral stroke has yet to be initiated. There is increasing evidence that P4 exerts a potent neuroprotective effect against ischemia-induced brain injury in experimental models (Chen et al., 1999; Kumon et al., 2000; Morali et al., 2005; Sayeed et al., 2006) when administered either before insult or after the onset of reperfusion (Murphy et al., 2002; Sayeed et al., 2007). Furthermore, the administration of P4 promotes functional recovery after cerebral ischemia (Gibson & Murphy, 2004; Sayeed et al., 2007). Important enough, a single injection of P4 (4 mg/kg) conducted even 2 h after transient focal brain ischemia reduced cortical infarct volumes (Jiang et al., 1996). Our recent study (Cai et al., 2008) has demonstrated that in male rats a single injection of P4 (4 mg/kg) at 1 h or 48 h prior to an experimental stroke shows protective effects against the ischemia-induced neuronal death and the deficits in spatial cognition and LTP induction. However, to date no systematic study has conducted concerning the effects of P4 against brain injury beyond 6 h following the onset of ischemia (Gibson et al., 2008). Therefore, the present study focused on the effective time-window of neuroprotection by P4 treatment, which would give useful information in treating stroke. Effects of P4 on the brain generally involve three principle mechanisms, including regulation of gene expression, activation of intracellular signal cascades and modulation of