Attenuation of mitochondrial and nuclear p38α signaling: A novel mechanism of estrogen neuroprotection in cerebral ischemia

P38 mitogen-activated protein kinase (MAPK) is a pro-apoptotic and pro-inflammatory protein that is activated in response to cellular stress. While p38 is known to be activated in response to cerebral ischemia, the precise role of p38 and its isoforms in ischemia-induced neuronal apoptosis remains unclear. In the current study, we examined the differential activation and functional roles of p38 alpha and p38 beta MAPK isoforms in short-term ovariectomized female rats treated with either the neuroprotective ovarian hormone 17beta-estradiol (E2) or placebo in a model of global cerebral ischemia (GC). GCI induced biphasic activation of total p38 in the hippocampal CM, with peaks at 30 min and 1 day after 10-min ischemia-reperfusion. Further study demonstrated that activated p38 alpha, but not p38 beta, translocated to the nucleus 30 min and 3 h post reperfusion, and that this event coincided with increased phosphorylation of activating transcription factor 2 (ATF2), a p38 target protein. Intriguingly, activated p38 alpha was also enhanced in mitochondrial fractions of CA1 neurons 1 day after GCI, and there was loss of mitochondrial membrane potential, as well as enhanced cytochrome c release and caspase-3 cleavage at 2 days post GCI. Importantly, E2 prevented the biphasic activation of p38, as well as both nuclear and mitochondrial translocation of p38 alpha after GCI and these findings correlated with attenuation of mitochondrial dysfunction and delayed neuronal cell death in the hippocampal CM. Furthermore, administration of a p38 inhibitor was able to mimic the neuroprotective effects of E2 in the hippocampal CM region by preventing nuclear and mitochondrial translocation of p38 alpha, loss of mitochondrial membrane potential, and neuronal apoptosis. As a whole, this study suggests that changes in subcellular localization of the activated p38 alpha isoform are required for neuronal apoptosis following GCI, and that E2 exerts robust neuroprotection, in part, through dual inhibition of activation and subcellular trafficking of p38 alpha. Published by Elsevier Ireland Ltd.