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 p38α and p38β 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 (GCI). GCI induced biphasic activation of total p38 in the hippocampal CA1, with peaks at 30 min and 1 day after 10-min
ischemia-reperfusion. Further study demonstrated that activated p38α, but not p38β, 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 p38α 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 p38α after GCI, and these findings correlated with attenuation of
mitochondrial dysfunction and delayed neuronal cell death in the hippocampal CA1. Furthermore, administration of a p38 inhibitor was able to mimic the
neuroprotective effects of E2 in the hippocampal CA1 region by preventing nuclear and mitochondrial translocation of p38α, loss of mitochondrial membrane potential, and neuronal apoptosis. As a whole, this study suggests that changes in subcellular localization of the activated p38α
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 p38α.