title: Attenuation of mitochondrial and nuclear p38α signaling: a novel mechanism of estrogen neuroprotection in cerebral ischemia.
abstract: 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.
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Scott
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Limor
authors.initials: L
authors.lastname: Raz
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, USA; Neurobiology Institute of Medical Research Centre, Hebei United University, Tangshan, Hebei 06300, China.
authors.forename: Ruimin
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, USA. Electronic address: qzhang@gru.edu.
authors.forename: Quanguang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048290:Mitogen-Activated Protein Kinase 11 / Q000235:genetics / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010052:Ovariectomy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D004958:Estradiol; D045304:Cytochromes c; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; D053148:Caspase 3
keywords: Apoptosis; Estrogen; Global cerebral ischemia; Neuroprotection; p38