title: Forebrain neuronal specific ablation of p53 gene provides protection in a cortical ischemic stroke model.
abstract: Cerebral ischemic injury involves death of multiple cell types at the ischemic sites. As a key regulator of cell death, the p53 gene has been implicated in the regulation of cell loss in stroke. Less focal damage is found in stroke animals pre-treated with a p53 inhibitor or in traditional p53 knockout (ko) mice. However, whether the p53 gene plays a direct role in regulating neuronal cell death is unknown. In this study, in contrast to the global inhibition of p53 function by pharmacological inhibitors and in traditional p53 ko mice, we utilized a neuronal specific conditional ko mouse line (CamcreTRP53(loxP/loxP)) to achieve forebrain neuronal specific deletion of p53 and examined the role of the p53 gene in ischemia-induced cell death in neurons. Expression of p53 after stroke is examined using the immunohistochemical method and the outcome of stroke is examined by analysis of infarction size and behavioral deficits caused by stroke. Our data showed that p53 expression is upregulated in the ischemic region in neuronal cells in wildtype (wt) mice but not in CamcreTRP53(loxP/loxP) ko mice. Deletion of the p53 gene in forebrain neurons results in a decreased infarction area in ko mice. Locomotor behavior, measured in automated activity chambers, showed that CamcreTRP53(loxP/loxP) ko mice have less locomotor deficits compared to wt mice after middle cerebral artery occlusion (MCAo). We conclude that manipulation of p53 expression in neurons may lead to unique therapeutic development in stroke.
authors.affiliation: Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA.
authors.forename: E
authors.initials: E
authors.lastname: Filichia
authors.affiliation: National Institute of Drug Abuse, Baltimore, USA.
authors.forename: H
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Case Western Reserve University, Cleveland, USA.
authors.forename: X
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA.
authors.forename: K
authors.initials: K
authors.lastname: Jin
authors.affiliation: National Institute of Aging, Baltimore, USA.
authors.forename: N
authors.initials: N
authors.lastname: Greig
authors.affiliation: Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA.
authors.forename: B
authors.initials: B
authors.lastname: Hoffer
authors.affiliation: Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA. Electronic address: yxl710@case.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000150:complications; D002135:Calcium-Binding Proteins; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008124:Locomotion / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D016548:Prosencephalon / Q000473:pathology*; D020521:Stroke / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D016159:Tumor Suppressor Protein p53; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse; D010751:Phosphopyruvate Hydratase
keywords: conditional p53 knockout; neuroprotection; stroke