title: p53 inhibition provides a pivotal protective effect against ischemia-reperfusion injury in vitro via mTOR signaling.
abstract: Tumor suppressor p53 has recently been reported to have numerous functions independent of tumorigenesis, including neuronal survival during ischemia. The mammalian target of rapamycin (mTOR) signaling pathway plays a central role in the regulation of metabolism, cell growth, development, and cell survival. Our recent work has demonstrated the neuroprotective effects of the mTOR pathway. Considering that p53 is also an important regulator of mTOR, to further clarify the role of p53 and the mTOR signaling pathway in neuronal ischemic-reperfusion injury, we used mouse primary mixed cultured neurons with an oxygen glucose deprivation (OGD) model to mimic an ischemic-reperfusion injury in vitro. A lentiviral system was also used to inhibit or overexpress p53 to determine whether p53 alteration affects OGD and reperfusion injury. Our results show that activated p53 was induced and it suppressed mTOR expression in primary mixed cultured neurons after OGD and reperfusion. Inhibiting p53, using either a chemical inhibitor or lentiviral-mediated shRNA, exhibited neuroprotective effects in primary cultured neurons against OGD and reperfusion injury through the upregulation of mTOR activity. Such protective effects could be reversed by rapamycin, an mTOR inhibitor. Conversely, p53 overexpression tended to exacerbate the detrimental effects of OGD injury by downregulating mTOR activity. These results suggest that p53 inhibition has a pivotal protective effect against an in vitro ischemia-reperfusion injury via mTOR signaling and provides a potential and promising therapeutic target for stroke treatment.
authors: Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors: Xiaomu
authors: X
authors: Li
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors: Shixin
authors: S
authors: Gu
authors: Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors: Yan
authors: Y
authors: Ling
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors: Chao
authors: C
authors: Shen
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors: Xiaoyun
authors: X
authors: Cao
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China. Electronic address: xierong3034@126.com.
authors: Rong
authors: R
authors: Xie
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D018696:Neuroprotective Agents; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Ischemic reperfusion injury; OGD; mTOR; p53