Open AccessMild Therapeutic Hypothermia Protects the Brain from Ischemia/Reperfusion Injury through Upregulation of iASPP
Author(s) -
Xiangrong Liu,
Shaohong Wen,
Shunying Zhao,
Feng Yan,
Shichao Zhao,
Di Wu,
Xunming Ji
Publication year - 2018
Publication title -
aging and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.808
H-Index - 54
ISSN - 2152-5250
DOI - 10.14336/ad.2017.0703
Subject(s) - hypothermia , medicine , apoptosis , ischemia , pharmacology , downregulation and upregulation , puma , neuroprotection , stroke (engine) , brain ischemia , small interfering rna , reperfusion injury , anesthesia , transfection , biology , cell culture , biochemistry , mechanical engineering , genetics , gene , engineering
Mild therapeutic hypothermia, a robust neuroprotectant, reduces neuronal apoptosis, but the precise mechanism is not well understood. Our previous study showed that a novel inhibitor of an apoptosis-stimulating protein of p53 (iASPP) might be involved in neuronal death after stroke. The aim of this study was to confirm the role of iASPP after stroke treated with mild therapeutic hypothermia. To address this, we mimicked ischemia/reperfusion injury in vitro by using oxygen-glucose deprivation/reperfusion (OGD/R) in primary rat neurons. In our in vivo approach, we induced middle cerebral artery occlusion (MCAO) for 60 min in C57/B6 mice. From the beginning of ischemia, focal mild hypothermia was applied for two hours. To evaluate the role of iASPP, small interfering RNA (siRNA) was injected intracerebroventricularly. Our results showed that mild therapeutic hypothermia increased the expression of iASPP and decreased the expression of its targets, Puma and Bax, and an apoptosis marker, cleaved caspase-3, in primary neurons under OGD/R. Increased iASPP expression and decreased ASPP1/2 expression were observed under hypothermia treatment in MCAO mice. iASPP siRNA (iASPPi) or hypothermia plus iASPPi application increased infarct volume, apoptosis and aggravated the neurological deficits in MCAO mice. Furthermore, iASPPi downregulated iASPP expression, and upregulated the expression of proapoptotic effectors, Puma, Bax and cleaved caspase-3, in mice after stroke treated with mild therapeutic hypothermia. In conclusion, mild therapeutic hypothermia protects against ischemia/reperfusion brain injury in mice by upregulating iASPP and thus attenuating apoptosis. iASPP may be a potential target in the therapy of stroke.