Date Published: June 1, 2018
Publisher: JKL International LLC
Author(s): Xiangrong Liu, Shaohong Wen, Shunying Zhao, Feng Yan, Shangfeng Zhao, Di Wu, Xunming Ji.
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.
To our knowledge, this is the first study to describe the beneficial effect of iASPP after stroke, especially if applied with mild hypothermia. In this study, we demonstrated several findings relevant to therapeutic hypothermia. First, mild hypothermia upregulated the expression of iASPP and downregulated its targets in primary neurons under OGD/R. Second, downregulation of iASPP after stroke or stroke plus therapeutic hypothermia increased infarct volume and cell death, and aggravated neurological deficits in MCAO mice. Third, downregulation of iASPP increased the expression of its targets and apoptosis in mice after stroke.