Abstract
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.
Highlights
Ischemic stroke is one of the major causes of death and disability worldwide, hitherto, tissue plasminogen activator is the only effective drug for ischemic stroke patients but has a relatively narrow therapeutic time window of 4.5 h [1]
Downregulation of inhibitor of an apoptosisstimulating protein of p53 (iASPP) by small interfering RNA aggravated focal cerebral ischemia injury in middle cerebral artery occlusion (MCAO) mice treated with mild therapeutic hypothermia or normothermia, proposing iASPP as a potential therapeutic target for ischemic stroke
To detect whether hypothermia affects the expression of iASPP and its targets related to apoptosis in vitro, primary cortical neurons were treated with oxygen–glucose deprivation/reperfusion (OGD/R) and mild therapeutic hypothermia (33°C) or normothermia (37°C)
Summary
Ischemic stroke is one of the major causes of death and disability worldwide, hitherto, tissue plasminogen activator is the only effective drug for ischemic stroke patients but has a relatively narrow therapeutic time window of 4.5 h [1]. Mild therapeutic hypothermia (32°C-35°C) has been recognized as an effective neuroprotectant in experimental stroke models as well as patients with stroke and extends the therapeutic window for other neuroprotectants [2,3,4,5,6] Multiple mechanisms, such as inhibition of apoptosis, necrosis and inflammatory response, are involved in neuroprotection of mild therapeutic hypothermia after cerebral ischemia [5,6,7]. Downregulation of iASPP by small interfering RNA (siRNA) aggravated focal cerebral ischemia injury in MCAO mice treated with mild therapeutic hypothermia or normothermia, proposing iASPP as a potential therapeutic target for ischemic stroke. After an hour of OGD, the glucose-free Dulbecco's Modified Eagle Medium was displaced by the original culture media and neurons were returned to normal cultured conditions for 24 h
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