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Introduction: Hypothermia is an effective neuroprotectant against stroke, but its application is limited by delayed onset, prolonged duration, and significant complications. Mild hypothermia is more clinically practical but offers weaker neuroprotection. This study investigated whether the neuroprotective effects of mild hypothermia can be enhanced by phenothiazine neuroleptics (chlorpromazine and promethazine), which were reported to have depressive or hibernation-like roles on the CNS. We also worked to elucidate the role of the PI3K/Akt signaling pathway in this protective mechanism.Methods: A total of 131 adult male Sprague-Dawley rats were randomly divided into 6 groups: sham, stroke without treatment (2-hour right middle cerebral artery occlusion), and 4 treatment groups with 1) mild hypothermia (anal temperature 33-350C), 2) phenothiazines (1mg/kg chlorpromazine & 1mg/kg promethazine, anal temperature 37.8-38.30C), 3) combination of mild hypothermia and phenothiazines, and 4) both therapies with the addition of a p-Akt antagonist (LY294002 was injected into the lateral ventricle 30 minutes before ischemia). Infarct volume, neurological deficit, and apoptotic cell death were determined 24h post reperfusion. Expression of p-Akt, cleaved Caspase-3, pro-apoptotic (AIF & Bax) and anti-apoptotic proteins (Bcl-2 & Bcl-xL) was assessed by Western blot at 6h and 24h after reperfusion.Results: The combination of hypothermia and phenothiazines decreased (P<0.01) infarct volume and neurological deficit. This change was associated with a reduction (P<0.01) of apoptotic cell death. Each treatment alone did not induce significant neuroprotection. The combination therapy, but not each alone, promoted (P<0.01) the expression of p-Akt, accompanied with increased expression of anti-apoptotic proteins and decreased expression of pro-apoptotic proteins. The neuroprotective effects were blocked by p-Akt inhibition.Conclusion: Mild hypothermia-induced neuroprotection was enhanced by phenothiazines in an experimental ischemia/reperfusion injury model. This study supports the involvement of the PI3K/Akt signaling pathway. This novel therapeutic strategy could be developed as an effective treatment for acute ischemic stroke.