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Background and Purpose: Previous studies have demonstrated depressive or hibernation-like roles of phenothiazine neuroleptics [combined chlorpromazine and promethazine (C+P)] in brain activity. This ischemic stroke study aimed to establish neuroprotection by reducing oxidative stress and improving brain metabolism through post-ischemic C+P administration.Methods: Sprague-Dawley rats (n=272) were subjected to transient (2 or 4 h) middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion, or permanent (28 h) MCAO without reperfusion. At 2 h after ischemic onset, rats received either an intraperitoneal (IP) injection of saline or two doses of C+P. Body temperatures, brain infarct volumes, and neurological deficits were examined. Oxidative metabolism and stress were determined by levels of ATP, NADH, and reactive oxygen species (ROS). Protein kinase C-δ (PKC-δ) and Akt expression were determined by Western blotting.Results: In both transient and permanent ischemia models, C+P administration significantly induced a dose-dependent reduction in body temperature and neuroprotection within as early as 5 min and lasting up to 12 h. Body temperature reduction either only slightly or did not enhance C+P-induced neuroprotection, as determined by infarct volumes and neurological deficits post-stroke. C+P therapy improved brain metabolism as determined by increased ATP levels and NADH activity, as well as diminished ROS production. These therapeutic effects were associated with alterations in PKC-δ and Akt protein expression.Conclusions: C+P treatments conferred neuroprotection in severe stroke models by suppressing the damaging cascade of metabolic events, most likely independent of drug-induced hypothermia. These findings may direct us towards the development of an efficacious, practical, and accessible neuroprotective therapy in stroke patients.