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Introduction: Hibernation, in which the lowering of metabolism and body temperature reduces the energetic needs of brain cells, has emerged as a frontier in the search for neuroprotective agents against ischemia. In fact, it has been partially achieved clinically with therapeutic hypothermia. Metabolically slowed, hibernation-like states lead to a decrease in ischemic damage and improved neurologic outcomes. However, decreasing body temperature can cause serious systemic complications. Thus, finding ways to induce a hibernation-like drop in metabolism without also inducing hypothermia is clinically important. It was shown that pharmacological hibernation with Chlorpromazine and Promethazine (C+P) resulted in decreased brain activity and decreased body temperature. Here, by isolating these two effects, and by investigating effects on NADPH oxidase (NOX), the key component in the pathway most central to oxidative injury during ischemia, we sought to determine whether the neuroprotective effect of C+P is dependent or independent from its effect on body temperature.Methods: Sprague-Dawley rats were subjected to 2h MCAO, and 6 or 24 h reperfusion, upon which rats received an IP injection of saline or C+P (8 mg/kg). Temperature was maintained at 37°C, or allowed to spontaneously change. Infarct volumes and neurological deficits were examined. Oxidative stress was determined by levels of ATP, lactate, NADH and reactive oxygen species (ROS). NOX activity and expression of NOX subunits (p47phox, gp91phox, p22phox and p67phox) were measured at 6 and 24 h reperfusion.Results: In 2 h MCAO rats, body temperatures were significantly reduced by 10C after C+P within 5 min. At 2 h, body temperatures reached 340C and remained significantly low for up to 6 h. Following 6 and 24 h of reperfusion, C+P decreased infarct volume, neurological deficit, lactate and ROS levels, but increased ATP and NADH. NOX activity and subunit expressions were down-regulated. C+P-induced neuroprotection was not affected by maintaining temperature at 370C.Conclusion: C+P administration provided neuroprotection in ischemic stroke independently of reductions in body temperature. Our results suggest temperature reduction may be a result of metabolic depression, rather than a cause.