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Enhanced beneficial effects of mild hypothermia by phenothiazine drugs in stroke therapy

Abstract Objectives: Hypothermia is a well-recognised and effective neuroprotectant because of its depressive effect on metabolism. However, its application in focal ischaemic stroke is limited by delayed onset, prolonged duration, the need for extensive medical and nursing efforts and significant complications. This study combined mild hypothermia with phenothiazine drugs to enhance its neuroprotective effects, thus potentially avoiding side effects. Methods: Fifty-four male Sprague-Dawley rats were induced with a 2-hour right middle cerebral artery (MCA) occlusion using an intraluminal filament. Five groups were tested: the stroke group without treatment (anal temperature 37.8–38.3°C), the mild hypothermia group (anal temperature 35.0°C), the drugs group (1 mg/kg chlorpromazine and 1 mg/kg promethazine, anal temperature at 37.8–38.3°C), combination therapy with the mild hypothermia and drugs group and the normal control group (anal temperature 37.8–38.3°C). The treatments immediately followed reperfusion. The extent of brain injury was evaluated by infarct volume and behaviour performance. Results: The combination treatment of mild hypothermia with phenothiazine drugs demonstrated salient and significant (P < 0.001) reductions in infarct volume (30.0 ± 15.14%) when compared to the stroke group (52.77 ± 8.99%). A better recovery of long-term motor performance was also observed for those receiving the combination therapy. However, when administered independently, neither the mild hypothermia therapy (53.8 ± 10.3%) nor phenothiazine regimen (55.7 ± 9.00%) had significant therapeutic effects on infarct volume (P = 0.85 and 0.61, respectively). Discussion: This study provides a novel and promising therapeutic strategy in the management of acute stroke.