Drug-induced Hypothermia by 5HT1A Agonists Provide Neuroprotection in Experimental Stroke: New Perspectives for Acute Patient Treatment

Abstract

Drug-induced hypothermia reduces brain damage in animal stroke models and is an undiscovered potential in human stroke treatment. We studied hypothermia induced by the serotonergic agonists S14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine) and ipsapirone in a rat stroke model and in man by literature meta-analysis. Rats had 60 minutes of middle cerebral artery occlusion (MCAO) and then 7 days of survival. Body temperatures were monitored for 22 hours. Thirty minutes after MCAO, 1 group (n = 9) received bolus of S14671 (.75 mg/kg) and continuous infusion of .06 mg/kg hour(-1) S14671 for 20 hours. Other MCAO rats (n = 7) had bolus of ipsapirone (.75 mg/kg) and continuous infusion of .25 mg/kg hour(-1) ipsapirone for 3 hours. Controls (n = 9; n = 5) received similar amounts of vehicle as bolus and continuous infusion for 20 hours/3 hours. Additional controls of the S14761 effect in MCAO were performed as previously mentioned (n = 10) but with rats kept normothermic by a heating lamp for 22 hours. Finally, a meta-analysis of ipsapirone-induced hypothermia in man was included. Infarct volumes were reduced by 50% in hypothermic rats versus controls (P < .05). S14671 rats kept normothermic did not show infarct reduction (P > .05). The body temperature after stroke was reduced 1.0-3.0°C compared with controls for 20 hours with S14671 treatment and for 6 hours with ipsapirone treatment. In humans, ipsapirone reduced temperature in average with .55 °C ranging between .1-1.4 °C. 5-hydroxytryptamine receptor 1A (5HT(1A)) agonists significantly reduce infarct volumes in MCAO rats primarily because of the hypothermic drug effect. 5HT(1A) agonists may be introduced to reduce body temperatures rapidly and prepare patients for further therapeutic hypothermia.