Abstract: The present study is to assess the prophylactic effect of quinacrine (QA), an anti-malarial drug, against heatstroke in rats. Conscious rats were orally given equal volume normal saline or QA (dissolved in normal saline and final dosage for rats was 4.5, 9.0 and 18 mg·kg^-1). An hour later rats were put into a warm water circulated hot chamber (41.0±0.5) ℃. Rectal temperature (core temperature, T_co) of rats in hot chamber was continuously monitored by a thermocouple. T_co and survival time of rats showed that QA pre-treatment postponed the hyperthermia, and increased the survival time of rats in hot chamber. Primary striatum neurons’ culture from new born rats was maintained with D-MEM and 10% FBS. After immuno-cytochemistry identification with antibodies against neural specific proteins, culture received 20 μmol·L^-1 QA only for 1 h and followed by 43.0 ℃ heat treatment for another hour, or 20 μmol·L^-1 QA for 1 h followed by 43.0 ℃ heat treatment for another hour. Control culture received heat treatment only. Cultures were labeled with the fluorescent indicator DPH and the relative membrane fluidity of neurons was measured with the help of fluorescent polarized spectrophotometer. ［³H］ Arachidonic acid (AA) labeled membrane of E.Coli cells was used as substrate to determine cPLA₂ activity of neurons. Gas chromatography and mass spectrum were also employed to detect on the level of fatty acids level in rat striatum neurons. Results from cells indicated that inhibition of cPLA₂, reduction the release of active fatty acids such as AA, and possibly, stabilization of the cell membrane which was disturbed by hot treatment, may contribute to the mechanism underlying heat protection and heatstroke preventive effects of quinacrine.