Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats

Abstract

Dextromethorphan (DM) has been observed to afford neuroprotection in a variety of in vitro and in vivo experimental models of CNS injury. We have evaluated the neuroprotective activity of DM following both transient (2 h) and permanent focal cerebral ischemia in the rat. Middle cerebral artery occlusion (MCAO) was produced in male Sprague-Dawley rats using the intraluminal filament technique. Animals were dosed s.c with 20 mg/kg DM at 0.5, 1, 2, 4, and 6 hours post occlusion. Analysis of brain injury was performed 24 hours after permanent occlusion or reperfusion. Following transient MCAO, vehicle treated rats exhibited a total infarct volume of 203 +/- 33 mm3. DM produced a 61% reduction in infarct volume to 79 +/- 13 mm3. Permanent MCAO produced a larger infarct volume (406 +/- 44 mm3) which was not significantly reduced in size by treatment with DM (313 +/- 58 mm3). Infarcted hemispheric oedema was not different in vehicle treated rats following transient or permanent MCAO and was not reduced by DM in either group. Following transient MCAO, rectal temperature was elevated 1,2 and 5 hours post occlusion. While not inducing hypothermia or altering physiological parameters such as blood pressure and blood gases, DM attenuated this injury-related increase in temperature, an effect which appeared to correlate with its ability to protect neurons in temperature regulating hypothalamic centres. The DM-induced reduction in infarction demonstrated in our model of transient focal cerebral ischemia provides further support for the in vivo neuroprotective activity of this compound. Importantly, these data demonstrate the limited neuroprotective efficacy of DM when attempting to combat more severe focal ischemic injuries and imply that drug-induced hypothermia is not ultimately responsible for its protective action.