DEXTROMETHORPHAN PROTECTS AGAINST CEREBRAL INJURY FOLLOWING TRANSIENT, BUT NOT PERMANENT, FOCAL ISCHEMIA IN RATS

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 tran sient (2 h) and permanent focal cerebral ischemia in the rat. Middle c erebral artery occlusion (MCAO) was produced in male Sprague-Dawley ra ts using the intraluminal filament technique. Animals were dosed s.c w ith 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 re perfusion. Following transient MCAO, vehicle treated rats exhibited a total infarct volume of 203 +/- 33 mm(3). DM produced a 61% reduction in infarct volume to 79 +/- 13 mm(3). Permanent MCAO produced a larger infarct volume (406 +/- 44 mm(3)) which was not significantly reduced in size by treatment with DM (313 +/- 58 mm(3)). Infarcted hemispheri c oedema was not different in vehicle treated rats following transient or permanent MCAO and was not reduced by DM in either group. Followin g transient MCAO, rectal temperature was elevated 1, 2 and 5 hours pos t 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 co rrelate with its ability to protect neurons in temperature regulating hypothalamic centres. The DM-induced reduction in infarction demonstra ted in our model of transient focal cerebral ischemia provides further support for the in vivo neuroprotective activity of this compound. Im portantly, these data demonstrate the limited neuroprotective efficacy of DM when attempting to combat more severe focal ischemic injuries a nd imply that drug-induced hypothermia is not ultimately responsible f or its protective action.