Nicergoline enhances glutamate re-uptake and protects against brain damagein rat global brain ischemia

Whereas a 2-3 degrees C decrease in intraischemic brain temperature can be neuroprotective, mild brain hyperthermia significantly worsens outcome. Our previous study suggested that an ischemic injury mechanism which is sensit ive to temperature may not actually increase the extracellular glutamate co ncentration ([Glu](e)) during the intraischemic period, but rather impairs the Glu re-uptake system, which has been suggested to be involved in the re versed uptake of Glu. We speculated that enhancing Glu re-uptake, pharmacol ogically or hypothermically, may shorten exposure to high [Glu](e) in the p ostischemic period and thereby decrease its deleterious excitotoxic effect on neuronal cells. In the present study, rats treated with nicergoline (32 mg/kg, i.p.), an ergot alkaloid derivative, showed minimal inhibition of th e [Glu](e) elevation which characteristically occurs during the 10-min intr aischemic period, while Glu re-uptake was dramatically improved in the post ischemic period, when severe transient global ischemia was caused by mild h yperthermia. Moreover, the nicergoline (32 mg/kg, i.p.) treated rats showed reduced cell death morphologically and clearly had a far lower mortality. The present study suggests that the development of therapeutic strategies a imed at inhibition or prevention of the reversed uptake of glutamate releas e during ischemia, i.e., activation of the glutamate uptake mechanism, is a promising approach to reduce neural damage occurring in response to brain ischemia. (C) 1999 Elsevier Science B.V. All rights reserved.