Bis(7)-tacrine protects retinal ganglion cells against excitotoxicity via NMDA receptor inhibition

·AIM:To investigate whether bis(7)-tacrine,a multifun-ctional drug,inhibits N-methyl-D-aspartate (NMDA)-activated current in retinal ganglion cells(RGC) and provides neuroprotection against retinal cell damage.·METHODS:Purified RGC cultures were obtained from retinas of 1-3 days old Sprague-Dawley(SD) rats,following a two-step immunopanning procedure.After 7 days of cultivation,the inhibition of NMDA-activated current by bis(7)-tacrine was measured by using patch-clamp recording techniques.In animal experiments,RGCs were damaged after intravitreal injection of NMDA (5|ìL,40nmol) in adult rats.Bis(7)-tacrine(0.05,0.1,0.2mg/kg) or memantine(20mg/kg) was intraperitoneal administered to the rats fifteenminutes before intravitreally injection of NMDA.RGC damage was analyzed by histologic techniques,TUNEL and retrograde labeling techniques.·RESULTS:Whole-cell patch-clamp recordings demonstrated that NMDA (30|ìmol/L) resulted in approximately-50 pA inward currents that were blocked by bis(7)-tacrine(1|ìmol/L).Histological examination and retrograde labeling analysis revealed that bis(7)-tacrine induced a significant neuroprotective effect against NMDA-induced cell damage 7 days after NMDA injection.TUNEL staining showed that pretreatment with bis(7)-tacrine was effective in ameliorating NMDA-induced apoptotic cell loss in the retinal ganglion cell layer 18 hours after injection.·CONCLUSION:Bis(7)-tacrine possesses remarkable neur-oprotective activities against retinal excitotoxicity through inhibition of NMDA receptors.·