THE DESGLYCINYL METABOLITE OF REMACEMIDE HYDROCHLORIDE IS NEUROPROTECTIVE IN CULTURED RAT CORTICAL-NEURONS

The neuroprotective actions of remacemide and its anticonvulsant metab olite 1,2-diphenyl-2-propylamine monohydrochloride (desglycinylremacem ide; DGR), a low-affinity NMDA receptor antagonist, were investigated using primary rat cortical neuronal cultures. Exposure of cortical cul tures to NMDA (100 mu M) for 15 min killed 85% of the neurons during t he next 24 h. This neurotoxicity was blocked in a concentration-depend ent manner by adding DGR (5-20 mu M), but not its remacemide precursor (10-100 mu M), to the cultures during the time of NMDA exposure. This suggests that the neuroprotective, as well as the anticonvulsant, acti vity of remacemide is mediated by DGR. Neuroprotective concentrations of DGR also inhibited two of the principal acute effects of NMDA. DGR (5-20 mu M) prevented the loss of membrane-associated protein kinase C (PKC) activity that developed by 4 h after transient exposure to 100 mu M NMDA and reduced the NMDA-triggered increases in intracellular fr ee Ca2+ concentration ([Ca2+](i)) by up to 70%. By contrast, remacemid e (50 and 100 mu M) did not prevent the NMDA-induced loss of PKC activ ity or reduce the [Ca2+](i) responses. These data suggest that DGR pro tection against NMDA-mediated toxicity in cultured cortical neurons is associated with a reduction of NMDA-triggered [Ca2+](i) surges and a prevention of the loss of membrane-associated PKC activity. In additio n, the inhibition of NMDA-triggered [Ca2+](i) responses by DGR was qua litatively different from the inhibition of these responses by the hig h-affinity NMDA-receptor antagonists MK-801 and phencyclidine. This ma y be a consequence of DGR's lower affinity for the NMDA receptor.