Inhibitors of phospholipase C prevent glutamate neurotoxicity in primary cultures of cerebellar neurons

The role of phospholipase C in the molecular mechanism of glutamate neuroto xicity was assessed in primary cultures of cerebellar neurons. It is shown that 1-[6-[[(17b)-3-methoxyestra- 1,3,5(10)-trien-17-yl]amino] hexyl]-1H-py rrole-2,5-dione (U-73122) and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosph orylcholine (Et-18-OCH3), two agents that inhibit phospholipase C, prevent glutamate and N-methyl-D-aspartic acid (NMDA) neurotoxicity. It is shown th at both compounds prevent glutamate neurotoxicity at concentrations lower t han those required to inhibit carbachol-induced hydrolysis of inositol phos pholipids. In contrast, it was a good correlation between the concentration s of U-73122 and Et-18-OCH3 required to inhibit NMDA-induced hydrolysis of phospholipids and those required to prevent glutamate and NMDA neurotoxicit y. NMDA-induced hydrolysis of phospholipids is inhibited by nitroarginine, an inhibitor of nitric-oxide synthase, and is mimicked by the nitric oxide- generating agent S-nitroso-N-acetylpenicillamine. The results reported indi cate that glutamate neurotoxicity would be mediated by activation of NMDA r eceptors, leading to activation of nitric-oxide synthase and increased form ation of nitric oxide, which results in increased activity of phospholipase C. Inhibition of phospholipase C by U-73122 or Et-18-OCH3 prevents glutama te-induced neuronal death.