Cannabinoids are a structurally diverse group of mostly lipophilic molecules that bind to cannabinoid receptor. In fact, endocannabinoids are a class of signaling lipids that are synthesized from lipid precursors in plasma membranes via calcium ions or G- protein- dependent processes and exhibit cannabinoid-like actions by binding to cannabinoid receptors. Following exposure PC12 cells to Paraoxon (200 μM), a marked reduction in cell survival was observed (P<0.001). Treatment of the cells with WIN 55,212-2 (0.1 μM) NMDA (100μM) prior to Paraoxon exposure significantly elevated cell survival (P<0.0001). Also, the cannabinoid antagonist (AM 251) did not inhibit the neuroprotection induced by WIN 55,212-2 (P<0.05). But, NMDA receptor antagonist (MK801) did inhibite neuroprotection induced by NMDA (P<0.001). These results indicate that WIN 55,212-2 and NMDA protect PC12 cells on paraoxon induced toxicity.In addition, the neuroprotective effect of WIN 55,212-2 and NMDA was cannabinoid receptor-independent and NMDA receptor dependent.