The study by Dawson et al. investigates the role of nitric oxide (NO) in mediating glutamate neurotoxicity in primary cortical cultures. NO, initially identified as an endothelium-derived relaxing factor, is also a key neuronal messenger. The researchers found that nitric oxide synthase (NOS) inhibitors, such as Nω-methyl-L-arginine (N-Arg) and Nω-monomethyl-L-arginine (Me-Arg), prevent neurotoxicity induced by N-methyl-D-aspartate (NMDA) and other excitatory amino acids. This effect is reversed by L-arginine, suggesting a competitive mechanism. Depletion of arginine in the culture medium or treatment with arginase also reduces NMDA toxicity. Sodium nitroprusside, which releases NO, causes dose-dependent cell death, and this effect is blocked by reduced hemoglobin, which binds NO. These findings establish that NO plays a crucial role in glutamate neurotoxicity, potentially through the formation of cGMP and the generation of reactive oxygen species. The study highlights the therapeutic potential of centrally selective NOS inhibitors in conditions involving glutamate-mediated neurotoxicity.The study by Dawson et al. investigates the role of nitric oxide (NO) in mediating glutamate neurotoxicity in primary cortical cultures. NO, initially identified as an endothelium-derived relaxing factor, is also a key neuronal messenger. The researchers found that nitric oxide synthase (NOS) inhibitors, such as Nω-methyl-L-arginine (N-Arg) and Nω-monomethyl-L-arginine (Me-Arg), prevent neurotoxicity induced by N-methyl-D-aspartate (NMDA) and other excitatory amino acids. This effect is reversed by L-arginine, suggesting a competitive mechanism. Depletion of arginine in the culture medium or treatment with arginase also reduces NMDA toxicity. Sodium nitroprusside, which releases NO, causes dose-dependent cell death, and this effect is blocked by reduced hemoglobin, which binds NO. These findings establish that NO plays a crucial role in glutamate neurotoxicity, potentially through the formation of cGMP and the generation of reactive oxygen species. The study highlights the therapeutic potential of centrally selective NOS inhibitors in conditions involving glutamate-mediated neurotoxicity.