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In this study, we analyzed the mechanism of selective motor neuronal death, a characteristic of amyotrophic lateral sclerosis, using embryonic rat spinal cord culture. When dissociated cultures were exposed to low‐level glutamate (Glu) coadministered with the Glu transporter inhibitor L‐trans‐pyrrolidine‐2,4‐decarboxylate (PDC) for 24 hours, motor neurons were selectively injured through N‐methyl‐D‐asparate (NMDA) and α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA)/kainate receptors. Nitric oxide synthase (NOS) inhibitors attenuated this toxicity, and long‐acting nitric oxide (NO) donors damaged motor neurons selectively. Nonmotor neurons survived after exposure to low‐dose Glu/PDC, but Glu‐induced toxicity was potentiated by coadministration of an NO‐dependent guanylyl cyclase inhibitor. In addition, 8‐bromo‐cyclic GMP, a soluble cyclic GMP analogue, rescued nonmotor neurons, but …