Mechanism of selective motor neuronal death after exposure of spinal cord to glutamate: Involvement of glutamate‐induced nitric oxide in motor neuron toxicity and nonmotor neuron protection

Abstract

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-aspartate (NMDA) and alpha-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 not motor neurons, exposed to high-dose Glu/PDC. Twenty-four hours' incubation with PDC elevated the number of neuronal NOS-immunoreactive neurons by about twofold compared with controls, and a double-staining study, using the motor neuron marker SMI32, revealed that most of them were nonmotor neurons. These findings suggest that selective motor neuronal death caused by chronic low-level exposure to Glu is mediated by the formation of NO in nonmotor neurons, which inversely protects nonmotor neurons through the guanylyl cyclase-cyclic GMP cascade. Induction of neuronal NOS in nonmotor neurons might enhance both the toxicity of motor neurons and the protection of nonmotor neurons, which could explain the pathology of amyotrophic lateral sclerosis.

Excitotoxicity and Amyotrophic Lateral Sclerosis

“…Motor neurons may also be more sensitive to glutamate-induced NO production [110] , although we found no involvement of NO synthase in the excitotoxic death in our motor neuron/glial cell coculture system [113] . Another mechanism that could be responsible for the selectivity of the motor neuron death is that motor neurons are more sensitive to mitochondrial dysfunction due to increased Ca 2+ infl ux in mitochondria.…”

Induction of Neuronal and Inducible Nitric Oxide Synthase in the Motoneurons of Spinal Cord Following Transient Abdominal Aorta Occlusion in Rats

“…It was suggested that induction of 3-L-nitrotyrosine might activate the motoneuronal death [33]. The in vitro study has shown that glutamate-induced NO may be involved in selective motor neuronal death after exposure of spinal cord to glutamate [34]. Although it has been shown that apoptosis may contribute to the motor neuronal death [7,35], our study using the TUNEL staining method (unpublished data) has failed to reveal DNA fragmentation in the motoneurons.…”

Reaction of endogenous progenitor cells in a rat model of posttraumatic syringomyelia

“…The initial cyst formation is thought to be caused by inflammatory processes, hematoma, infarction, or excitatory amino acid overproduction after trauma. 20,26,28,45 In this model, an excitatory amino acid triggers inflammation, cellular injury, and neuronal death and contributes to the initial cyst formation. 5,49 A subsequent imbalance between CSF inflow and outflow causes syrinx enlargement.…”