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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
Author(s) -
Urushitani Makoto,
Shimohama Shun,
Kihara Takeshi,
Sawada Hideyuki,
Akaike Akinori,
Ibi Masakazu,
Inoue Ryotaku,
Kitamura Yoshihisa,
Taniguchi Takashi,
Kimura Jun
Publication year - 1998
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410440514
Subject(s) - amyotrophic lateral sclerosis , motor neuron , glutamate receptor , spinal cord , neuron , chemistry , ampa receptor , nitric oxide synthase , neuroscience , soluble guanylyl cyclase , pharmacology , premovement neuronal activity , nmda receptor , nitric oxide , biology , medicine , biochemistry , receptor , disease , organic chemistry , guanylate cyclase
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 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 chornic 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 casade. 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.