Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID: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. 981 36

Mechanisms of the process of neuronal degeneration in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD) remain unsolved. Oxidative stress might be a possible mechanism of neuronal cell death. Glutamate is an excitatory amino acid and its excessive release can cause intracellular calcium influx, activation of calcium-dependent enzymes such as nitric oxide (NO) synthase (NOS), and production of toxic oxygen radicals. Excessive release of glutamate, therefore, can be used as a model of experimental oxidative stress. Continuous exposure to low levels of glutamate potentiates selective motor neuronal death mediated by NO, which inversely protects nonmotor neurons through the guanylyl cyclase-cGMP cascade. Mesencephalic dopaminergic neurons are resistant to cytotoxicity induced by NO. The protecting mechanism from NO neurotoxicity in dopaminergic neurons is based on inhibition of conversion of NO to peroxynitrite anion, and is possibly due to suppression of superoxide anion production. Dopamine D 2 agonists provide protection mediated not only by the inhibition of dopamine turnover but also via D 2-type dopamine receptor stimulation and the subsequent synthesis of proteins that scavenge free radicals. In addition, nicotinic receptor stimulation may be able to protect neurons from oxidative stress induced by A beta.
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PMID:[Neuronal cell death in neurodegenerative disorders and oxidative stress]. 1037 84

Glutamate and reactive oxygen species including nitric oxide (NO) and superoxide anion (O2.-) have been postulated to play pivotal roles in the pathogenesis of the neuronal cell loss that is associated with several neurological disease states including Parkinson's disease and amyotrophic lateral sclerosis. In mesencephalic cultures, nondopaminergic neurons but not dopaminergic neurons are susceptible to NO cytotoxicity, although both types of neurons are damaged by glutamate. Methylphenylpyridium ion (MPP+) selectively enhances glutamate and NO cytotoxicity against dopaminergic neurons of mesencephalic cultures. It is suggested that glutathione plays an important role in the expression of NO-mediated glutamate cytotoxicity in dopaminergic neurons. In cultured spinal neurons, glutamate coadministered with the glutamate transporter inhibitor selectively damages motor neurons. Motor neurons are injured by NO, whereas nonmotor neurons are protected by NO through the guanylyl cyclase-cGMP cascade. It is suggested that selective motor neuronal death caused by chronic low-level exposure to glutamate is mediated by the formation of NO in nonmotor neurons. It is possible that neurotoxicity induced by NO and O2.- associated with neurodegenerative disorders is regulated by intracellular defense systems such as glutathione and cGMP.
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PMID:[Neuronal response to radical stress]. 1062 40

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuronal death. In addition to elucidate the "cell death mechanism", we think it is also important to clarify the "cell survival mechanism", to understand the pathogenesis of this intractable disease. Glutamate (Glu) is an excitatory neurotransmitter in the central nervous system, and is implicated in the pathogenesis of ALS. In this report, we presented our current research, investigating the mechanism of Glu-induced selective motor neuronal death, derived from the study of primary culture of rat embryonic spinal cord. In brief, 1) motor neurons are selectively injured by long-term exposure to low-dose Glu through the activation of nNOS to generate NO and ONOO-: 2) nonmotor neurons are protected by cGMP which is formed by NONdependent guanylyl cyclase: 3) chronic exposure of spinal neurons to Glu increases nNOS positive neurons only in nonmotor neurons. These results indicate the cascade of Glu-calcium influx-NO generation is toxic to motor neurons and protective to nonmotor neurons. The different effect of cGMP on motor neurons and nonmotor neurons against Glu-induced excitotoxicity may explain the selective motor neuronal death of ALS. Further investigation might advance the possibility of new therapy against ALS.
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PMID:[Nitric oxide-induced neurotoxicity versus neuroprotection; relationship with selective motor neuronal death]. 1079 Oct 88

Missense mutations in the human Cu/Zn superoxide dismutase gene (SOD-1) cause many cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS). The accumulation of intracellular calcium is one of the primary mechanisms of motor neuronal degeneration associated with mutations in SOD-1. In order to investigate the effect of various calcium modulators and the SOD-1 mutation on neuronal death, we tested motoneuron-neuroblastoma hybrid (VSC 4.1) cells constitutively expressing human SOD-1 gene with mutations (A4V, G93A) or wild-type. These cells were treated with endogenous calcium releaser (ryanodine, thapsigargin, cyclic ADP-ribose) or calcium mobilizer through cell membrane (4-bromo-calcium ionophore A23187). In particular, calcium ionophore reduced survival in the cells expressing mutant SOD-1. Cell death was associated with increased nitric oxide (NO) generation. This toxicity was attenuated when a nitric oxide synthase (NOS) inhibitor was added. Exogenous NOadministration (S-nitrosoglutathione) also induced cell death. The NO-dependent guanylyl cyclase-cGMP cascade inhibitor protected the mutant cells from the toxic effects of calcium ionophore. Our data suggests that motoneuron degeneration with the SOD-1 mutation may be mediated by calcium dysregulation, particularly by the exogenous calcium influx. This process induces oxidative stress generation that results in motor neuronal death through the guanylyl cyclase-cGMP dependent cascade.
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PMID:Alteration in intracellular calcium homeostasis reduces motor neuronal viability expressing mutated Cu/Zn superoxide dismutase through a nitric oxide/guanylyl cyclase cGMP cascade. 1215 55