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)

The etiology of various age-related neurological diseases remains unknown. Sporadic forms ofAlzheimer's, Parkinson's and Lou Gehrig's disease have been linked to environmental factors that cause neuronal cell death either by excitotoxicity or by inducing oxidative stress. Our recent studies have demonstrated that various compounds not previously associated with these diseases, i.e. methionine sulfoximine (MSO), originally isolated from 'agenized' flour, and sitosterol glucoside (BSSG), isolated from the seed of the cycad, appear to be neurotoxins, likely acting by excitotoxic mechanisms. For these compounds, the primary excitotoxic effect appears to involve glutamate release followed by NMDA receptor activation. Lactate dehydrogenase assays demonstrate that both compounds cause rapid cell death in vitro. In addition, both compounds appear to alter antioxidant defense mechanisms, acting particularly on levels of reduced glutathione (GSH). In vivo application of MSO has historically been linked to behavioral abnormalities, including seizures, in various species. Our recent experiments have demonstrated that mice fed cycad flour containing sitosterol glucoside have severe behavioral abnormalities of motor and cognitive function, as well as significant levels of neurodegeneration in cortex, hippocampus, spinal cord and other CNS regions measured post mortem. The combined weight of excitotoxic action, in concert to a decline in antioxidant defenses, induced by molecules such as methionine sulfoximine and sitosterol glucoside is hypothesized to be causal to neuronal degeneration in various neurological diseases. Understanding the mechanisms of action of these and functionally related molecules may serve to focus attention on potential neurotoxins present in the human environment. Only once such molecules have been identified, can we begin to design appropriate pharmaceutical strategies to prevent or halt the progression of the age-related neurological diseases.
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PMID:Synergistic versus antagonistic actions of glutamate and glutathione: the role of excitotoxicity and oxidative stress in neuronal disease. 1199 Apr 49

This study was aimed at investigating the effect of glutamate on motor neurons in organotypic cultured spinal cord slices treated by threohydroxyaspartate (THA), an inhibitor of glutamate transporter. The spinal cord cultures were prepared using lumbar spinal cord slices from 8-day-old rat. Various concentration of THA(50 micromol/L,100 micromol/L,500 micromol/L) was added into the culture medium respectively. Ventral alpha-motor neurons survival was evaluated by immunohistochemistry staining monoclonal antibody SMI-32, a nonphosphorylated neurofilament marker, and interneurons in dorsal horn were identified by monoclonal anti-calretinin antibody staining. Lactate dehydrogenase (LDH) level in the culture medium was also measured. The spinal cord slices in the control group could maintain excellent organotypic cellular organization and a stable population of ventral alpha-motor neurons. THA caused a slow dose-dependent loss of alpha-motor neurons and an increase in LDH enzyme activity in the culture medium while dorsal interneurons were less damaged. 100 micromol/L THA resulted in a significant decrease in (alpha-motor neurons after cultured for 4 weeks. On the contrary, the interneurons in the dorsal horn were less affected. It was also observed in patients with amyotrophic lateral sclerosis (ALS). Excellular Glu mainly caused selective alpha-motor neuron death, and motoneurons were more sensitive to glutamate excitotoxicity than sensory neurons in the spinal cord.
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PMID:[Effects of glutamate transport inhibitor on organotypic cultured spinal cord slices]. 1601 Dec 51

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.
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PMID:Oligodendroglia metabolically support axons and contribute to neurodegeneration. 2316 28

In vertebrates, the myelination of long axons by oligodendrocytes and Schwann cells enables rapid impulse propagation. However, myelin sheaths are not only passive insulators. Oligodendrocytes are also known to support axonal functions and long-term integrity. Some of the underlying mechanisms have now been identified. It could be shown that oligodendrocytes can survive in vivo by aerobic glycolysis. Myelinating oligodendrocytes release lactate through the monocarboxylate transporter MCT1. Lactate is then utilized by axons for mitochondrial ATP generation. Studying axo-glial signalling and energy metabolism will lead to a better understanding of neurodegenerative diseases, in which axonal energy metabolism fails. These include neurological disorders as diverse as multiple sclerosis, leukodystrophies, and amyotrophic lateral sclerosis.
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PMID:The role of myelin and oligodendrocytes in axonal energy metabolism. 2409 33