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)

Effects of chronic denervation upon in vivo forearm metabolism were studied in six patients and six controls. The diagnosis was amyotrophic lateral sclerosis in four patients, the neuronal form of Charcot-Marie Tooth disease in one patient, and an unclassified chronic disease of the lower motor neurons in one patient. In all cases the forearm muscles showed clinical weakness and electrical evidence of denervation, while muscle biopsy from a proximal muscle of the upper limb showed typical denervation atrophy. At rest there was increased oxygen utilization and lactate output as well as a tendency for increased uptake of glucose and long chain fatty acids from arterial blood per 100 ml of forearm tissue. During exercise the abnormally high lactate output increased further. An increased arterial lactate concentration was present during rest and exercise. Oxidation of fatty acids was not impaired. It is suggested that these abnormalities are consistent with an augmented utilization of blood borne fuels at rest by denervated muscles. A concurrent regional ischemia of muscles during rest and exercise, possibly due to defective autoregulation of skeletal muscle blood flow, may explain the abnormally high lactate generation.
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PMID:The effects of partial chronic denervation on forearm metabolism. 48 96

Acute neurological injury from hypoxia-ischemia, hypoglycemia, and trauma is thought to be predominantly mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the brain and the subsequent influx of calcium ions through receptor-operated channels. Several chronic degenerative diseases, such as Huntington's disease and the amyotrophic lateral sclerosis-Parkinsonism-dementia complex found on Guam, may share a similar pathogenesis due to a glutamate-like toxin. This laboratory recently reported that exposure to a reducing agent, such as dithiothreitol (DTT), selectively increases ionic current flow through NMDA-activated channels in several types of central neurons; conversely, oxidizing agents reverse this effect. To investigate the novel influence of redox modulation on NMDA neurotoxicity, in the present in vitro study we monitored survival of an identified central neuron, the retinal ganglion cell, approximately 24 h after a brief exposure to DTT. To determine the degree of killing specifically related to activation of the NMDA receptor, 2-amino-5-phosphonovalerate (APV, a selective NMDA antagonist) was added to sibling cultures. APV-preventable, glutamate-induced death was increased 70 +/- 9% with DTT treatment. This effect was totally blocked by the concomitant addition of an oxidizing agent, 5,5-dithiobis-2-nitrobenzoic acid (DTNB). These findings suggest that the enhanced killing following chemical reduction with DTT is mediated at the NMDA receptor site, and that the redox state of the NMDA receptor is crucial for the survival of neurons facing glutamate-related injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Redox modulation of NMDA receptor-mediated toxicity in mammalian central neurons. 197 Jan 45

Amino acids such as L-glutamate und L-aspartate are major excitatory neurotransmitters in the mammalian central nervous system (CNS) and potential neurotoxins (excitotoxins), which can destroy central neurons by excessive activation of respective receptors. In the last three decades evidence has accumulated that excitatory amino acids (EAA) are involved in many neurological diseases and that pharmacological intervention offers prospects of novel and more effective therapies. Three different receptor types for EAA have been identified, each being named by the selective agonist to which it is preferentially sensitive, i.e. N-methyl-D-aspartate- (NMDA), kainate- and quisqualate-receptors. In this review interest is focused primarily on the NMDA-receptor, whose structure has been subject of numerous electrophysiological and biochemical studies. Today, it is well established that the NMDA-receptor-ionophore complex has an agonist binding site for glutamate, NMDA and related EAAs which is coupled with an ion channel permeable to Na+, K+, Cl- and Ca2+. Four other binding sites for glycine, phencyclidine, Mg2+ and Zn2+ have been identified which can differentially modulate the function of the NMDA receptor. An additional polyamine binding site has recently been reported. Numerous studies on experimental animals demonstrate that modulators of NMDA-mediated neurotransmission may have antiepileptic, anxiolytic, muscle-relaxant and memory-enhancing effects. Particular interest has gained the possible neuroprotective efficacy of NMDA-receptor antagonists in neurological diseases such as hypoxia/ischemia, hypoglycemia, epilepsy and chronic neurodegenerative disorders (Huntington's, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, and AIDS encephalopathy).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The N-methyl-D-aspartate receptor complex. Various sites of regulation and clinical consequences]. 197 26

We have already described that ragged red fiber (RRF), core/targetoid fiber and type 1 fiber predominance were found at autopsy in the diaphragm taken from patients with chronic obstructive pulmonary diseases. The purpose of the present study is to investigate morphological and histochemical changes in the diaphragm in denervating neurologic disorders. The diaphragm in the costal portion was taken from 22 autopsy cases including 4 with amyotrophic lateral sclerosis (ALS), 4 cerebrovascular diseases, 3 Parkinson disease, 2 olivopontocerebellar atrophy. In addition, 4 diaphragm muscles were biopsied at the time of surgery for lung cancer. In the diaphragm we observed not only RRF and core/targetoid fiber but also cytoplasmic body and ring fiber in many cases. These findings were, however, not specific for neurologic disorders. Focal cytochrome c oxidase deficiency was found in muscles with RRF. It should be emphasized that RRF was absent in 3 of 4 cases with ALS and in a case with elevated hemidiaphragm from phrenic nerve paralysis. In the previous report, we suggested that RRF was formed under the relative ischemic state in overworking diaphragm. The relative ischemia means a condition that oxygen (energy) demand for respiratory work exceeds over oxygen supply from the blood in the overworking diaphragm. The reason why no RRF was found in the denervated muscle is that the ischemic state in the denervated muscles is relieved by immobilization after denervation. Karpati et al conformed that denervation prevented ischemic state in the muscle. Other histochemical features in the diaphragm included cytoplasmic body and ring fiber.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Morphological changes in human diaphragm--ragged red fiber, core/targetoid fiber, cytoplasmic body, and ring fiber]. 255 86

Ischemia of the motoneurons in the anterior horn is a well known pathological entity. Their clinical signs and symptoms are similar to those of amyotrophic lateral sclerosis. Evidence by selective angiography of angiomas of the spinal cord or compression or deviation of Adamkiewicz artery may be suggestive of an initial vascular lesion. Various data (knowledge of development or lesions during experimental ischemia, selective electrophysiologic analysis of anterior horn neurons, evidence of precise circumstances of spinal vascular disorder or spinal arteriography) suggest that anterior horn ischemia is a multiple aspect phenomenon. Our 4 cases illustrate this hypothesis and demonstrate under confirmed vascular circumstances the different clinical aspects of anterior horn ischemic lesions. In addition to typical amyotrophic paralysis unusual or misleading symptoms may occur such as claudication, paroxysmal contractures or progressive spastic paraparesis. Investigations required and possible treatment of the lesions are simplified by awareness of these various clinical aspects.
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PMID:[Ischemia of the anterior horn of the spinal cord]. 264 83

We examined specimens of skin overlying the sacral region, among the most common sites of bedsores, from patients with amyotrophic lateral sclerosis (ALS) and controls, and found that in ALS patients, collagen fibrils had a greater density and became more tightly packed with the duration of illness. Our results suggest that the increased density of collagen fibrils may protect the skin of ALS patients from pressure ischemia, a major cause of bedsore formation.
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PMID:Increased dermal collagen density in amyotrophic lateral sclerosis. 334 11

The recent molecular cloning of BDNF and CNTF based on traditional protein purification and protein sequencing and the identification and cloning of NT-3 and NT-4 by homology cloning strategies has led to a tremendous flurry of interest in the biology of these proteins and initiation of studies to assess their potential utility in neurological disorders ranging through degenerative disease, stroke and ischemia, trauma and peripheral neuropathies. Tissue culture studies have been very useful in identifying neuronal specificities of the neurotrophins and CNTF and in combination with localization studies of these growth factors and their receptors have provided the basis for in vivo studies. Initial animal studies with BDNF indicate efficacy of BDNF in models of Alzheimer's and Parkinson's disease and small fiber sensory neuropathy. Studies with CNTF have similarly progressed from in vitro findings, especially the discovery that CNTF is a growth factor for motor neurons, to in vivo findings where CNTF has been shown to be effective in slowing symptoms of motor neuron dysfunction in three genetic models. Based on these positive animal data, CNTF is currently in clinical trials for the potential treatment of motor neuron disease or amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.
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PMID:Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor. 783 3

1. Wobbler mice suffer an autosomal recessive mutation producing severe motoneuron degeneration and dense astrogliosis, with increased levels of glial fibrillary acidic protein (GFAP) in the spinal cord and brain stem. They have been considered animal models of amyotrophic lateral sclerosis and infantile spinal muscular atrophy. 2. Using Wobbler mice and normal littermates, we investigated the effects of the membrane-active steroid Lazaroid U-74389F on the number of GFAP-expressing astrocytes and glucocorticoid receptors (GR). Lazaroids are inhibitors of oxygen radical-induced lipid peroxidation, and proved beneficial in cases of CNS injury and ischemia. 3. Four days after pellet implantation of U-74389F into Wobbler mice, hyperplasia and hypertophy of GFAP-expressing astrocytes were apparent in the spinal cord ventral and dorsal horn, areas showing already intense astrogliosis in untreated Wobbler mice. In control mice, U-74389F also produced astrocyte hyperplasia and hypertophy in the dorsal horn and hyperplasia in the ventral-lateral funiculi of the cord. 4. Given in vivo U-74389F did not change GR in spinal cord of Wobbler or control mice, in line with the concept that it is active in membranes but does not bind to GR. Besides, U-74390F did not compete for [3H]dexamethasone binding when added in vitro. 5. The results suggest that stimulation of proliferation and size of GFAP-expressing astrocytes by U-74389F may be a novel mechanism of action of this compound. The Wobbler mouse may be a valuable animal model for further pharmacological testing of glucocorticoid and nonglucocorticoid steroids in neurodegenerative diseases.
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PMID:The 21-aminosteroid U-74389F increases the number of glial fibrillary acidic protein-expressing astrocytes in the spinal cord of control and Wobbler mice. 871 60

Oxidative mechanisms of damage have been implicated indirectly in the damage to brain tissue caused acutely by ischemia or chronically by neurodegenerative diseases. A direct link between pathogenesis and antioxidant enzyme systems has come from studies of a genetic form of amyotrophic lateral sclerosis (ALS). ALS causes the degeneration of motor neurons in cortex, brainstem and spinal cord with consequent progressive paralysis and death. The disease occurs in both sporadic and familial forms. Some 20% of kindreds in which ALS is inherited in an autosomal dominant fashion have mutations in the gene (SOD1) encoding Cu, Zn superoxide dismutase (SOD). Several SOD1 mutations have been shown by ourselves and others to cause motor neuron disease when expressed at high levels in transgenic mice, whereas transgenic mice expressing comparable amounts of wild-type human SOD do not show clinical disease. Thus, we have argued that motor neuron disease is caused by gain-of-function mutations in the human SOD1 gene. Our current experiments investigate the link between mutation of SOD1 and oxidative pathways of damage.
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PMID:Pathogenic mechanisms in familial amyotrophic lateral sclerosis due to mutation of Cu, Zn superoxide dismutase. 873 1

An abnormal axonal membrane conductance might contribute to human diabetic neuropathy. To test this idea, we have compared the threshold changes produced by long-lasting (100-200 ms) de- and hyperpolarizing currents applied to median motor and sensory axons at the wrist in 63 diabetic patients with those from 50 normal controls and 27 amyotrophic lateral sclerosis (ALS) patients. Averages of the threshold electrotonus plots for motor and sensory axons of diabetic patients showed more subexcitability during, and slower recovery following, the application of hyperpolarizing currents. Such alterations have been previously found in isolated rat nerves after inhibition of axonal inward rectification by means of cesium ions. The abnormalities in diabetics were positively correlated with the age of patients and the presence of neuropathy. Threshold electrotonus seen in diabetes differed strongly from the effects of acute ischemia and were unlike changes recorded in ALS. The data indicate that an abnormal inward rectification of peripheral axons is associated with diabetic neuropathy. A better understanding of the neurobiology of this conductance might provide information about the pathophysiology of this disease.
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PMID:Abnormal axonal inward rectification in diabetic neuropathy. 880 52


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