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

The striatum, together with the hippocampus, is one of the most vulnerable regions in the brain. Recently, genetic abnormalities or mutations have been linked to various neurodegenerative diseases, that is, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), etc., but the processes from genetic abnormality to the final phenotypic expression are not well understood. Disturbances in energy metabolism especially in mitochondrial energy compromise could facilitate genetic abnormalities and enhance neuronal cell death. Here, we report that the striatum is the most vulnerable brain region to systemic intoxication with 3-nitropropionic acid (3-NPA), an inhibitor of succinate dehydrogenase inducing energy compromise. We hypothesize that the striatum-specific lesion by 3-NPA is due to cummulative insults characteristic to the striatum including glutamatergic excitotoxicity, dopaminergic toxicity, vulnerability of the lateral striatal artery and high activity in the glutamate-transporter. The former two are extravascular in origin while the latter two are intra-/perivascular. We also discuss the possibility that a high turnover rate in metabolism of nitric oxide (NO) might underlie the vulnerability of the lateral striatal artery. We posit that systemic intoxication with 3-NPA offers a good animal model to investigate the pathophysiology of neuronal/glial cell death, neurodegenerative disease, dysfunction of the blood-brain barrier (BBB), neuroimmune disorders, and stroke.
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PMID:The striatum is the most vulnerable region in the brain to mitochondrial energy compromise: a hypothesis to explain its specific vulnerability. 1075 30

Abnormal glutamate metabolism is implied in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and cerebrospinal fluid (CSF) glutamate levels appear to be elevated. Since nitric oxide (NO) inhibits glutamate transport, excessive amounts of nitric oxide could underlie the glutamate induced neurotoxicity in ALS. Stable metabolites of NO (NO2- + NO3-) levels were determined in serum and CSF of sporadic ALS patients and control subjects. NO2- + NO3- levels were higher in ALS, in males and in serum samples compared to controls, females and CSF, respectively. Furthermore, while the difference between serum and CSF NO2- + NO3- levels was significant in males (higher in serum) no such difference was observed in females. Our results suggest that nitric oxide may be involved in the pathogenesis of ALS directly or indirectly and in a sexually dimorphic manner.
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PMID:Increased cerebrospinal fluid and serum nitrite and nitrate levels in amyotrophic lateral sclerosis. 1076 91

We carried out an immunohistochemical investigation of the spinal cords of 15 patients with sporadic amyotrophic lateral sclerosis (ALS), using antibodies to inducible nitric oxide synthase (iNOS) and nitrotyrosine; our purpose was to search for a possible role of increased oxidative damage in the motor system that may contribute to the neurodegenerative process in this disease. Specimens from 16 patients without any neurological disease served as controls. In the controls, normal-appearing neurons and their dendrites were negatively immunostained for iNOS. In the ALS patients, most of normal-appearing anterior horn neurons did not show iNOS immunoreactivity either in the perikarya or in their dendrites. However, many of the degenerated neurons showing central chromatolysis or simple atrophy demonstrated focally or diffusely positive iNOS immunoreactivity within the perikarya and their neuronal processes. In the neuropil of the anterior horns, the reactive astrocytes were more intensely immunostained for iNOS as compared with the controls. Some of the swollen proximal axons (spheroids) were focally or diffusely immunostained by the antibody. The corticospinal tracts demonstrated positive iNOS immunoreactivity of proliferated reactive astrocytes. The immunostaining pattern of nitrotyrosine in the anterior horn neurons of the spinal cord was similar to that of iNOS. These findings suggest that selective nitric oxide-mediated oxidative damage in the motor system plays a part in the pathomechanism of the neuronal degeneration in the spinal cord of sporadic ALS.
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PMID:iNOS and nitrotyrosine immunoreactivity in amyotrophic lateral sclerosis. 1096 50

To clarify the biological significance of the neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions characteristically found in patients with familial amyotrophic lateral sclerosis with superoxide dismutase-1 (SOD1) gene mutations and in transgenic mice expressing human SOD1 with G85R mutation, the detailed protein composition in both types of inclusions was immunohistochemically analyzed using 45 different antibodies. Both types of inclusions had very strong immunoreactivity for SOD1. The SOD1-positive inclusions in both cell types were also immunoreactive for the insoluble advanced glycation endproducts (AGEs) such as Nepsilon-(carboxymethyl)lysine (CML), pyrraline and pentosidine: both inclusions in both conditions were ultrastructurally composed of the granule-coated fibrils that had immunoreactivities to CML and pyrraline. Both types of inclusions were negative for stress-response proteins (SRPs), 4-hydroxy-2-nonenal (HNE), acrolein, nitric oxide synthases (NOSs) and nitrotyrosine as representative markers of oxidative stress. The neurons and astrocytes of the normal individuals and non-transgenic mice showed no significant immunoreactivity for SOD1, AGEs, SRPs, HNE, acrolein, NOSs or nitrotyrosine. Our results suggest that a portion of the SOD1 composing both type of inclusions, probably toxic mutant SOD1, is modified by the AGEs, and that the formation of the AGE-modified SOD1 is one of the mechanisms responsible for the aggregation involving no significant oxidative mechanisms.
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PMID:Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)-positive inclusions are common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with a G85R mutation. 1104 71

Estrogens have been reported to exert neuroprotection in the brain, but there have been no reports of such neuroprotection in spinal motor neurons, the neurons selectively involved in amyotrophic lateral sclerosis (ALS). In this study, we demonstrated that 17beta-estradiol and its biologically inactive stereoisomer, 17alpha-estradiol, prevented glutamate- and nitric oxide (NO)-induced selective motor neuronal death observed in primary cultures of the rat spinal cord. The dose of estradiols required for motor neuron protection was greatly reduced by co-administration with glutathione. The results of this study shows that estradiol protects spinal motor neurons from excitotoxic insults in vitro, and may have application as a treatment for ALS.
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PMID:Protection of cultured spinal motor neurons by estradiol. 1109 6

Continuous subcutaneous administration of polyamine-modified catalase that has increased permeability at the blood-brain barrier showed both a highly significant delay in onset and an increase in survival in a transgenic mouse model of familial amyotrophic lateral sclerosis having a point mutation in the gene encoding copper/zinc superoxide dismutase. These results suggest that hydrogen peroxide-mediated oxidative stress with subsequent free radical damage involving nitric oxide and possibly hydroxyl radicals in motor neurons may be the culprit in familial amyotrophic lateral sclerosis.
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PMID:Therapeutic benefit of polyamine-modified catalase as a scavenger of hydrogen peroxide and nitric oxide in familial amyotrophic lateral sclerosis transgenics. 1111 54

We investigated the spinal cords of 15 patients with sporadic amyotrophic lateral sclerosis (ALS) immunohistochemically using an anti-human neuronal nitric oxide synthase (nNOS) antibody to examine whether there is increased nNOS immunoreactivity in anterior horn neurons. Specimens from 16 patients without any neurological disease served as controls. In the controls, nNOS immunoreactivity of large anterior horn neurons was detected in 10 out of 16 cases. However, there were few nNOS-positive neurons, and most of large anterior horn neurons were spared. In the ALS patients, the mean number of nNOS-positive anterior horn neurons per transverse section of L4 and L5 was significantly larger (16.2 +/- 10.9) than that in the controls (7.0 +/- 9.2) (P < 0.0001). Moreover, 41.4% of large anterior horn neurons in ALS showed nNOS immunoreactivity in remarkable contrast to 7.6% in the controls. All ALS patients, whether showing mild, moderate or severe depletion of anterior horn neurons, displayed a higher percentage of nNOS-positive anterior horn neurons than the control patients showing nNOS immunoreactivity (P < 0.01). Most of the remaining anterior horn neurons in ALS showed more intense nNOS immunoreactivity on the surface of the neurons and their neuronal processes compared with the controls. Degenerated anterior horn neurons frequently demonstrated more intense nNOS immunoreactivity on the surface of the neurons than normal-appearing neurons. Some anterior horn cells displayed nNOS immunoreactivity in the somata. Dot-like nNOS deposits on anterior horn neurons were also positively immunoreactive with anti-synaptophysin antibody. Thus, increased nNOS expression is located mainly at the synaptic sites on the anterior horn neurons in sporadic ALS, which may be related to the degeneration of anterior horn neurons in this disease. Further studies are needed to determine whether the increased nNOS immunoreactivity plays a neuroprotective or neurotoxic role in the anterior horn neurons, and to show nitric oxide production in ALS.
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PMID:Neuronal nitric oxide synthase immunoreactivity in the spinal cord in amyotrophic lateral sclerosis. 1135 6

Evidence of an overload of reactive oxygen species and peroxynitrite, a derivative of nitric oxide, in sporadic amyotrophic lateral sclerosis suggests that peroxynitrite could impair cholinergic functions. Because of the impossibility of obtaining synaptosomes from vertebrate neuromuscular junctions, we used cholinergic synaptosomes purified from Torpedo marmorata electroneurons to characterize the defects triggered by peroxynitrite in more detail. Addition of peroxynitrite or its donor 3-morpholinosydnonimine abolished high-affinity choline uptake and synthesis of acetylcholine from acetate. T. marmorata choline acetyltransferase (ChAT) was impaired to the same extent as bovine brain ChAT. A hallmark of peroxynitrite action is the nitration of tyrosine residues in proteins. Peroxynitrite induced a concentration-dependent appearance of nitrotyrosines in several neuronal proteins from synaptosomes and, more readily, from synaptic vesicles. Peroxynitrite also triggered tyrosine nitrations in purified ChAT. Peroxynitrite-dependent nitrations were impaired when synaptosomes were pretreated with thioreductants (glutathione, N-acetyl cysteine, dithiothreitol) or antioxidants (uric acid, melatonin, bovine serum albumin, desferrioxamine). Deleterious effects of peroxynitrite on choline transport and ChAT activity were prevented by the thioreductants but only partially by the antioxidants, suggesting a mechanism other than tyrosine nitration, which may involve cysteine oxidation. Further development of protective agents acting on choline transport and on ChAT activity may offer interesting therapeutic possibilities with respect to cholinergic dysfunction occurring in neurodegenerative diseases.
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PMID:Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants. 1156 47

1. The Wobbler mouse suffers an autosomal recessive mutation producing severe motoneuron degeneration and astrogliosis in the spinal cord. It has been considered a suitable model of human motoneuron disease, including the sporadic form of amyotrophic lateral sclerosis (ALS). 2. Evidences exist demonstrating increased oxidative stress in the spinal cord of Wobbler mice, whereas antioxidant therapy delayed neurodegeneration and improved muscle trophism. 21-Aminosteroids are glucocorticoid-derived hydrophobic compounds with antioxidant potency 3 times higher than vitamin E and 100 times higher than methylprednisolone. They do not bind to intracellular receptors, and prevent lipid peroxidation by insertion into membrane lipid bilayers. 3. In common with the spinal cord of ALS patients, Wobbler mice present astrocytosis with hyperexpression of glial fibrillary acidic protein (GFAP), and increased expression of nitric oxide synthase (NOS) and growth-associated protein (GAP-43) in motoneurons. Here, we review our studies on the effects of a 21-aminosteroid on GFAP, NOS, and GAP-43. 4. First, we showed that 21-aminosteroid treatment further increased GFAP-expressing astrocytes in gray matter of the Wobbler spinal cord. This effect may provide neuroprotection if one considers a trophic and beneficial function of astrocytes during the course of degeneration. Other neuroprotectans used in Wobbler mice (T-588) also increased pre-existing astrocytosis. 5. Second, histochemical determination of NADPH-diaphorase, a parameter indicative of neuronal NOS activity, showed that the 21-aminosteroid down-regulated the high activity of this enzyme in ventral horn motoneurons. Therefore, suppression of nitric oxide by decreasing NADPH-diaphorase (NOS) activity may provide neuroprotection considering that excess NO is highly toxic to motoneurons. 6. Finally, 21-aminosteroid treatment significantly attenuated the aberrant expression of both GAP-43 protein and mRNA in Wobbler motoneurons. Hyperexpression of GAP-43 possibly indicated abnormal synaptogenesis, denervation, and muscle atrophy, parameters which may return to normal following antioxidant steroid treatment. 7. Besides 21-aminosteroids, other steroids also behave as neuroprotectans. In this regard, degenerative diseases may constitute potential targets of these hormones, based on the fact that the spinal cord expresses in a regional and cell-specific fashion, receptors for androgens. progesterone, adrenal steroids, and estrogens.
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PMID:Cellular basis of steroid neuroprotection in the wobbler mouse, a genetic model of motoneuron disease. 1156 36

Several studies have suggested that excessive generation of nitric oxide (NO) may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). Recently, a selective induction of the neuronal isoform of nitric oxide synthase (nNOS) in glial cells has been reported in an animal model of familial ALS. We therefore examined in postmortem tissue the expression of nNOS in patients with sporadic ALS and patients without any history of neurological disease. Using immunohistochemistry, we found an up-regulation of nNOS in glial cells of the spinal cord and subcortical white matter in ALS patients compared to controls. The enhanced glial nNOS expression seen in ALS patients could conceivably contribute to motoneuronal degeneration through NO-mediated cytotoxic effects.
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PMID:Glial cells of the spinal cord and subcortical white matter up-regulate neuronal nitric oxide synthase in sporadic amyotrophic lateral sclerosis. 1157 93


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