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)

Numerous studies have established the key role of the Golgi apparatus (GA) in post-translational processing, transport and targeting of proteins destined for secretion, lysosomes and plasma membranes. Moreover, several studies performed in our laboratories have shown that the size of the immunocytochemically detected neuronal GA is a reliable index of neuronal activity in aging, Alzheimer's disease (AD) and amyotrophic lateral sclerosis. It has been suggested that in AD there is decreased neuronal activity, e.g. in terms of glucose metabolism and protein synthetic capability. To further explore the hypothesis of decreased neuronal activity in AD, in this study the size of the GA was measured in pyramidal neurons of the CA1 area of the hippocampus of non-demented controls and AD patients. The size of the GA was measured separately in neurons with and without neurofibrillary tangles (NFT). Moreover, in order to establish a correlation between the density of NFT and the size of the GA, the density of extraneuronal NFT was determined around each neuron and related to the size of its GA. The results, quantified by image analysis, indicate that there is a significant reduction in GA size in the neurons of the CA1 area of the hippocampus of AD patients. However, there was no significant relationship between the size of the GA and the presence or absence of intracellular NFT. In addition, there was no correlation between the density of extracellular NFT and GA size of adjacent neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased activity of hippocampal neurons in Alzheimer's disease is not related to the presence of neurofibrillary tangles. 766 60

Amyotrophic lateral sclerosis/parkinsonism-dementia complex is a highly prevalent neurodegenerative disorder among the native Chamorro population of Guam, and is characterized by widespread formation of neurofibrillary tangles. In the present study, the distribution of neurofibrillary tangles was quantitatively assessed in the cerebral cortex of cases presenting with either predominant amyotrophic lateral sclerosis or parkinsonism-dementia symptomatology. Results show that although the regional and laminar lesion distribution is qualitatively similar in both groups, cases with predominant parkinsonism-dementia generally have higher lesion densities than cases with amyotrophic lateral sclerosis. Interestingly, layer II of the entorhinal cortex was affected to the same degree in both conditions. In both groups, the CA1 field of the hippocampus, subiculum, and entorhinal cortex were the most affected areas. In the neocortex, the perirhinal and inferior temporal cortex consistently had higher lesion densities than the frontal, parietal, and cingulate cortex, whereas the visual cortex was practically devoid of lesions. Also, most of the neurofibrillary tangles were located in the supragranular layers of the neocortex, with relatively low densities in the infragranular layers, in both brain groups. Interestingly, the primary motor cortex contained more neurofibrillary tangles in parkinsonism-dementia than in amyotrophic lateral sclerosis cases. It is possible that the differences in regional neurofibrillary tangle densities reflect the variable severity of the dementing process observed between the two groups of patients. Several studies on Alzheimer's disease and related disorders indicate that the regional and laminar cortical localization of neurofibrillary tangles may parallel the degeneration of specific corticocortical projections. The present data suggest that the population of corticocortical projections involved in Guamanian cases differs substantially from that affected in Alzheimer's disease. The differential distribution and densities of the lesions may contribute to the differences in symptomatology and severity of dementia among Alzheimer's disease and Guamanian cases, although these neurodegenerative disorders as well as related illnesses may share certain etiopathogenetic mechanisms.
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PMID:Amyotrophic lateral sclerosis and parkinsonism-dementia from Guam: differences in neurofibrillary tangle distribution and density in the hippocampal formation and neocortex. 795 61

Hirano bodies are bright eosinophilic intracytoplasmic inclusions which have a highly characteristic crystalloid fine structure. They occur preferentially in the neuronal processes of the CA1 area in Ammon's horn in a wide variety of conditions, especially amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam, Alzheimer's disease, Pick's disease and 'normal' elderly individuals. Hirano bodies contain epitopes of actin, actin-associated proteins, tau, middle molecular weight neurofilaments subunit and a C-terminal fragment of beta-amyloid precursor protein. In addition to the CA1 area of Ammon's horn, they have also been identified in many other areas of the nervous system in humans and various experimental animals. Although usually observed in neurons, Hirano bodies may also be present in other cell types. It is the consensus that Hirano bodies in the pyramidal layer of CA1 originate largely from an age-related alteration of the microfilamentous system.
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PMID:Hirano bodies and related neuronal inclusions. 820 38

We report the presence of round eosinophilic intranuclear inclusions in a patient with sporadic amyotrophic lateral sclerosis (ALS). The inclusions were limited to the hippocampal pyramidal neurons; they were frequently encountered in the CA1 and CA2 regions and much less frequently in the CA3 and CA4 regions and in the subiculum. Ultrastructurally, they consisted of randomly oriented straight filaments, each about 8-14 nm in diameter, some of which had a tubular appearance in cross-section. Electron-dense, granular material was intermingled with the filaments. Immunohistochemically, all the inclusions were positive for ubiquitin, but were negative for several kinds of cytoskeletal protein, including actin, glial fibrillary acidic protein, vimentin, neurofilament polypeptides, keratin, tubulin, tau protein and microtubule-associated protein 2. To our knowledge, this type of neuronal intranuclear inclusion has not so far been reported in ALS, and its distribution limited to the hippocampal formation is of great interest.
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PMID:Eosinophilic intranuclear inclusions in the hippocampal pyramidal neurons of a patient with amyotrophic lateral sclerosis. 993 Sep 2

The investigation of oxygen radical-induced lipid peroxidative neuronal damage in the context of acute and chronic neurodegenerative disorders has been largely limited to the use of ex vivo analytical methodologies. These are often fraught with sensitivity or specificity problems, or they are indirect. Furthermore, none of the analytical methods allow precise anatomical identification of the cells that are undergoing peroxidative injury. This paper describes an immunocytochemical method for localization of central nervous system (CNS) lipid peroxidation (LP) that employs a rabbit-derived antibody raised against malondialdehyde (MDA)-modified rabbit serum albumin (RSA). MDA is a breakdown product of peroxidized membrane polyunsaturated fatty acids that avidly binds to cellular proteins. Using the anti-MDA-RSA, we herein illustrate increased MDA-derived immunostaining: (1) in the spinal cord of transgenic familial amyotrophic lateral sclerosis (ALS) mice; and (2) in the selectively vulnerable gerbil hippocampal CA1 region after a 5 min episode of forebrain ischemia and its relationship to the time course of neuronal degeneration.
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PMID:Immunocytochemical method for investigating in vivo neuronal oxygen radical-induced lipid peroxidation. 935 Sep 62

Energy metabolism is impaired in the Cu,Zn superoxide dismutase transgenic mouse model of amyotrophic lateral sclerosis. The goal was to investigate tolerance against single and repetitive hypoxia in C57B6SJL-TgN(SOD1-G93A)1GUR mice (G93A mice). Posthypoxic recovery (15 min hypoxia, 45 min recovery) of population spike amplitude in hippocampal region CA1 was 38 +/- 29% (mean +/- SD) in controls and 67 +/- 41% (ns) in G93A mice at day 40. Upon in vivo pretreatment with 20 mg/kg 3-nitropropionate posthypoxic recovery increased to 82 +/- 32% (P < 0.01) in controls and decreased to 35 +/- 33% in G93A mice (P < 0.05 to pretreated controls). Results at day 80 and 110 were similar. We conclude that G93A mice show a long-lasting impairment to sustain repetitive hypoxic episodes whereas tolerance to a single hypoxic episode is comparable to controls.
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PMID:Impaired tolerance to repetitive hypoxia in hippocampal slices of Cu,Zn superoxide dismutase transgenic mice. 1062 9

In the previous study, we reported increased NOS expression in the astrocytes in the spinal cord of the transgenic mice that are used as ALS animal model. In the present study, we performed immunocytochemical studies to investigate the changes of nitrotyrosine-immunoreactivity in the brains of the transgenic mice, and demonstrated in vivo evidence of peroxynitrite-mediated oxidative damage in the pathogenesis of ALS. In the spinal cord of the transgenic mice, immunocytochemistry showed intensely stained nitrotyrosine-IR glial cells with the appearance of astrocytes, but no nitrotyrosine-IR glial cells were observed in the spinal cord of the control mice. In the transgenic mice, nitrotyrosine-IR neurons were observed in the hypoglossal nucleus, lateral reticular nucleus, medullary reticular formation and cerebellar nuclei. Interestingly, nitrotyrosine-IR neurons were observed in the hippocampal formation and septal area of the transgenic mice. In the hippocampus, nitrotyrosine-IR neurons in the CA1 region showed intense staining, and the immunoreactivity was localized mainly in the pyramidal cell layer. Recent studies have shown that antioxidants and selective neuronal NOS inhibitor increase survival in the SOD1 transgenic mouse model of FALS. It is possible that therapy with these agents may slow the neurodegenerative process in human ALS, perhaps through reduction of nitrotyrosine formation.
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PMID:Immunocytochemical study on the distribution of nitrotyrosine in the brain of the transgenic mice expressing a human Cu/Zn SOD mutation. 1062 20

Frontotemporal dementia (FTD) with motor neuron disease means amyotrophic lateral sclerosis (ALS) with dementia. In the cerebrum of this condition, the medial cortex of the rostral temporal lobe is constantly and most remarkably involved. Another constant and quite characteristic lesion is neuronal loss localized to the CA1-subiculum transitional area at the level of the pes hippocampi. The rostral portion of the parahippocampal gyrus, and the amygdaloid nucleus are also involved. Ubiquitinated intracytoplasmic inclusions are seen in the dentate granule cells and parahippocampal gyrus neurons. Some cases of ALS without dementia show the identical temporal lobe degeneration as well as the cortical ubiquitinated inclusions, thus raising the possibility of overlooked dementia or premature death of the patients. Similarly, recently proposed motor neuron disease-inclusion dementia may be a forme fruste of ALS with dementia.
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PMID:Frontotemporal dementia with motor neuron disease (amyotrophic lateral sclerosis with dementia). 1093 41

Riluzole is a neuroprotective agent the efficacy of which was proven in amyotrophic lateral sclerosis in human and in animal models of cerebral ischemia. However, the dosage used in animal experiments was much higher than that in human. We investigated the efficacy of low dose riluzole, which was similar to the dose used in human trials, in animal model of global ischemia. Global ischemia was induced in male Mongolian gerbils for 5min under monitoring of rectal temperature. Riluzole (0.8 mg/kg) were injected intraperitoneally 30min before ischemia. Seven days after ischemia, animals were decapitated and surviving nerve cells in hippocampal CA1 area were quantified. The number of surviving cells was compared between in riluzole-treated and control groups and the former showed statistically significant better survivals than the latter (P<0.001).
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PMID:Neuroprotective effect of low dose riluzole in gerbil model of transient global ischemia. 1104 79

Infusion of the K(+) channel blocker 4-aminopyridine in the hippocampus induces the release of glutamate, as well as seizures and neurodegeneration. Since an imbalance between excitation and inhibition, as well as alterations of ion channels, may be involved in these effects of 4-aminopyridine, we have studied whether they are modified by drugs that block glutamatergic transmission or ion channels, or drugs that potentiate GABA-mediated transmission. The drugs were administered to anesthetized rats subjected to intrahippocampal infusion of 4-aminopyridine through microdialysis probes, with simultaneous collection of dialysis perfusates and recording of the electroencephalogram, and subsequent histological analysis. Ionotropic glutamate receptor antagonists clearly diminished the intensity of seizures and prevented the neuronal damage, but did not alter substantially the enhancement of extracellular glutamate induced by 4-aminopyridine. None of the drugs facilitating GABA-mediated transmission, including uptake blockers, GABA-transaminase inhibitors and agonists of the A-type receptor, was able to reduce the glutamate release, seizures or neuronal damage produced by 4-aminopyridine. In contrast, nipecotate, which notably increased extracellular levels of the amino acid, potentiated the intensity of seizures and the neurodegeneration. GABA(A) receptor antagonists partially reduced the extracellular accumulation of glutamate induced by 4-aminopyridine, but did not exert any protective action. Tetrodotoxin largely prevented the increase of extracellular glutamate, the electroencephalographic epileptic discharges and the neuronal death in the CA1 and CA3 hippocampal regions. Valproate and carbamazepine, also Na(+) channel blockers that possess general anticonvulsant action, failed to modify the three effects of 4-aminopyridine studied. The N-type Ca(2+) channel blocker omega-conotoxin, the K(+) channel opener diazoxide, and the non-specific ion channel blocker riluzole diminished the enhancement of extracellular glutamate and slightly protected against the neurodegeneration. However, the two former compounds did not antagonize the 4-aminopyridine-induced epileptiform discharges, and riluzole instead markedly increased the intensity and duration of the disharges. Moreover, at the highest dose tested (8mg/kg, i.p.), riluzole caused a 75% mortality of the rats. We conclude that 4-aminopyridine stimulates the release of glutamate from nerve endings and that the resultant augmented extracellular glutamate is directly related to the neurodegeneration and is involved in the generation of epileptiform discharges through the concomitant overactivation of glutamate receptors. Under these conditions, a facilitated GABA-mediated transmission may paradoxically boost neuronal hyperexcitation. Riluzole, a drug used to treat amyotrophic lateral sclerosis, seems to be toxic when combined with neuronal hyperexcitation.
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PMID:Seizures and neurodegeneration induced by 4-aminopyridine in rat hippocampus in vivo: role of glutamate- and GABA-mediated neurotransmission and of ion channels. 1111 4


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