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)

Excitatory amino acids (EAA) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). We have analyzed the distribution of the N-methyl-D-aspartate (NMDA) 1-(1-(2-thienyl)-cyclohexyl) piperidine (TCP), kainate and alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid (AMPA) quisqualate subtypes of EAA receptors using quantitative receptor autoradiography in the cervical and thoracic spinal cords of patients who have died with ALS, and of controls. We observed that in control spinal cords [3H]TCP/NMDA binding sites were located both in the ventral and dorsal horns with the highest densities being situated in lamina II. [3H]AMPA and [3H]kainate binding sites were present almost exclusively in the substantia gelatinosa of the dorsal horn. In ALS, the distribution of these 3 types of receptors was unchanged, but [3H]TCP/NMDA binding was decreased both in the dorsal and ventral horns. [3H]kainate binding was possibly decreased in substantia gelatinosa, of ALS cords. However, the limited sample size available for [3H]kainate binding did not permit statistical analysis. [3H]AMPA binding sites were unaltered in ALS. These results indicate that there is a preferential reduction in NMDA receptors in ALS. We suggest that should an excitotoxic mechanism be involved in the pathogenesis of ALS, then NMDA receptors may be the target of this effect.
 ...
PMID:Alterations in spinal cord excitatory amino acid receptors in amyotrophic lateral sclerosis patients. 132 Apr 44

We investigated glutamate receptor-mediated neurotoxicity in vivo by means of infusing three specific agonists for non-NMDA receptors (acromelic acid A (ACRO), kainic acid and 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)) into the adult rat spinal subarachnoid space. ACRO induced long-lasting pure motor, rigid-spastic paraparesis in a dose-dependent manner (EC50: 220 pmol/h) that was accompanied by selective degeneration of spinal interneurons; leaving large anterior horn cells intact. Kainate and AMPA induced paraplegia but with relatively non-selective neuronal damage when given in doses more than 40-fold larger than those required for ACRO. When AMPA (> 100 nmol/h) was infused continuously using a mini-osmotic pump for more than 2 days, rats displayed progressive changes in motor behavior due to extensive damage in the caudal spinal cord where small neurons in the dorsal horns were the most vulnerable. Co-administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) specifically prevented neurotoxicity, suggesting a non-NMDA receptor-mediated mechanism. These results indicate that the non-NMDA receptor is heterogeneous, mediating neuronal damage with different selectivity. It is also suggested that chronic activation of glutamate receptors is capable of inducing slowly progressive neuronal death, which suggests relevance to the pathogenesis of ALS.
 ...
PMID:Acute and late neurotoxicity in the rat spinal cord in vivo induced by glutamate receptor agonists. 759 34

The reduction of glutamate content has been observed in the spinal cord of the wobbler mouse, a purported model of amyotrophic lateral sclerosis (ALS). To elucidate glutamate receptors in the wobbler spinal cord, we measured densities of N-methyl-D-aspartate (NMDA), kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) and metabotropic glutamate (mGlu) binding sites using in vitro autoradiography. In wobbler mice, NMDA, kainate, and AMPA binding sites were increased in the dorsal horn and kainate binding sites were also increased in the intermediate zone. However, mGlu binding was unchanged. These results disagree with those observed in ALS spinal cords, in which NMDA and kinate binding sites are decreased. The wobbler mouse may have the glutamate dysfunction, but in a different way from ALS.
 ...
PMID:Quantitative autoradiographic distribution of glutamate receptors in the cervical segment of the spinal cord of the wobbler mouse. 795 5

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons. Glutamate, a potent central-nervous-system toxin, has been proposed as one possible factor in this motoneuron disease. Serum from patients with ALS is known to be toxic when added to neurons in culture. We report on the toxicity to rat neurons in culture of cerebrospinal fluid (CSF) from patients with ALS. CSF were obtained from 10 ALS patients, 10 neurological controls, and 10 other controls. ALS CSF was added at dilutions of 50%, 20%, or 10% and neuron survival was assessed after 24 h. The neuroprotective effects of antagonists to two glutamate receptors were also assessed. ALS CSF was significantly neurotoxic, with a neuronal survival rate of only 47% compared with 80% or so for control CSF. This neurotoxicity was blocked by CNQX, an antagonist to the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor but not by two N-methyl-D-aspartate (NMDA) antagonists. ALS CSF contains a specific neurotoxic factor which is AMPA/kainate-like which could have a role in the neuronal degeneration of this disease.
 ...
PMID:Cell culture evidence for neuronal degeneration in amyotrophic lateral sclerosis being linked to glutamate AMPA/kainate receptors. 809 16

Glutamate is one of the major excitatory neurotransmitter in the central nervous system. Glutamate acts on 4 different post synaptic receptors; NMDA (N-Methyl-D-aspartate) AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), Kainate and metabotropic receptors. The three former receptors are linked to membrane ion channels whereas metabotropic receptors are coupled with a G protein. Glutamate is involved in the physiologic processes of learning, memory and motricity. Glutamate is also a potent neurotoxin responsible for toxic neuronal death of post synaptic neurons. This action has been denominated excitotoxicity and occurs as a consequence of a prolonged or a strong activation of glutamate post-synaptic receptors. The rise in intracellular calcium seems to play a major role in the pathological events following excitotoxicity. The pathophysiology of several acute or chronic neurological disorders has been linked to excitotoxicity. This excitotoxic process could be present in acute neuronal death observed in stroke, hypoglycemia and traumatisms of the central nervous system and in chronic neuronal degeneration observed in Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease and neuro AIDS. A better knowledge of the cellular events induced by excitotoxicity will allow to consider new therapeutic approaches in various neurological disorders.
 ...
PMID:[Role of glutamate and excitotoxicity in neurologic diseases]. 876 52

Glutamate is the major mediator of fast excitatory neurotransmission in the mammalian central nervous system. Disturbances of this neurotransmitter system have been implicated in chronic degenerative neurological disease. Recently, major advances in our knowledge and understanding of the molecular biology of the glutamatergic receptor system have been made. It is now known that functional glutamate receptors consist of various combinations of some 20 identified subunits. A growing body of circumstantial evidence suggests that the non-N-methyl-D-aspartate subtype of glutamate receptors may mediate, at least in part, the selective motor neuron death seen in the human neurodegenerative disease amyotrophic lateral sclerosis. We have used subunit specific immunocytochemistry to study the distribution and potential subunit composition of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) selective glutamate receptors, (a subgroup of non-N-methyl-D-aspartate selective glutamate receptors formed by combinations of GluR1-4 subunits), in the human motor system. Motor neurons in the spinal cord, brainstem, and motor cortex were relatively strongly immunoreactive with the GluR2/3 subunit antibody, moderately so with the GluR4 subunit antibody, and showed relatively low levels of immunoreactivity with the GluR1 subunit antibody. This is the first detailed study of AMPA receptor subunit expression in the human motor system. Motor neurons express a distinct subunit profile when compared with other groups of neurons in the human nervous system. There were no significant differences in the pattern of relative AMPA subunit expression (GluR2/3 > or = GluR4 > GluR1) between groups of motor neurons typically affected (in the spinal cord and hypoglossal nucleus), or spared (oculomotor and Onufs nucleus) by the amyotrophic lateral sclerosis disease process. However, oculomotor motor neurons had higher levels of expression of all AMPA subunit proteins which may indicate greater AMPA mediated glutamatergic input in the normal function of this neuronal population. This study does not support a role for differential subunit composition of AMPA receptors in determining the selective vulnerability of motor neurons in amyotrophic lateral sclerosis. However, the overall density of receptors may be of importance.
 ...
PMID:An immunocytochemical study of the distribution of AMPA selective glutamate receptor subunits in the normal human motor system. 884 86

The cause of the selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) remains unexplained. One potential pathogenetic mechanism is chronic toxicity due to disturbances of the glutamatergic neurotransmitter system, mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive glutamate receptors. Functional AMPA receptors consist of various combinations of four subunits (designated GluR1-4). The GluR2 subunit is functionally dominant and renders AMPA receptors impermeable to calcium. Most native AMPA receptors in the mammalian central nervous system (CNS) contain the GluR2 subunit and are calcium impermeable. We have investigated the composition of AMPA receptors expressed on normal human spinal motor neurons by in situ hybridization to determine their likely subunit stoichiometry. Highly significant levels of mRNA were detected for the GluR1, GluR3, and GluR4 subunits. However, GluR2 subunit mRNA was not detectable in this cell group. The absence of detectable GluR2 mRNA in normal human spinal motor neurons predicts that they express calcium-permeable AMPA receptors unlike most neuronal groups in the human CNS. Expression of atypical calcium-permeable AMPA receptors by human motor neurons provides a possible mechanism whereby disturbances of glutamate neurotransmission in ALS may selectively injure this cell group.
 ...
PMID:Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. 926 30

Excitotoxicity secondary to the loss of glutamate transporters (GluT) has been proposed as a possible pathogenetic mechanism for neuronal degeneration in amyotrophic lateral sclerosis. We therefore investigated whether prolonged in vivo pharmacologic inhibition of GluT would result in neuronal damage in the rat. DL-Threo-beta-hydroxyaspartate (THA), a potent GluT inhibitor, and glutamate were continuously infused into the rat spinal subarachnoid space by using a mini-osmotic pump. Animals that received both THA and glutamate, but not those received either singly, displayed tail paralysis with or without hind-limb paralysis and urinary incontinence after the third postoperative day. Pathologically, symptomatic animals exhibited neuronal loss with a variable extent of gliosis preferentially involving the dorsal horn of the lumbosacral cord. In the rostral spinal segments adjacent to those regions of intense pathologic changes, small neurons in the dorsal horn were selectively destroyed, a pattern similar to the late-onset neuronal damage induced by continuous intrathecal administration of 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) [R. Nakamura et al., Brain Res. 654 (1994) 279-285]. These behavioral and pathologic changes were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), suggesting that pharmacologic blockade of GluT causes selective neuronal damage in vivo by AMPA receptor activation.
 ...
PMID:AMPA receptor-mediated slow neuronal death in the rat spinal cord induced by long-term blockade of glutamate transporters with THA. 938 6

The etiology of amyotrophic lateral sclerosis (ALS) remains unknown although an existence of neurotoxic substances in cerebrospinal fluid (CSF) from ALS patients have been postulated. In order to investigate a possible effect of CSF from ALS patients on cellular signaling in spinal neurons, we compared Fos-like immunoreactivity (Fos-LI) in organotypic cultures of rat lumbar spinal cord after addition of CSF from ALS patients or another neurologic disease. Fos-LI was normally present predominantly in dorsal horn neurons, whereas only a few ventral horn neurons were positive for Fos-LI. The number of Fos-LI positive neurons significantly increased in dorsal horn with addition of CSF from ALS patients as well as glutamate at 100 microM. However, the increase was not observed with addition of CSF from other neurologic diseases. The increase in Fos-LI positive neurons in dorsal horn was reversed by a further supplement of MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, but not of CNQX, an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate antagonist. These results indicate that there may be substances in CSF from ALS patients that stimulate Fos expression in certain populations of spinal neurons via the NMDA receptors.
 ...
PMID:Enhanced Fos expression in rat lumbar spinal cord cultured with cerebrospinal fluid from patients with amyotrophic lateral sclerosis. 1031 42

Amyotrophic lateral sclerosis is characterized by motoneuron degeneration, in which glutamate-induced cell death is thought to play a pathogenic role. This excitotoxic process is mediated by cytosolic Ca2+ overload. The glutamatergic ionotropic channel molecules, which constitute a major route of Ca2+ entry, were present on cultured spinal motoneurons. Using ratio RT-PCR, the relative presence in isolated motoneurons of the GluR subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor was evaluated. GluR1 and GluR2 mRNAs were present abundantly, while GluR3 and GluR4 mRNAs were much less abundant. The relative amount of mRNAs encoding the different protein isoforms responsible for Ca2+ uptake into the internal stores and for controlled release of Ca2+ from these stores was also determined. For the sarco/endoplasmic reticulum Ca2+ ATPases (SERCAs), only the SERCA2b class 4 splice variant was found. The inositol 1,4,5-trisphosphate receptor (IP3R) mRNAs were mainly transcribed from the IP3RI and IP3RII genes. Heterogeneity was also observed for the ryanodine receptors (RyR) as the RyR1, RyR2 and RyR3 mRNAs were present.
 ...
PMID:Calcium handling proteins in isolated spinal motoneurons. 1057 26


1 2 3 4 Next >>