Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of non-competitive (MK-801, phencyclidine, and ketamine) and competitive (CGP 39551, CGS 19755, and NPC 12626) N-methyl-D-aspartate (NMDA) receptor antagonists on locomotor activity in inbred CBA and C57, and in outbred NMRI mice were examined. Administration of the non-competitive NMDA antagonists produced a dose-dependent increase in well-coordinated locomotor activity at lower doses, followed by a bizarre behavioral syndrome (head weaving, body rolling, rotations, ataxia) after higher doses. The pharmacological profile of the competitive antagonists CGP 39551, CGS 19755, and NPC 12626 was more complex. CGP 39551 dose-dependently inhibited locomotor activity, whereas CGS 19755 and NPC 12626 displayed a biphasic action, that is low doses inhibited locomotor activity, whereas higher doses produced mild behavioral stimulation. The behavioral effects of NMDA antagonists appear to be genetically determined, since CBA animals were most sensitive to both non-competitive and competitive antagonists, followed by NMRI and C57 animals. The differential effects of NMDA antagonists in various strains of mice suggest that the observed behavioral differences may be due to genetic differences in the NMDA/glutamate receptor channel complex.
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PMID:Genetic differences in the effects of competitive and non-competitive NMDA receptor antagonists on locomotor activity in mice. 183 7

Canine Inherited Ataxia (CIA) is an autosomal recessive cerebellar disease of Gordon Setters associated with degeneration of Purkinje and granule cells. To define specific biochemical correlates of neuronal loss, synaptic neurochemical parameters were measured in three cerebellar regions (vermis, "pars intermedia," and hemisphere) at early and late stages of this disease. At one and a half years of age, affected dogs showed the most severe lesions in the "pars intermedia," with a 39% decrease in the number of Purkinje cells and a 29% decrease in granule cells. Neurochemical measurements demonstrated decreased [3H]muscimol binding and elevations in norepinephrine concentration (248% above control) and [3H]glutamate receptor binding (118% above control). At five years of age, reduction of Purkinje cells in the three cerebellar regions ranged from 65 to 91% while loss of granule cells was between 13 and 53%. [3H]Muscimol binding remained low throughout the cerebellum (38 to 59% of control) and norepinephrine concentration and [3H]glutamate binding were markedly reduced from the levels observed at one and a half years. Glutamate decarboxylase activity, [3H]QNB binding and GABA concentration were relatively unaffected. Our results indicate that neurochemical parameters associated with cerebellar neuronal systems demonstrate specific alterations in a chronic degenerative disorder. This study also indicates the importance of evaluating neurochemical measurements with regard to both spared and degenerating neuronal systems and emphasizes the role of compensatory neurochemical alterations in cerebellar degenerative disorders.
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PMID:Synaptic neurochemical alterations associated with neuronal degeneration in an inherited cerebellar ataxia of Gordon Setters. 650 89

Amantadine has been shown to displace [3H]MK 801 from its binding site on the NMDA receptor. We have therefore studied the motor effects of amantadine in normal and 24 h reserpine-treated mice to determine whether the behavioural profile of this drug resembles that of other NMDA receptor antagonists (e.g. MK 801). In common with the latter, amantadine (5-40 mg/kg IP) produced a modest dose-dependent sedation in dopamine-intact mice, with a reduction in locomotion and other species-typical behaviours (e.g. rearing and grooming), but with no signs of the hyperactivity, stereotypy, ataxia or loss of muscle tone commonly seen with MK 801. Amantadine (5-80 mg/kg IP) effected a small increase in motility in akinetic reserpine-treated mice by itself, but this response was highly variable and not statistically significant. As with MK 801, amantadine significantly inhibited the locomotion induced by the selective D2 agonist RU 24213 (5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.5 mg/kg SC) in monomine-depleted mice, without altering the animals' responsiveness to threshold doses of these drugs. However, amantadine did not facilitate the locomotion induced by threshold (3 mg/kg IP) or fully active doses (30 mg/kg IP) of the selective D1 agonist SKF 38393, which distinguishes amantadine from other NMDA receptor blockers. Since the potentiation of dopamine D1-dependent locomotion may be a major factor in the antiparkinson activity of MK 801 and other glutamate receptor antagonists, the inability of amantadine to potentiate SKF 38393 in this study suggests the mechanism of its anti-akinetic activity differs from that of conventional glutamate blocking drugs.
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PMID:Locomotor effects of amantadine in the mouse are not those of a typical glutamate antagonist. 760 88

We examined the abilities of 7-nitroindazole and methylene blue, inhibitors of the neuronal isoform of nitric oxide synthase (NOS) and nitric oxide-stimulated guanylate cyclase activity respectively, to attenuate explosive episodic jumping behavior(s) ("popping") elicited by MK-801 in mice. MK-801, like phencyclidine (PCP), is a high-affinity, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. We have postulated that MK-801-elicited popping behavior in mice represents an animal model of schizophrenia, because popping behavior is markedly inhibited/antagonized by both typical and atypical antipsychotic drugs. In the present study, popping behavior induced by MK-801 was measured using an automated detection system that quantifies vertical displacements on the testing platform. 7-Nitroindazole (100 mg/kg) and methylene blue (32 and 100 mg/kg) significantly reduced the number and force of MK-801-elicited popping behavior. Mouse rotorod performance did not differ between animals receiving 7-nitroindazole, methylene blue, or their respective vehicles, suggesting that attenuation of MK-801-elicited popping behavior was not due to either sedation or ataxia caused by 7-nitroindazole or methylene blue. Our findings suggest that nitric oxide may, in part, mediate behaviors induced by NMDA receptor antagonists, like MK-801, and that inhibitors of NOS may have antipsychotic actions.
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PMID:7-Nitroindazole and methylene blue, inhibitors of neuronal nitric oxide synthase and NO-stimulated guanylate cyclase, block MK-801-elicited behaviors in mice. 879 90

Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous Lurcher mice (Lc/+) display ataxia as a result of a selective, cell-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal development. Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid- and hindbrain neurons during late embryogenesis. We have used positional cloning to identify the mutations responsible for neurodegeneration in two independent Lc alleles as G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta2 glutamate receptor gene (GluR delta2). Lc/+ Purkinje cells have a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta2(Lc) protein in Xenopus oocytes confirmed these results, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Thus the activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death.
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PMID:Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. 928 76

The antiepileptic drug (AED) topiramate is a monosaccharide derivative with a sulfamate functionality. It modulates voltage-dependent sodium conductance, potentiates gamma-aminobutyric acid-evoked currents, and blocks the kainate/AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of the glutamate receptor. Topiramate is rapidly absorbed and has linear, proportional, steady-state pharmacokinetics. It has no known clinically significant effect on plasma levels of carbamazepine, valproic acid, or phenobarbital, although it may increase plasma concentrations of phenytoin in some patients. When topiramate is used with hepatic enzyme-inducing AEDs, its plasma concentrations are approximately 50% lower than when it is administered alone. The efficacy of topiramate 200 to 1000 mg/d administered in two divided doses as adjunctive therapy for partial-onset seizures was investigated in five double-masked, placebo-controlled trials. The median percentage reduction in average monthly seizure frequency from baseline was 12% for placebo, compared with 30% for the 200-mg/d group and 48% for the 400-mg/d group. At a dosage of 400 mg/d, a seizure reduction of 75% or greater was seen in 22% of topiramate patients, compared with 7% of those receiving placebo; up to 9% of topiramate patients, compared with none of those receiving placebo, became seizure free. Although little additional efficacy was seen at dosages of 600, 800, and 1000 mg/d, dosing should be individualized, because some patients may respond to higher dosages. When topiramate is combined with other AEDs, the most common side effects at dosages of 200 to 400 mg/d are somnolence, dizziness, ataxia, psychomotor slowing, hesitant speech, and wordfinding difficulties. Most patients who experienced adverse events during the first 8 weeks of the trials no longer experienced them by their last visit. Although there was a 1.5% incidence of renal stones that may be associated with carbonic anhydrase inhibition, more than 75% of patients experiencing a stone continued on therapy.
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PMID:Topiramate: a review of preclinical, pharmacokinetic, and clinical data. 944 41

Mice infected with the LP-BM5 murine leukemia virus (MuLV) develop an immune deficiency syndrome together with an encephalopathy characterized by impairments in spatial learning and memory. These cognitive deficits are evident before the appearance of neuron loss and lymphoid cell invasion of the brain. Nonetheless, a prominent gliosis and a variety of neurochemical changes precede the development of cognitive deficits. The neurochemical abnormalities include significant decreases in striatal Met-enkephalin and substance P (but not somatostatin), increases in concentrations of quinolinic acid and platelet-activating factor, and alterations in brain fyn kinase. At this stage of the infection, some of these neurochemical changes can be reversed by glutamate receptor antagonists, cytokine inhibitors, and anti-retroviral agents. In later stages of the infection, however, the infected mice develop irreversible neuronal loss, invasion of hematopoietic cells, and increased viral burden in the CNS. In addition, motor-neuron dysfunction (hindlimb paralysis, weakness, and ataxia) and seizures are sometimes observed during the late stages of infection. Thus, the LP-BM5 MuLV-infected mouse is a useful model for studying the chronology of neurodegenerative changes, ranging from reversible neuron dysfunction to irreversible neuron loss, that are associated with retrovirus-induced immunodeficiency.
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PMID:The encephalopathy associated with murine acquired immunodeficiency syndrome. 962 8

The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethylimidazo[1,2a]quinoxal ine-2-carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). In comparison, the prototype non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose-dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED50 of 4.9 mg kg(-1). Up to 20 mg kg(-1), only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg(-1), and the glycine/NMDA site antagonist L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent.
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PMID:LU 73068, a new non-NMDA and glycine/NMDA receptor antagonist: pharmacological characterization and comparison with NBQX and L-701,324 in the kindling model of epilepsy. 986 55

Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous lurcher mice (Lc/+) display ataxia due to a selective, cell-autonomous, apoptotic death of 90% of cerebellar Purkinje cells during postnatal development. Homozygous lurcher mice (Lc/Lc) die shortly after birth due to massive loss of mid- and hindbrain neurons during late embryogenesis. We identified the mutations responsible for neurodegeneration in two independent Lc alleles as identical G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta 2 glutamate receptor gene (GluRE2). Lc/+ Purkinje cells displayed a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta 2Lc protein in Xenopus oocytes confirmed these results, demonstrating that lurcher is an inherited neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Further characterization of GluR delta 2 signaling and the activation of apoptotic death in Lc Purkinje cells have begun to yield mechanistic insights into this neurodegenerative disease, and to highlight its relationship to neuronal loss following ischemia.
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PMID:GluR delta 2 and the development and death of cerebellar Purkinje neurons in lurcher mice. 1041 27

The orphan glutamate receptor delta2 is selectively expressed in Purkinje cells and plays a critical role in cerebellar function. Recently, the ataxia of hotfoot-4J (ho-4J) mice was shown to be caused by a 170-amino acid deletion in the N-terminal region of delta2 receptors. To understand delta2 receptor function, we characterized these mutant receptors (delta2ho) in Purkinje cells. Immunohistochemical staining showed that delta2ho receptors of the ho-4J homozygotes were abundantly expressed but localized to the Purkinje cell soma; in wild-type mice, delta2 receptors were predominantly present at distal dendrites of Purkinje cells. In addition, delta2ho receptors of the ho-4J mice were sensitive to endoglycosidase H, a finding suggesting that delta2ho receptors were not transported beyond the endoplasmic reticulum (ER) or cis-Golgi apparatus. To gain further insights into the mechanisms of this phenomenon, we characterized delta2ho receptors in transfected HEK293 cells. delta2ho receptors expressed in HEK293 cells were also sensitive to endoglycosidase H. Immunohistochemical staining showed that delta2ho receptors colocalized with proteins retained in the ER. Furthermore, delta2ho receptors were not labelled by membrane-impermeable biotinylation reagents. Coimmunoprecipitation assays showed that the intermolecular interaction of delta2ho receptors was significantly weaker than those of wild-type delta2 receptors, a finding suggesting that the ho-4J region is involved in oligomerization of delta2 receptors. Thus, delta2ho receptors were retained in the ER, probably by the quality control mechanism that detects unstable oligomers. We conclude that the absence of delta2 receptors on the cell surface by failed transport from the ER of Purkinje cells causes ataxia.
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PMID:Mutation in hotfoot-4J mice results in retention of delta2 glutamate receptors in ER. 1240 64


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