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)

Rats rendered diabetic by alloxan monohydrate were studied to investigate the effect of increased blood glucose upon the concentration of various putative neurotransmitter amino acids in the cerebellum. No modification was found in the concentrations of glutamate, gamma aminobutyric acid (GABA), glutamine, glycine or taurine, but there was a significant decrease in the cerebellar concentration of aspartate in the diabetic animals. This raises the question of the specificity of the aspartic acid defect found in some form of ataxia.
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PMID:Effect of alloxan diabetes on cerebellar amino acids. 64 90

The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the novel competitive NMDA receptor antagonist CGP 39551 on levels of 11 amino acids, including several excitatory and inhibitory neurotransmitters, were studied in 12 brain regions of rats. Both drugs were administered at doses which produced comparable behavioural effects (ataxia, hyperactivity). Amino acids were determined in brain tissue by high-performance liquid chromatography after o-phthaldialdehyde precolumn derivatization. MK-801 (0.1 mg/kg, i.p.) moderately increased the concentration of glutamate and GABA in several brain regions. Other amino acids (glutamine, taurine, asparagine, alanine, serine) were only altered in single brain regions, or were not altered at all (aspartate, glycine, threonine, arginine). In contrast to MK-801, CGP 39551 (10 mg/kg, i.p.) increased glutamate levels only in the cerebellum, and produced no significant alterations in levels of GABA. The data demonstrate differences in alterations of amino acid levels in response to competitive and non-competitive NMDA receptor antagonists and support the assumption that competitive NMDA antagonists may be more selective than non-competitive antagonists.
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PMID:Regional alterations in brain amino acids after administration of the N-methyl-D-aspartate receptor antagonists MK-801 and CGP 39551 in rats. 167 57

GDEE, an antagonist of the AA2 or quisqualic acid category of excitatory amino acid receptor, decreases behavioral activity and locomotor stimulation induced by cocaine and amphetamine when locally injected into the nucleus accumbens. The present experiment was intended to examine the effects of systemic GDEE and other excitatory amino acid antagonists on stimulant-induced locomotor activity. GDEE markedly attenuated the stimulant effect of amphetamine, and partially blocked the effects of phencyclidine (PCP). Apomorphine-induced cage climbing behavior was partially decreased by lower dosages of GDEE, but was almost completely blocked by the highest dosage tested. Amphetamine-induced stimulation of locomotor activity was not decreased by any of the other excitatory amino acid antagonists that were tested, including MK-801, 2-amino-7-phosphonoheptanoic acid (APH), or CNQX. APH decreased stereotypy only at a high dosage (250 mg/kg), which also produces ataxia. Several other compounds, including L-glutamic acid gamma ethyl ester (GMEE), L-glutamic acid, glycine, and L-glutamine did not block amphetamine-induced stimulation in molar dosages equivalent to the highest dosage of GDEE (8 mmol/kg). It is concluded that the AA2 excitatory amino acid receptor is important in the expression of activating effects of stimulant drugs.
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PMID:A possible role of AA2 excitatory amino acid receptors in the expression of stimulant drug effects. 197 5

Thallium, a rodenticide, has been shown to produce several neurological symptoms including motor weakness, ataxia, tremor, convulsion, coma and death. The present study was designed to evaluate the effects of acute or subacute exposure to thallium on several neurochemical biomarkers in rat brain. In the acute study, adult male CD rats were treated with 0 or 20 mg thallium/kg intraperitoneally (ip) and sacrificed 2, 6, or 24 hr after exposure. In the subacute study, animals were treated with 0 or 5 mg thallium/kg ip daily for 10 days and sacrificed 24 hr after the last dose. Acute injections of thallium produced in the frontal cortex significant increases in glutamine concentration after 6 hr and in taurine after 6 and 24 hr. In hippocampus, significant decreases in aspartic acid and taurine concentrations were found after 6 hr. Subacute exposure to thallium produced significant increases of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and serotonin (5-HT) in amygdala and increases in 5-HT concentration in hypothalamus. DA or muscarinic cholinergic (MCh) receptor binding did not show any significant alterations in caudate nucleus or frontal cortex after acute or subacute exposure to thallium. However, when membranes prepared from control caudate nuclei were incubated with thallium (1-100 microM) in vitro, we observed a dose-dependent decrease in DA and MCh receptor binding. These data suggest that the neurotoxicity produced by thallium exposure may be associated with changes in the concentrations of amino acids and other neurotransmitters in various regions of the rat brain.
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PMID:Thallium intoxication produces neurochemical alterations in rat brain. 217 76

Acivicin is an investigational amino acid antitumor antibiotic currently being evaluated in Phase II clinical trials. In humans acivicin causes reversible, dose-limiting central nervous system (CNS) effects including somnolence, ataxia, personality changes, and hallucinations. We have observed and reported previously that acivicin-treated cats exhibit symptoms (ataxia, sedation, somnolence) resembling CNS toxicity reported in humans. We hypothesized that if acivicin uptake into brain were mediated by a saturable transport system common to endogenous amino acids, drug uptake and CNS toxicity might be blocked by elevation of normal amino acid concentrations in circulating plasma. To test this hypothesis, cats received constant-rate i.v. infusions of either saline or Aminosyn, 10% (a commercially available mixture of 16 amino acids not containing glutamine, glutamate, aspartate, or cysteine) for 4 h prior to and 18 h subsequent to administration of acivicin at a dose producing marked behavioral changes in control cats. Presence or absence of ataxia and sedation were noted at intervals after acivicin treatment. Results showed that Aminosyn infusion prevented CNS symptoms in six of eight cats. Subsequent experiments showed that acivicin levels in brain tissue of Aminosyn-treated cats were 13% of the drug levels in saline-infused cats. Acivicin levels in most peripheral tissues were also decreased significantly by Aminosyn infusion but not to the extent observed in brain. Decreased brain uptake was shown to be due to a combination of amino acid blockade of drug transport into that organ and of increased total body clearance of drug. Concomitant Aminosyn treatment did not alter the efficacy of acivicin in mice bearing L1210 leukemia or MX-1 human mammary carcinoma. Further studies demonstrated that a solution containing only four large neutral amino acids (leucine, isoleucine, phenylalanine, and valine) could also protect cats from acivicin-induced CNS toxicity, apparently without increasing acivicin total body clearance. However, a mixture of several other amino acids contained in Aminosyn (alanine, arginine, tyrosine, histidine, proline, serine, and glycine) failed to prevent CNS toxicity. We conclude that cotreatment with Aminosyn or a mixture of large neutral amino acids could protect cancer patients from acivicin-induced CNS toxicity without ablating antitumor efficacy.
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PMID:Prevention of central nervous system toxicity of the antitumor antibiotic acivicin by concomitant infusion of an amino acid mixture. 238 52

The investigational amino acid antitumor agent, acivicin, has been reported to cause dose-related and reversible CNS toxicity in humans characterized by sedation, ataxia, hallucinations, personality changes, and other symptoms. In a series of studies aimed at characterizing this toxicity, we investigated several species as potential animal models, determined the effects of acivicin on neuronal action potentials, and measured drug effects on the brain content of several putative amino acid neurotransmitters. In mice, we were unable to demonstrate any effects of acivicin in a battery of tests used in identifying and classifying CNS-active agents of potential therapeutic utility. In rats, unlike phencyclidine and certain other psychotomimetic drugs, acivicin produced no impairment of shock avoidance or brightness discrimination in animals trained on an automated Y-maze. In contrast to the rodent species, acivicin effects were perceived as resembling those of cyclazocine by rhesus monkeys trained to discriminate between psychoactive drugs and saline by food reinforcement. Cats treated with acivicin exhibited dose-related symptoms of sedation, somnolence, and ataxia. Iontophoretically applied acivicin was shown to have no effect on the spontaneous firing rate of dorsal horn interneurones in spinal cats. At the time of peak CNS symptoms in cats treated with 100 mg/kg acivicin, content of gamma-aminobutyric acid (GABA; nmoles/mg protein) was elevated from 57-140% in cerebellum, diencephalon, midbrain, and corpus callosum compared to control animals. Brain contents of glutamate, glutamine, and aspartate were not altered in cats experiencing neurotoxicity. These studies have shown that some symptoms of acivicin CNS toxicity are shared by humans and higher non-human species such as the cat and the monkey but not by rodents. Acivicin itself is apparently not a CNS excitant or depressant, but metabolites of the drug could be. Acivicin may also cause increases in the GABA content of localized regions of brain.
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PMID:Animal behavioral and neurochemical effects of the CNS toxic amino acid antitumor agent, acivicin. 271 Oct 26

Five vervet monkeys were administered increasing doses (4--12 mg/kg/day) of d-amphetamine over a period of 35 days. Three phases od behavioural change were discerned: phase 1 during which animals exhibited repetitive stereotyped action sequences with rapid head movements, occasional abnormal grooming, picking at the cage, hand-staring and snatching; phase 2 in which behaviour became progressively more restricted and animals became markedly unresponsive to auditory, visual and tactile stimuli; phase 3 was characterised by the abrupt development of gross over-responsiveness to environmental stimuli, ataxia and tremor. At post-mortem, by comparison with controls, amphetamine-treated monkeys showed marked depletions of the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in corpus striatum and cerebral cortex and reductions in the activities of tyrosine hydroxylase and dopa decarboxylase in striatum. Turnover of these monoamines, assessed by high-performance liquid chromatography determinations of their respective metabolites, was also reduced. These findings are interpreted as evidence of monoamine neurone destruction, most severely in the case of DA neurones. Though there was a non-significant reduction in 3H-spiperone binding (reaching almost 50% in nucleus accumbens), numbers of receptors for the monoamines nA and 5-HT were not significantly changed, and the activities of the enzymes choline acetyltransferase and glutamine decarboxylase were similar in experimental and control animals. The contrast of these findings with those seen in post-mortem brains in schizophrenia is discussed.
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PMID:Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey. 613 May 56

Acivicin, an L-glutamine antagonist, was administered to 37 evaluable patients with refractory advanced solid tumors in a phase I trial. A total of 67 evaluable 72-hr iv infusions were given at 3- to 4-week intervals. Doses ranged from 3.0 to 90 mg/m2/course. Reversible CNS toxicity was dose-limiting and included lethargy, somnolence, anxiety, hallucinations, and paranoid psychoses. Four of five patients experienced unacceptable CNS toxicity at 90 mg/m2. Three of eight patients experienced reversible diaphoresis and chills without fever at 75 mg/m2, and two had dizziness and ataxia. Hematopoietic toxicity, nausea, emesis, and diarrhea were mild and dose-related. One patient developed a blue-green discoloration of the infusion arm. Serial plasma and urine specimens from 13 patients were assayed for acivicin using a microbiologic method. Peak plasma levels at the end of the 72-hr infusions correlated with dose and ranged from 0.09 to 1.10 microgram/ml. When data from six patients were fitted to a two-compartment open model, alpha-half-life ranged from 1.1 to 63 mins, while beta-half-life ranged fro 338 to 629 mins. Renal clearance ranged from 6 to 24 mL/min, and nonrenal clearance accounted for 58%-83% of the total drug clearance. CNS toxicity correlated with plasma acivicin levels which exceeded 0.9 microgram/ml for greater than 16 hrs, but not with peak plasma levels or with the integrals of the concentration x time curves. Minor responses were seen in one patient with melanoma, in one with epidermoid pulmonary carcinoma, and in two with colon carcinoma. A starting dose of 60 mg/m2/course was recommended for phase II trials, with possible escalation to 75 mg/m2 in the second course if the drug was well-tolerated.
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PMID:Phase I trial and pharmacokinetics of acivicin administered by 72-hour infusion. 687 83

Expansion of trinucleotide repeats is now recognized as a major cause of neurological disease. At least seven disorders result from trinucleotide repeat expansion: X-linked spinal and bulbar muscular atrophy (SBMA), two fragile X syndromes of mental retardation (FRAXA and FRAXE), myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). The expanded trinucleotide repeats are unstable, and the phenomenon of anticipation, i.e., worsening of disease phenotype over successive generations, correlates with increasing expansion size. In this review, we compare the clinical and molecular features of the trinucleotide repeat diseases, which may be classified into two types. Fragile X and myotonic dystrophy are multisystem disorders usually associated with large expansions of untranslated repeats, while the four neurodegenerative disorders, SBMA, Huntington's disease, SCA1, and DRPLA, are caused by smaller expansions of CAG repeats within the protein coding portion of the gene. CAG repeats encode polyglutamine tracts. Polyglutamine tract expansion thus appears to be a common mechanism of inherited neurodegenerative disease. Although polyglutamine tract lengthening presumably has a toxic gain of function effect in the CAG trinucleotide repeat disorders, the basis of this neuronal toxicity remains unknown.
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PMID:Trinucleotide repeat expansion in neurological disease. 799 66

A subgroup of trinucleotide repeat diseases result from abnormal expansions of CAG repeats which are translated into polyglutamine stretches. As yet there is little understanding of how the polyglutamines function either normally, or when expanded. We have investigated these sequences in the Machado-Joseph disease, androgen receptor and spinocerebellar ataxia type 1 genes in humans and other primates. None of the 748 normal chromosomes that were examined had more than 34 uninterrupted glutamine codons in the Machado-Joseph disease gene. Similarly, no normal alleles with more than 39 uninterrupted glutamine codons have been reported for the other disease genes associated with polyglutamine expansions. Sequence analyses of the repeats in primates revealed shorter polyglutamine stretches in some of the non-human primates at all three loci and marked diversions from the expected polyglutamines in the orang-utan Machado-Joseph gene and in the marmoset spinocerebellar ataxia type 1 gene. These data suggest that conservation of these polyglutamine stretches may not always be necessary for normal gene function.
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PMID:Sequence variation and size ranges of CAG repeats in the Machado-Joseph disease, spinocerebellar ataxia type 1 and androgen receptor genes. 854 43


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