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)

Superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6) are important enzymes involved in protection of the cell from harmful effects of oxidative degradation. The respective substrates for these enzymes, superoxide anion and hydrogen peroxide, can be generated within the cell either by normal metabolism or by ionizing radiation. The hypothesis that the inherent radiosensitivity associated with the human autosomal recessive disease Ataxia telangiectasia is due to decreased levels of SOD and/or catalase was tested. The results suggest that fibroblast cells derived from ataxia patients are normal with respect to these two enzymes.
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PMID:Superoxide dismutase and catalase activities in Ataxia telangiectasia and normal fibroblast cell extracts. 48 42

The effect of excitatory amino acid receptor antagonists, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5, 10-imine hydrogen maleate ((+)-MK-801), (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and (+/-)-2-amino-4-phosphonobutanoic acid (AP-4), on penile erection and yawning induced by subcutaneous apomorphine (80 micrograms/kg), intracerebroventricular (i.c.v.) oxytocin (30 ng) and adrenocorticotropin (ACTH)-(1-24) (10 micrograms) was studied in male rats. Intraperitoneal (0.1-0.4 mg/kg) and i.c.v. (10-50 micrograms) (+)-MK-801 prevented dose dependently the penile erection and yawning induced by the three drugs. The (+)-MK-801 effect coincided with the appearance of head weaving, body rolling, hyperlocomotion and ataxia. Haloperidol (0.5 mg/kg i.p.) antagonized the prevention by (+)-MK-801 of oxytocin responses. Penile erection but not yawning was also prevented by high, but not low doses of CPP and CNQX, which impaired motor performance, AP-4 was ineffective at all doses tested. The above compounds were ineffective when injected into the paraventricular nucleus of the hypothalamus, the brain area where apomorphine and oxytocin act to induce penile erection and yawning. The results suggest that excitatory amino acid transmission is not involved in the expression of penile erection and yawning induced by the above compounds.
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PMID:Effect of excitatory amino acid receptor antagonists on apomorphine-, oxytocin- and ACTH-induced penile erection and yawning in male rats. 135 47

The toxicity, uptake, tissue distribution, elimination, and covalent binding of 2-[14C]methyl-[2.3-14C]acrylonitrile (MeAN) in male Sprague-Dawley rats were investigated. Following an oral administration of 100 mg/Kg body weight (0.5 LD50, 8 microCi/Kg bw) the rats exhibited several signs of toxicity including ataxia, convulsions, mild diarrhea, salivation, lacrimation, and bladder urine retention. The treated animals excreted 43% of the 14C in the urine, 14% in the feces, and 2.5% in the expired air as 14CO2 in 10 days. Hydrogen cyanide was not detectable. Red blood cells retained significant amounts of radioactivity for more than 10 days after treatment. MeAN was extensively absorbed through the gastrointestinal tract and distributed in all the tissues of the rats. The major concentrations of the radioactivity were found with up to 25% of the administered dose in bone, liver, spleen, kidney, blood, and the gastrointestinal tract. This study indicates that MeAN is rapidly absorbed and distributed and the major route of excretion is urinary.
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PMID:Toxicity and tissue distribution of methacrylonitrile in rats. 227 63

2-(Diethylamino)-N-[4-(2-fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl] acetamide (1) was recently found to have an antipsychotic-like profile in behavioral animal tests but, unlike clinically available antipsychotic agents, did not interact with dopamine receptors. Compound 1 was apparently metabolized to (5-amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (2), which was both active in the behavioral animal tests and toxic. The synthesis and pharmacological evaluation of a series of 1,3-dialkyl-4-(iminoarylmethyl)-1H-pyrazol-5-ols are described in which the hydroxy and imine functionalities were selected as possible isosteric replacements for the amino and ketone groups of the earlier series. The initial target, 1,3-dimethyl-4-(iminophenylmethyl)-1H-pyrazol-5-ol (28), like known antipsychotics, reduced spontaneous locomotion in mice at doses that did not cause ataxia, and unlike known agents, it did not bind to D2 dopamine receptors in vitro. An examination of the SAR of related compounds indicated that maximal activity was obtained with analogues containing methyl groups at the 1- and 3-positions on the pyrazole ring and with a 3-chloro substituent on the phenyl ring. Replacement of the hydrogen atom of the imine moiety with various substituents led to loss of activity. Attempts to synthesize the 2-fluorophenyl compound analogous to 2 resulted in ring-closure to 1,3-dimethyl[1]benzopyrano[2,3-c]pyrazol-4-(1H)-one (65). 4-[(3-Chlorophenyl)iminomethyl]-1,3-dimethyl-1H-pyrazol-5-ol (41) was evaluated in additional tests. It inhibited conditioned avoidance responding in both rats and monkeys but, unlike available antipsychotic drugs, did not elicit dystonic movements in a primate model of antipsychotic-induced extrapyramidal side effects.
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PMID:1,3-Dialkyl-4-(iminoarylmethyl)-1H-pyrazol-5-ols. A series of novel potential antipsychotic agents. 288 97

Vitamin E malabsorption and deficiency during chronic childhood cholestasis has been associated with a progressive ataxic neurologic syndrome. Hyporeflexia, the first sign of neurologic dysfunction, may begin prior to age 2 years, but severe symptoms do not develop until age 5 to 10 years. To establish the age of onset of neuropathologic lesions, we prospectively evaluated four young children with severe cholestasis. Malabsorption and deficiency of vitamin E were documented by low serum vitamin E concentrations, low serum vitamin E to total serum lipids ratios, elevated hydrogen peroxide hemolysis, and impaired absorption of a pharmacologic dose of alpha-tocopherol. Abnormal neurologic findings in two patients were limited to areflexia, ptosis, mild truncal ataxia, and hypotonia; two patients had minimal signs of neurologic dysfunction. Sural nerve histology at age 6 to 25 months revealed a degenerative axonopathy involving large-caliber myelinated fibers, but without quantitative axonal loss. Muscle histology and histochemistry tests yielded normal results. Our study suggests that neurologic injury may occur during the first two years of life in vitamin E-deficient children with cholestatic hepatobiliary disease, obligating aggressive attempts at correcting this deficiency state at a very young age.
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PMID:Vitamin E deficiency during chronic childhood cholestasis: presence of sural nerve lesion prior to 2 1/2 years of age. 630 96

Antagonists of the NMDA receptor-channel complex may be useful for the treatment of thrombotic stroke, head injury and epilepsy. Their clinical use, however, could be limited by the incidence of side effects such as ataxia. I have therefore investigated the relationship between functional antagonism of the N-methyl-D-aspartate (NMDA) receptor-channel complex in vivo and disturbances of motor coordination. Antagonism of the NMDA receptor-channel complex was assessed by measuring a compounds ability to inhibit NMDA-induced lethality in mice, disturbances of motor coordination were measured by the rotarod technique. NMDA dose-dependently induced convulsions and ultimately caused death in mice (LD50 = 137 +/- 4 mg/kg i.p.). Noncompetitive NMDA antagonists of either an arylcyclohexylamine (phencyclidine, (+)/(-)-MK-801 [10-11-dihydro-5-methyl-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate] and ketamine) or a benzomorphan (dextrorphan and N-allylnormetazocine) structure, competitive antagonists (CGP 37849 [(R,S)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid monohydrate] and CGP 39551 [(R,S)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid 1-ethyl ester]) or a glycine site antagonist (L-687,414 [(3R,4R)-3-amino-4-methyl-1-hydroxy-pyrrolidin-2-one-(-)-tartrate salt]) inhibited NMDA-induced lethality after s.c. administration. These compounds also interfered with motor coordination. There was an excellent correlation (r = 0.97) between the two effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Many agents that antagonize the NMDA receptor-channel complex in vivo also cause disturbances of motor coordination. 751 20

The role of the N-methyl-D-aspartate (NMDA) receptors in hyperlocomotion induced by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), a potent and selective noncompetitive NMDA receptor antagonist, was examined in male ddY mice. A low dose of MK-801 [0.2 mg/kg, intraperitoneally (IP)] produced a marked increase in locomotor activity without obvious staggering gait. In contrast, a high dose (1 mg/kg, IP) induced a typical motor syndrome characterized by increased locomotor activity, stereotyped behavior, and severe ataxia. NMDA (60-120 mg/kg, IP), an NMDA receptor agonist, dose dependently antagonized hyperlocomotion induced by a low dose of MK-801 (0.2 mg/kg). However, even a high convulsive dose of NMDA (240 mg/kg, IP) could not completely antagonize the hyperactivity induced by MK-801. On the other hand, neither a high dose of N-methyl-L-aspartate (400 mg/kg, IP), a stereoisomer of NMDA, nor a critical subconvulsive dose of kainate (10 mg/kg, IP), a non-NMDA receptor agonist, reversed MK-801-induced hyperlocomotion. The activity induced by MK-801 was potently suppressed by low doses of haloperidol (0.05-0.1 mg/kg, IP), a dopamine (DA) receptor antagonist, in a dose-dependent manner. These data for MK-801 were similar to those for phencyclidine and ketamine, other noncompetitive NMDA receptor antagonists. These results suggest that noncompetitive NMDA receptor antagonist-induced hyperlocomotion is mediated, at least in part, by NMDA receptor antagonism, although this hyperactivity may also involve dopaminergic mechanisms through indirect (perhaps by reducing NMDA receptor-mediated neurotransmission) and/or direct (by inhibiting DA uptake) effects on DA neurons.
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PMID:Involvement of N-methyl-D-aspartate (NMDA) receptors in noncompetitive NMDA receptor antagonist-induced hyperlocomotion in mice. 766 42

The toxicity, uptake, tissue distribution, elimination, and covalent binding of [1-14C]allylnitrile (ALN) in male Sprague-Dawley rats were investigated. Following an oral administration of 57.5 mg/kg body weight (0.5 LD50, 23.4 mu Ci/kg, body weight), the rats exhibited several signs of toxicity, including ataxia, convulsions, mild diarrhea, salivation, lacrimation, and bladder urine retention. The treated animals excreted 41% of the radioactivity in the urine, 6% in the feces, and 34% in the expired air in 10 days. Hydrogen cyanide was not detectable in the expired air. Red blood cells retained significant amount of radioactivity for more than 5 days after treatment. ALN was extensively absorbed through the gastrointestinal tract and distributed in all the tissues of the rats. The major concentrations of the radioactivity were found in bone, kidney, blood, and the gastrointestinal tract. The subcellular fractions of the liver, kidney, heart, lung, and brain showed substantial accumulation of radioactivity from ALN up to 48 hr following dosing. Among the chemical fractions of the liver, the proteins exhibited much higher retention of radioactivity from ALN than the nucleic acid and phospholipid fractions, with a peak at 1 hr. This study indicates that ALN is rapidly absorbed and distributed in the rat and the major route of excretion is urinary followed by the expired air.
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PMID:Toxicokinetics of allynitrile in rats. 810 May 2

A novel series of octahydrophenanthrenamines and their heterocyclic analogues have been synthesized as potential noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor complex. The compounds were evaluated for their affinity at the phencyclidine (PCP) binding site by determining their ability to displace [3H]TCP from crude rat brain synaptic membranes. A wide range of affinities were observed, with the most potent analogs possessing IC50's equivalent to that of the reference agent MK-801 (3, dizocilpine). NMDA antagonist activity was demonstrated by prevention of glutamate-induced accumulation of [45Ca2+] in cultured rat cortical neurons. Selected compounds were also studied in vivo to determine their ability to prevent the lethal effects of systemically injected NMDA in the mouse. In general, the SAR of the phenanthrenamine series may be summarized as follows: (a) for the amino group at C4a, NHMe > NH2 > NHEt >> NC5H10; (b) for the B-ring substitution, X = CH2 > S > O; (c) unsaturation of the C ring decreases receptor affinity; (d) cis-ring fusion between the B and C rings is desirable; (e) 6-hydroxy or 6-methoxy substitution of the phenanthrenamine system identified an additional hydrogen bonding interaction that substantially increased receptor affinity; (f) spiro analogues (such as 55, IC50 = 3400 nM), which altered the point of attachment of the C ring, caused a substantial reduction in PCP-site affinity. Molecules from this series were useful for refining a pharmacophore model consistent with previous models of the PCP site. In this model, the (R)-(+)-phenanthrenamine 13 superimposes closely onto MK-801 (3), and the angular 4a-amino group is believed to hydrogen bond with a putative receptor site atom. In the phenanthrenamine and thiaphenanthrenamine series, the (R)-(+)-enantiomers (9, 13, and 44) are more potent by approximately 5-10-fold than their corresponding (S)-(-)-enantiomers with respect to their affinity for the PCP site, their ability to prevent accumulation of [45Ca2+] in cultured neuronal cells, and their protection against the lethal effects of NMDA in mice. In general, there was no separation between the dose that prevented NMDA lethality and the dose that produced ataxia in mice, except in the case of the thiaphenanthrenamines 41 and 43. We have not yet obtained evidence that this small separation in activity offers a therapeutic advantage in the treatment of cerebral ischemia or other neurodegenerative disorders.
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PMID:Synthesis and pharmacological evaluation of 4a-phenanthrenamine derivatives acting at the phencyclidine binding site of the N-methyl-D-aspartate receptor complex. 833 37

Several dominantly inherited, late onset, neurodegenerative diseases are due to expansion of CAG repeats, leading to expansion of glutamine repeats in the affected proteins. These proteins are of very different sizes and, with one exception, show no sequence homology to known proteins or to each other; their functions are unknown. In some, the glutamine repeat starts near the N-terminus, in another near the middle and in another near the C-terminus, but regardless of these differences, no disease has been observed in individuals with fewer than 37 repeats, and absence of disease has never been found in those with more than 41 repeats. Protein constructs with more than 41 repeats are toxic to E. coli and to CHO cells in culture, and they elicit ataxia in transgenic mice. These observations argue in favour of a distinct change of structure associated with elongation beyond 37-41 glutamine repeats. The review describes experiments designed to find out what these structures might be and how they could influence the properties of the proteins of which they form part. Poly-L-glutamines form pleated sheets of beta-strands held together by hydrogen bonds between their amides. Incorporation of glutamine repeats into a small protein of known structure made it associate irreversibly into oligomers. That association took place during the folding of the protein molecules and led to their becoming firmly interlocked by either strand- or domain-swapping. Thermodynamic considerations suggest that elongation of glutamine repeats beyond a certain length may lead to a phase change from random coils to hydrogen-bonded hairpins. Possible mechanisms of expansion of CAG repeats are discussed in the light of looped DNA model structures.
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PMID:Glutamine repeats and inherited neurodegenerative diseases: molecular aspects. 899 86


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