UMLS:C0004134 - FACTA Search

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Query: UMLS:C0004134 (ataxia)
15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rett syndrome is an increasingly recognized progressive disorder in females, commencing in infancy and characterized by autistic behavior, gait ataxia, stereotyped movements, seizures and generalized growth and mental retardation, possibly associated with disorders of central biogenic amine synthesis. The gene locus and pathogenesis of Rett syndrome are unknown. Autopsy studies in nine girls dying between 4 and 17 years, and sural nerve and muscle biopsies from two girls aged 3 and 17 years showed: (1) diffuse cortical atrophy/micrencephaly, with a decrease in brain weight by 12% to 34% of age-matched controls, apparently related to the duration of the disorder; (2) mild diffuse cortical atrophy with increased amounts of neuronal lipofuscin and occasional mild gliosis, but without signs of a storage disorder; (3) underpigmentation of the zona compacta nigrae, which showed fewer well-pigmented neurons for age and fewer melanin granules per neuron, while total numbers of nigral neurons and the substructure of neuromelanin were normal for age. No pathological changes were seen in other transmitter-specific brain stem nuclei; (4) immunoreactivity for tyrosine hydroxylase was slightly reduced in nigral and hypothalamic neurons, and the pituitary gland showed decreased immunoreaction for prolactin and growth hormone; (5) ultrastructurally, in frontal cortex and caudate nucleus, isolated abnormal neurites and reactive or degenerative axonal swellings were seen; the latter are possibly related to the nigral changes, suggesting some dysfunction of the dopaminergic nigrostriatal system, which is supported by neurochemical data; (6) preliminary biochemical studies revealed increased beta-endorphines in thalamus and cerebellum; (7) peripheral nerves demonstrated increase in small fibers without demyelination and increased numbers of neurofilaments in axons, suggesting distal axonopathy, while skeletal muscle showed alterations in the sarcoplasmic reticulum with circular profiles in the Z-filaments. These nonspecific changes may be interpreted as early signs of denervation. The variety of lesions in the central, neuroendocrine and peripheral neuromuscular systems in Rett syndrome are discussed with regard to their clinical and biochemical significance.
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PMID:Neuropathology of Rett syndrome. 290 May 87

Seven cell specific marker enzymes in brain and optic nerve and morphological evaluation by light microscopy were used to characterize the neurotoxicity associated with exposure of rats to hexachlorophene (HCP; 40 mg/kg/day, po, for 9 days). In vitro exposure to HCP at concentrations up to 100 microM had no direct inhibitory effect on the marker enzymes, validating their use in evaluating brain function in vivo. Rats exhibited a reduction in body weight gain, weakness, and ataxia of the hind limbs by the ninth day of HCP exposure. At 24 hr following the last day of exposure to HCP, the activities of the three neuron specific enzymes, glutamic acid decarboxylase, tyrosine hydroxylase, and choline acetyltransferase, in rat brain were unchanged from those of the vehicle-treated control group. Of the two astroglial enzyme markers measured, a small but significant increase was observed in the activity of nonneuronal enolase in the cerebellum and glutamine synthetase in the hippocampus of HCP-treated rats. The optic nerve appeared to be the most sensitive tissue in that the activity of both the astroglial marker, nonneuronal enolase, and the myelin marker, 2',3'-cyclic nucleotide phosphohydrolase, was significantly decreased following HCP exposure. This decrease in enzyme activity is consistent with the histological observations demonstrating extensive vacuolization and edema in the optic nerve after exposure to HCP.
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PMID:Effect of short-term exposure to hexachlorophene on rat brain cell specific marker enzymes. 290 23

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

An extensive neurochemical study has been performed on the CNS of Rolling mouse Nagoya (RMN), an ataxic mutant mouse. Although the symptoms observed are as severe as those found in Weaver mutants, little is known of the pathogenesis of the ataxia, except for a slight hypoplasia of the anterior part of the cerebellum. The present study revealed two major neurotransmitter-related abnormalities in the CNS. The first is a reduced concentration of glutamate, a putative transmitter of granule cells, and an increased concentration of glycine and taurine in the cerebellum of the RMN. The second is an increased activity of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, not only in the cerebellum but also in spinal cord, medulla oblongata, thalamus and hypothalamus. These results, together with previous data obtained from other ataxic mutant mice or experimentally-induced ataxic animals suggest that the cerebellum is the most severely affected part of the CNS in the RMN with the number of granule cells being reduced. The increase in the concentration of inhibitory amino acids and the widespread increase in tyrosine hydroxylase activity are probably not specific to the RMN but seem to be common to other ataxic animals with hypoplastic cerebellum and granule cell loss.
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PMID:Neurotransmitter abnormality in Rolling mouse Nagoya, an ataxic mutant mouse. 616 17

Low doses of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induce locomotor stimulation in mice, whereas higher doses are associated with ataxia, stereotyped behaviors and catalepsy. We investigated the role of dopamine receptors and presynaptic dopamine neurons in the locomotor effects of dizocilpine. For comparison, we studied several other drugs that induce locomotor stimulation in mice. Pretreatment of male mice with haloperidol (0.1 mg/kg, i.p.) completely prevented the stimulation of normally coordinated locomotion induced by a non-intoxicating dose of dizocilpine (0.1 mg/kg, i.p.); haloperidol also attenuated the locomotor stimulation produced by phencyclidine (PCP, 1 and 2 mg/kg, i.p.), d-amphetamine (2 and 5 mg/kg, i.p.) and diazepam (0.5 mg/kg, i.p.). Haloperidol (doses up to 2.5 mg/kg) did not attenuate the ataxia and decreased locomotion induced by higher doses of dizocilpine (1 and 2 mg/kg). The active cis isomer of flupenthixol (0.5 mg/kg, i.p.), an antagonist of both D1 and D2 dopamine receptors, also diminished the stimulant actions of all of the test drugs, whereas its inactive trans form did not. The selective D1 antagonist R(+/-)-SCH 23390 (0.1 mg/kg) and the selective D2 antagonist raclopride (1 mg/kg) had little effect on the stimulatory effect of dizocilpine, although they did reduce the stimulation produced by PCP, d-amphetamine and diazepam. However, pretreatment with a combination of R(+/-)SCH 23390 and raclopride completely prevented dizocilpine-induced locomotor stimulation. Pretreatment with alpha-methyl-p-tyrosine (AMPT, 50 and 250 mg/kg), an inhibitor of tyrosine hydroxylase, or with 6-hydroxydopamine (6-OH-DA, 50 micrograms, i.c.v.), a neurotoxin that destroys brain dopaminergic and noradrenergic neurons, did not attenuate the locomotor stimulation induced by dizocilpine, although these treatments did reduce the stimulant effects of d-amphetamine. In AMPT or 6-OH-DA pretreated mice, haloperidol (0.125 mg/kg) prevented the stimulatory effect of dizocilpine. These results support a role for dopamine receptors in the stimulation of normally coordinated locomotion by dizocilpine. However, the locomotor stimulant effect of dizocilpine, unlike that of d-amphetamine, can be expressed in the presence of D1 or D2 dopamine receptor blockade and does not appear to be dependent on intact presynaptic mechanisms.
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PMID:Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice. 856 5

The mutant mice tottering, leaner and the compound heterozygous tottering/leaner exhibit varying degrees of several abnormal neurological phenotypes including petit mal-like epilepsy, ataxia and an intermittent myoclonus-like movement disorder. Aberrant expression of tyrosine hydroxylase in cerebellar Purkinje cells of tottering, leaner and tottering/leaner mice has been observed previously [Austin M. C. et al. (1992) Molec. Brain Res. 15, 227-240; Hess E. J. and Wilson M. C. (1991) Neuron 6, 123-132]. In the present study, the distribution of tyrosine hydroxylase expression was compared with that of Zebrin II in Purkinje cells of adult homozygous tottering and compound heterozygous tottering/leaner mutant mice using single and double immunocytochemistry and double immunofluorescence. The pattern of Zebrin II expression in the cerebella of the mutant mice was identical to that described for normal mice [Hawkes R. et al. (1985) Brain Res. 333, 359-365; Hawkes R. and Leclerc N. (1987) J. comp. Neurol. 256, 29-41]. In addition, sections through tottering and tottering/leaner cerebella demonstrated an exact correspondence between the bands of tyrosine hydroxylase immunoreactivity and bands of Zebrin II immunoreactivity. Similarly, the compartments of the Purkinje cell layer which were negative for Zebrin II staining were also negative for tyrosine hydroxylase immunoreactivity. This study provides evidence that the cerebellar Purkinje cells of tottering and tottering/leaner mice were able to express a normal gene product, Zebrin II, in a normal spatial pattern and the same Purkinje cells can also express an aberrant gene product, tyrosine hydroxylase. This abnormal gene expression may indicate that at least some Purkinje cells in these mutant mice are not functioning normally. This possibility, taken together with the morphological changes observed in many mutant Purkinje cell axons, suggests that Purkinje cell function could be altered in tottering and tottering/leaner mice, thereby contributing to the neurological abnormalities exhibited by these mice. It is also possible that alteration in function of mutant Purkinje cells could correlate with the rostrocaudal zonation pattern described in this study.
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PMID:Co-localization of tyrosine hydroxylase and zebrin II immunoreactivities in Purkinje cells of the mutant mice, tottering and tottering/leaner. 905

Niemann-Pick disease Type C (NPC) is a progressive neurovisceral metabolic disorder that is caused in most patients by a defect in a recently found gene, NPC-1. Neurological damage includes visual disorders such as vertical supranuclear gaze palsy, movement disorders such as dystonia and ataxia, dementia, and seizures. So far the biochemical deficit, most likely manifested by delayed intracellular cholesterol transport, has not been correlated with the progressive neurological damage. A mutant Balb/C mouse with a defect in the same gene is used as a model to study NPC. Pathological examination of brain tissue obtained by autopsy from NPC patients or brains of affected NPC mice of different ages, revealed signs of extensive damage throughout the brain, including neurofibrillary tangles and intracellular storage of various compounds. Loss of cerebellar Purkinje cells was the most significant specific damage. The present study examined whether the neurochemical changes present in the NPC mouse brain were related to the pathological changes. The results show major alterations in the levels of serotonin and its main metabolite, 5-hydroxyindoleacetic acid, in the cerebellum and cortex of NPC mice. The levels of the inhibitory amino acid glycine were threefold higher in the cerebellum of NPC mice and those of glutamate and GABA decreased in the cortex. Tyrosine hydroxylase immunoreactivity was present in Purkinje cells, and the levels of L-DOPA increased specifically in the vermis of the cerebellum. These results are the first to indicate changes in neurotransmitters in NPC and that these could be correlated with some of the neuropathology of this disease.
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PMID:Neurochemical alterations in the cerebellum of a murine model of Niemann-Pick type C disease. 967 2

Ataxia-telangiectasia (AT) is a human disease caused by mutations in the ATM gene. The neural phenotype of AT includes progressive cerebellar neurodegeneration, which results in ataxia and eventual motor dysfunction. Surprisingly, mice in which the Atm gene has been inactivated lack distinct behavioral ataxia or pronounced cerebellar degeneration, the hallmarks of the human disease. To determine whether lack of the Atm protein can nonetheless lead to structural abnormalities in the brain, we compared brains from male Atm-deficient mice with male, age-matched controls. Atm-deficient mice exhibited severe degeneration of tyrosine hydroxylase-positive, dopaminergic nigro-striatal neurons, and their terminals in the striatum. This cell loss was accompanied by a large reduction in immunoreactivity for the dopamine transporter in the striatum. A reduction in dopaminergic neurons also was evident in the ventral tegmental area. This effect was selective in that the noradrenergic nucleus locus coeruleus was normal in these mice. Behaviorally, Atm-deficient mice expressed locomotor abnormalities manifested as stride-length asymmetry, which could be corrected by peripheral application of the dopaminergic precursor L-dopa. In addition, these mice were hypersensitive to the dopamine releasing drug D-amphetamine. These results indicate that ATM deficiency can severely affect dopaminergic neurons in the central nervous system and suggest possible strategies for treating this aspect of the disease.
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PMID:Selective loss of dopaminergic nigro-striatal neurons in brains of Atm-deficient mice. 977 May 41

Scrapie is a degenerative disease of the central nervous system of sheep and goats. The causative agent has been passaged to a number of laboratory species, including mice and hamster. Amyloid plaque formation and vacuolation, the signs of senile dementia, are found in the brains of mice infected with 87V scrapie agent. Dopamine (DA) and norepinephrine (NE) concentrations in the brains of scrapie-infected mice were measured with high-performance liquid chromatography-electrochemical detector (HPLC-ECD). A significant decrease in NE level was exhibited in all regions tested, whereas the level of DA decreased significantly only in cerebral cortex. Immunohistochemistry was used to examine immunoreactive catecholamine neurons in substantia nigra and locus ceruleus using antisera against tyrosine hydroxylase (TH). The population of TH-immunoreactive neurons in the substantia nigra and locus ceruleus were significantly decreased in scrapie-infected mice compared to controls. These data suggest that both the noradrenergic and dopaminergic system are sensitive to the action of scrapie agent 87V and that changes in the catecholamine levels in the brains of scrapie-infected mice may contribute to some of the clinical symptoms of the diseases, such as ataxia and apraxia.
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PMID:Extensive degeneration of catecholaminergic neurons to scrapie agent 87V in the brains of IM mice. 1032 12

Expression of tyrosine hydroxylase (TH) immunostaining in the cerebellum was examined in dilute-lethal mice (DL) prior to and following the onset of ataxia. DL walked normally on postnatal days 7 and 8. Falling over when walking was exhibited by about 20% of DL on day 9 and by all DL by day 10. TH-positive Purkinje cells in lobules IX and X of the vermis of either ataxic or non-ataxic DL were clearly observed on day 9 when compared to control mice, and had drastically increased by day 10. These results revealed that abnormal TH expression occurred in some Purkinje cells of DL cerebella, preceding the onset of ataxia.
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PMID:Abnormal expression of tyrosine hydroxylase immunoreactivity in Purkinje cells precedes the onset of ataxia in dilute-lethal mice. 1053 75

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