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)

1. The pharmacological properties of the benzodiazepine receptor ligand, FG 8205 (7-chloro-5,6-dihydro-5-methyl-6-oxo-3-(5-isopropyl-1,2,4-oxadiazol++ +-3-yl)-4H- imidazol[1,5a][1,4]benzodiazepine) have been examined. 2. FG 8205 potently displaced [3H]-flumazenil binding in rat cortical membranes with a Ki of 3.3 nM, but was inactive at 13 neurotransmitter recognition sites. 3. Consistent with a partial agonist profile, the affinity of FG 8205 for the benzodiazepine recognition site was increased in the presence of gamma-aminobutyric acid (GABA, 300 microM) by a degree (-log [IC50 in the presence of GABA/IC50 alone] = 0.34) significantly less than found for diazepam (0.46). FG 8205 also potentiated the inhibitory potency of the GABAA-receptor agonist, isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (-log dose-ratio = 0.2) was significantly less than that seen with diazepam (0.4). 4. In anticonvulsant studies, the ED50 doses of FG 8205 and diazepam needed to antagonize seizures induced by pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2-0.3 mg kg-1, i.p. However, even high doses of FG 8205 (50 mg kg-1) did not protect against seizures induced by electroshock. 5. FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5-50 mg kg-1 (i.p.). Similar doses of FG 8205 had a marked taming effect in cynomolgus monkeys. However, measures of sedation and ataxia (as measured by rotarod in the mouse, climbing behaviour in the rat, and by scoring arousal and co-ordination in primates) were slight and only transiently affected by FG 8205, and FG 8205 significantly antagonized the rotarod performance deficit induced by diazepam in the mouse. 6. While the potentiation by FG 8205 of the response to isoguvacine in the rat hippocampal slice and the anxiolytic-like effects of the compound in both rats and primates were reversed by the benzodiazepine receptor antagonist, flumazenil, high doses of the antagonist were able only marginally to block the protective effects of FG 8205 against seizures induced by PTZ in the mouse. 7. Thus, FG 8205 does not show the marked motor impairment characteristic of full agonists at the benzodiazepine receptor, consistent with its partial agonist profile in in vitro assay systems. Nevertheless, the compound has sufficient intrinsic activity to maintain high efficacy in anticonvulsant and anxiolytic tests.
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PMID:The pharmacological properties of the imidazobenzodiazepine, FG 8205, a novel partial agonist at the benzodiazepine receptor. 196 8

The distribution of neurotransmitter and neuromodulator receptors was studied in the brain of the rolling mouse Nagoya (RMN) and in controls, using in vitro receptor autoradiography. Quantitative autoradiography was used to map adenosine A1 (labeled with [3H]cyclohexyladenosine), GABAA [( 3H]muscimol), opiate [( 3H]naloxone), L-glutamate [( 3H]L-glutamate), benzodiazepine [( 3H]flunitrazepam), and muscarinic cholinergic [( 3H]quinuclidinyl benzilate) receptors. In the cerebellar cortex, GABAA and adenosine A1 binding sites were significantly reduced in the RMN, whereas other transmitter binding sites were not significantly altered. Adenosine A1 binding sites were also reduced in the cerebral cortex and caudate-putamen. Benzodiazepine binding was significantly decreased in the cerebral cortex and increased in the CA1 subfield of the hippocampus. These results suggest that neurochemical alterations in the caudate-putamen as well as in the cerebellar cortex play important roles in the ataxia and motor dysfunction of the RMN.
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PMID:Neurotransmitter receptors of the rolling mouse Nagoya: a quantitative autoradiographic study. 289 49

Chronic alcoholics who maintain abstinence often demonstrate remarkable improvement of neurological and mental dysfunction. This paper presents an overview of the clinical and laboratory work of our group. Reversible clinical manifestations include psychometric scores, ataxia, tremor, Parkinsonism, dyskinesia, cerebral atrophy, EEG parameters, and a CSF acidosis. Electrophysiological investigations showed that in the in vitro hippocampus of rats fed ethanol for several months there was evidence for diminished long-term potentiation, impaired neuronal inhibitory mechanisms (diminished inhibitory post-synaptic potentials and post-spike after hyperpolarisations), decreased neuronal specific membrane capacitance and increased specific membrane resistance. Golgi stains showed attenuation of hippocampal CA1 neuronal dendrites in rats fed ethanol for five months, which reverted to control size in rats permitted two months of alcohol withdrawal.
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PMID:Reversibility of alcohol-related brain damage: clinical and experimental observations. 347 66

Electroencephalographic, behavioral, and neuropathologic changes were monitored after infusions of the endogenous excitatory amino acid, quinolinic acid (QUIN), into the dorsal hippocampus of unanesthetized, freely moving rats. A dose of 120 nmol QUIN was required to reliably precipitate seizures although EEG changes were observed with doses as small as 3 nmol. Seizure episodes were characterized by repetitive periods of high-voltage spiking typically lasting 20 s but occasional longer multicomponent episodes (60 s) were also observed. The latency of specific QUIN-induced seizures was similar for all doses tested (19 to 32 min); however, the total number of seizures and total time in seizures increased in a dose-dependent fashion from 30 to 300 nmol QUIN. Seizure episodes were often associated with a frozen appearance of the animal and intermittent "wet dog shakes". Ataxia was apparent in animals receiving 120 and 300 nmol QUIN. Using light microscopic analyses, pyramidal cell degeneration was observed in the QUIN-injected hippocampus (CA3 and CA1 cells more susceptible than CA2 cells); dentate granule cells showed signs of degeneration only at the largest QUIN dose. No neuropathologic changes were found outside the injected hippocampus. Seizures and neuropathologic changes induced by 120 nmol QUIN were completely blocked by pre- or cotreatment with 12 nmol (-)2-amino-7-phosphonoheptanoic acid. Experiments with [3H]QUIN indicated that only 3% of the injected radioactivity was present in the dorsal hippocampus at the average time of seizure onset (25 min), and consisted entirely of unmetabolized QUIN. The potent convulsant properties of QUIN, an endogenous metabolite, may prove to be of relevance for the etiology of human temporal lobe epilepsy.
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PMID:Seizure activity and lesions after intrahippocampal quinolinic acid injection. 670 78

The inositol 1,4,5-trisphosphate (InsP3) receptor acts as an InsP3-gated Ca2+ release channel in a variety of cell types. Type 1 InsP3 receptor (IP3R1) is the major neuronal member of the IP3R family in the central nervous system, predominantly enriched in cerebellar Purkinje cells but also concentrated in neurons in the hippocampal CA1 region, caudate-putamen, and cerebral cortex. Here we report that most IP3R1-deficient mice generated by gene targeting die in utero, and born animals have severe ataxia and tonic or tonic-clonic seizures and die by the weaning period. An electroencephalogram showed that they suffer from epilepsy, indicating that IP3R1 is essential for proper brain function. However, observation by light microscope of the haematoxylin-eosin staining of the brain and peripheral tissues of IP3R1-deficient mice showed no abnormality, and the unique electrophysiological properties of the cerebellar Purkinje cells of IP3R1-deficient mice were not severely impaired.
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PMID:Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-trisphosphate receptor. 853 67

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. To investigate SCA1 pathogenesis and to gain insight into the function of the SCA1 gene product ataxin-1, a novel protein without homology to previously described proteins, we generated mice with a targeted deletion in the murine Sca1 gene. Mice lacking ataxin-1 are viable, fertile, and do not show any evidence of ataxia or neurodegeneration. However, Sca1 null mice demonstrate decreased exploratory behavior, pronounced deficits in the spatial version of the Morris water maze test, and impaired performance on the rotating rod apparatus. Furthermore, neurophysiological studies performed in area CA1 of the hippocampus reveal decreased paired-pulse facilitation in Sca1 null mice, whereas long-term and post-tetanic potentiations are normal. These findings demonstrate that SCA1 is not caused by loss of function of ataxin-1 and point to the possible role of ataxin-1 in learning and memory.
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PMID:Mice lacking ataxin-1 display learning deficits and decreased hippocampal paired-pulse facilitation. 965 Dec 31

The spontaneous recessive mutant mouse stargazer (stg) begins to show ataxia around postnatal day 14 and display a severe impairment in the acquisition of classical eyeblink conditioning in adulthood. These abnormalities have been attributed to the specific reduction in brain-derived neurotrophic factor (BDNF) and the subsequent defect in TrkB receptor signaling in cerebellar granule cells (GCs). In the stg mutant cerebellum, we found that EPSCs at mossy fiber (MF) to GC synapses are devoid of the fast component mediated by AMPA-type glutamate receptors despite the normal slow component mediated by NMDA receptors. The sensitivity of stg mutant GCs to exogenously applied AMPA was greatly reduced, whereas that to NMDA was unchanged. Glutamate release from MF terminals during synaptic transmission to GCs appeared normal. By contrast, AMPA receptor-mediated EPSCs were normal in CA1 pyramidal cells of the stg mutant hippocampus. Thus, postsynaptic AMPA receptor function was selectively impaired in stg mutant GCs, although the transcription of four AMPA receptor subunit genes in the stg GC was comparable to the wild-type GC. We also examined the cerebellum of BDNF knockout mice and found that their MF-GC synapses had a normal AMPA receptor-mediated EPSC component. Thus, the impaired AMPA receptor function in the stg mutant GC is not likely to result from the reduced BDNF-TrkB signaling. These results suggest that the defect in MF to GC synaptic transmission is a major factor that causes the cerebellar dysfunction in the stg mutant mouse.
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PMID:Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. 1040 40

BAY K 8644 (methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4[2-trifluoromethyl-phenyl]-pyridine-5-carboxylate), an activator of dihydropyridine-sensitive Ca(2+) channels, injected in rats [2 mg/kg intraperitoneally (i.p.)], induces behavioral changes including ataxia, increased sensitivity to auditory stimulation, stiff tail, arched back, limb tonus and clonus, and rolling over. Neurochemical changes in the brain 45 min after application of 2 mg/kg were characterized by a significant decrease of noradrenaline in the amygdala (-27.8%, P<0.02) and piriform cortex (-16.3%, P<0.02). No significant changes of catecholamines were found in the hippocampal subregions CA1, CA3 and dentate gyrus or in the septum as compared to controls. The dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the amygdala were elevated by 60% (P<0.02) and 66.7% (P<0.02), respectively. In the septum, a 52.6% (P<0.02) increase of HVA was observed. Analysis of amino acids revealed a marked increase of gamma-aminobutyric acid (GABA) content (+50.4%, P<0.001) in the septum. Pretreatment of the rats with the alpha(2)-adrenoceptor agonist, clonidine (0.1 mg/kg i.p.), 30 min before BAY K 8644 (2 mg/kg i.p.) injection completely abolished the behavioral and neurochemical changes. The data suggest that the Ca(2+)-dependent neurotransmitter release provoked by BAY K 8644 can be modulated by stimulation of presynaptic alpha(2)-adrenoceptors. The effect of clonidine on the GABAergic system may represent an important mechanism involved in the prevention of BAY K 8644-induced behavior.
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PMID:Clonidine modulates BAY K 8644-induced rat behavior and neurotransmitter changes in the brain. 1091 34

Mice lacking the Na(+)/H(+) exchanger isoform 1 (NHE1) manifest neurological diseases that include ataxia, motor deficits, and a seizure disorder. The molecular basis for the phenotype has not been clear, and it has not been determined how the lack of NHE1 leads, in particular, to the seizure disorder. We have shown in this work that hippocampal CA1 neurons in mutant mice have a much higher excitability than in wild-type mice. This higher excitability is partly based on an upregulation of the Na(+) current density (608.2 +/- 123.2 pA/pF in NHE1 mutant vs. 334.7 +/- 63.7 pA/pF in wild type in HCO/CO(2)). Alterations in Na(+) channel characteristics, including steady-state inactivation (shift of 18 mV in the depolarization direction in the mutant), recovery from inactivation (tau(h) = 5.22 +/- 0.49 ms in wild-type neurons and 2.20 +/- 0.20 ms in mutant neurons), and deactivation (at -100 mV, tau(d) = 1.75 +/- 0.53 ms in mutant and 0.21 +/- 0.05 ms in wild-type neurons) further enhance the differences in excitability between mutant and wild-type mice. Our investigation demonstrates the existence of an important functional interaction between the NHE1 protein and the voltage-sensitive Na(+) channel. We hypothesize that the increased neuronal excitability and possibly the seizure disorder in mice lacking the NHE1 is due, at least in part, to changes in Na(+) channel expression and/or regulation.
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PMID:Increased neuronal excitability and seizures in the Na(+)/H(+) exchanger null mutant mouse. 1144 48

IP3 is an important second messenger to release Ca2+ from internal store. IP3receptor (IP3R) works as an IP3 induced Ca2+ release channel and requires IP3 and Ca2+ as coagoinist. We found IP3R is involved in fertilization, meiosis and mitosis by using a specific antibody. We further found that IICR is essential for determination of dorsoventral axis formation. Neuronal type 1 IP3R-deficient mice generated by a gene-targeting technique exhibit a significant reduction of birth rate and abnormal behavior (ataxia and seizure). Long-term depression of the cerebellum was blocked in the type 1 IP3R-deficient mice. Long-term potentiation (LTP) of CA1 hippocampus was enhanced but depotentiation and LTP suppression was reduced in IP3R1-deficient mice. These evidences suggest that IICR is involved in neuronal plasticity. The coupling mechanism between ER Ca2+ stores and plasma membrane store-operated channels is crucial to Ca2+ signaling. Recently we found that IP3R interacts with the TRP3 Ca2+ channel on the plasma membrane and functional coupling of IP3R to TRP3 channel is important for store operated Ca2+ entry. Recently we found that IP3R is involved in determination of polarity and input specificity of activity-induced synaptic modification.
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PMID:[IP3 receptor, a Ca2+ oscilator--role of IP3 receptor in development and neural plasticity]. 1249 67


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