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 anticonvulsive properties of orally administered cinnarizine [(E)-1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine], its difluoro derivative flunarizine [(E)-1-(bis-(4-fluorophenyl)methyl)-4-(3-phenyl-2-propenyl)-piperazine], diphenylhydantoin and phenobarbital, were studied against maximal metrazol seizures (MMS) in rats and maximal electroshock seizures (MES) in mice. In rats (MMS), the lowest ED50 for protection against tonic extension of hindpaws was 4.10 mg/kg (1 h 35 min after treatment) with sodium phenobarbital, 6.04 mg/kg (5 h 45 min) with flunarizine dihydrochloride, 9.84 mg/kg (2 h 34 min) with cinnarizine and 19.30 mg/kg (3 h 38 min) with diphenylhydantoin. In mice (MES), protection against tonic extension of hindpaws was (2 h after treatment) 7.0 mg/kg with diphenylhydantoin, 13.2 mg/kg with sodium phenobarbital, 20.9 mg/kg with flunarizine kihydrochloride and 49.0 mg/kg with cinnarizine. Except at subtoxic doses no side effects were observed in rats and mice given cinnarizine, flunarizine kihydrochloride or kiphenylhydantoin. Phenobarbital induced ataxia in rats and mice at 22 mg/kg and 42.7 mg/kg, respectively, and loss of righting reflex at 112.8 mg/kg and 160 mg/kg, respectively. Flunarizine is the longest-acting drug and has the slowest onset. At a dose of twice the minimal ED50 flunarizine affords protection against tonic extension of hindpaws in rats (MMS) for 23 h 30 min dephenylhydantoin for 11 h 38 min, phenobarbital for 8 h 22 min and cinnarizine for 8 h 16 min. Peak effect was reached with flunarizine at 5 h 45 min, with diphenylhydantoin at 3 h 38 min, with cinnarizine at 2 h 34 min and with phenobarbital at 1 h 35 min. The anti-MMS profiles of cinnarizine and flunarizine resemble that of dephenylhydantoin as all three compounds are selective blockers of tonic extension of hindpaws. Phenobarbital antagonized the whole MMS-pattern, i.e., tremors, clonic convulsions and tonic extension of fore- and hindpaws. However, the effects of phenobarbital against tremors, clonic convulsions and tonic extension of forepaws may reflect more a general CNS-depressant effect than a specific anticonvulsive activity since neurotoxic effects (ataxia and loss of righting reflex) appear at the same doses.
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PMID:Anticonvulsive properties of cinnarizine and flunarizine in rats and mice. 124 63

Spinal seizures in mice induced by handling following pretreatment with a subconvulsive dose of strychnine could be blocked by competitive N-methyl-D-aspartate (NMDA) receptor antagonists (D-, L-, DL-CPPene (CPPene = (E)-4-(3-phophonoprop-2-enyl)-piperazine-2-carboxylic acid), D-AP5 (D-2-amino-5-phophonovalerate)) and compounds acting at receptor-coupled modulatory sites (R-HA 966, ifenprodil). NMDA cation channel antagonists (MK-801, phencyclidine) however, resulted in ataxia, tremor and loss of righting. There are differences between NMDA antagonists acting via the receptor and the cation channel in this model of spinal seizure.
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PMID:N-methyl-D-aspartate receptor antagonists and channel blockers have different effects upon a spinal seizure model in mice. 153 94

DL-beta-N-methylamino-alanine (DL-BMAA; 1-10 mumol i.c.v.) in mice induced a syndrome of: ataxia, ptosis, scratching, jumping, myoclonic jerks, clonic muscle spasms and tonic seizure, which was unaffected by pretreatment with D(-)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylate (D(-)-CPPene; i.p.), or by co-administration of gamma-D-glutamylamino-methylsulphonate (gamma-D-GAMS with DL-BMAA; i.c.v.). Pretreatment with 1-(aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; i.v.) decreased the incidence of clonic seizures for DL-BMAA, kainic acid and RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (RS-AMPA; i.c.v.). These results suggest an involvement of the AMPA/quisqualate subtype of excitatory amino acid receptors in acute BMAA toxicity.
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PMID:Receptor site specificity for the acute effects of beta-N-methylamino-alanine in mice. 198 Feb 47

The effect of i.c.v. administration of dodecasodium and dicalcium inositolhexakisphosphate (Na12IP6 and Ca2IP6, respectively) to mice and rats was studied. In mice, Na12IP6 (1-300 nmol) or Ca2IP6 (10-500 nmol) induced: ataxia, ground-hugging, tremor (often continuous), scratching, hyperlocomotion, wild running, myoclonic jerks, jumping, clonic muscle spasms, tonic seizure, followed by death or full recovery. The CD50 values for clonic seizures for Na12IP6 and Ca2IP6 were 16 and 49 nmol, respectively. The convulsant effect of Na12IP6 (15 nmol i.c.v.) was not blocked by pretreatment with D(-)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylate, but was dose dependently reduced by pretreatment with CaCl2 (30-60 nmol i.c.v.) and abolished by coadministration of CaCl2 (30 nmol) with Na12IP6 (i.c.v.). In rats, Na12IP6 (50 nmol i.c.v.) induced severe electroencephalographic seizures in the hippocampus and cortex. The potent convulsant effect of IP6 (administered i.c.v.) depends at least in part on a calcium-chelating action.
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PMID:Inositolhexakisphosphate is convulsant in mice and rats in the nanomolar range. 208 46

Review of all reports involving anthelmintics in dogs and cats to the IAPIC between January 1, 1986 and August 10, 1988, revealed that ivermectin (extra-label use) and piperazine accounted for over 50% of the calls assessed as toxicoses and suspected toxicoses. Both ivermectin and piperazine are gamma-aminobutyric acid (GABA) agonists and their major effects appear to be on the central nervous system. Ivermectin toxicoses at estimated doses of greater than or equal to 100-less than 500 micrograms/kg were reported more than once only in the collies (n = 25) and Australian shepherds (n = 10); these two breeds accounted for 46% (69 of 150) of the toxicoses and suspected toxicoses calls in dogs. Ataxia, behavioral disturbances, tremors, mydriasis, weakness/recumbency, apparent blindness, hypersalivation/drooling (dogs only), and coma were the most commonly reported clinical signs in dogs and cats with suspected ivermectin toxicoses. Shock, dyspnea, vomiting, and ataxia were the most common clinical signs attributed to the microfilaricidal activity of ivermectin. Piperazine was the anthelmintic with the greatest number of reports of toxicoses and suspected toxicoses in cats. Piperazine neurotoxicity in cats and dogs usually was manifested by muscle tremors, ataxia, and/or behavioral disturbances within 24 hours after estimated daily dose(s) between 20 and 110 mg/kg.
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PMID:Ivermectin and piperazine toxicoses in dogs and cats. 218 Jan 89

Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED50 = 4.5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3-10 mg/kg i.v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [3H]-5HT from the 5HT1a binding site in the hippocampus with IC50 values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [3H]-5HT from both 5HT1a and 5HT1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.
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PMID:Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. 243 24

Piperazine has been used to treat pinworm and roundworm infections for over 40 years. Piperazine-induced cerebellar ataxia, causing the dropping of objects, clumsiness, and gait abnormalities, has been infrequently reported, usually in the setting of overdose or renal insufficiency. The unusual case of an otherwise well child who developed ataxia following seven days of piperazine citrate therapy is reported.
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PMID:Piperazine neurotoxicity: worm wobble revisited. 767 26

In this study, we attempted to identify of the subtype(s) of alpha-2 adrenergic receptor (AR) involved in the control of motor behavior, nociception and the hippocampal synthesis of noradrenaline (NA) in the rat. The high efficacy alpha-2 AR agonists, xylazine and UK 14,304 [5-bromo-6-[2-imidazolin-2-yl-amino]quinoxaline], inhibited striatal accumulation of L-dopa in rats pretreated with NSD 1015 (an inhibitor of aromatic amino acid-decarboxylase), elicited a loss of the righting reflex in rats, provoked ataxia in the rotarod test in mice and elicited antinociception in the writhing and hot-plate tests in mice. Guanfacine and guanabenz, agonists acting preferentially at rat alpha-2A (R alpha-2A)/human alpha-2A (H alpha-2A) AR, mimicked the antinociceptive and motor actions of xylazine and UK 14,304 and likewise inhibited NA synthesis. The preferential R alpha-2A/H alpha-2A AR antagonist, [2-(2H-(1-methyl-1, 3-dihydroisoindole)methyl)-4, 5-dihydro-imidazole (BRL 44408), enhanced hippocampal synthesis of NA and blocked the antinociceptive and motor effects of UK 14,304, xylazine, guanfacine and guanabenz. Similarly, fluparoxan and des-fluorofluparoxan, preferential antagonists at R alpha-2A AR as compared to H alpha-2A AR, were highly active. In contrast, the preferential alpha-2B/alpha-2C AR antagonists, ARC 239 [2-(2-(4-o-methoxyphenyl)piperazine-1-yl)-ethyl)-4,4-dimethyl-1,3- (2H,4H)-isoquinolinedione] prazosin, corynanthine, spiroxatrine and [1,2-dimethyl-2,3,9,13-betetrahydro-1H-dibenzo(c,f)- imidazo(1,5-a)azepine (BRL 41992)], as well as the preferential H alpha-2A AR antagonist, [2-(2,6-dimethoxyphenoxyethyl)- aminomethyl-1,4-benzodioxane] (WB 4101), were only weakly active. Based on the actions of a total of 16, structurally diverse alpha-2 AR antagonists, a correlation matrix was constructed. This revealed a strong correlation among the tests (median r = 0.82) and allowed for a comparison between drug potency in inhibiting these alpha-2 AR-mediated actions and affinity at various populations of alpha-2 AR subtypes (see companion paper). Correlations for potency in the two motor tests were pronounced with R alpha-2A sites (0.85), modest with H alpha-2A sites (0.60) and alpha-2B sites (0.58) and poor with alpha-2C sites (0.35). For the two antinociceptive tests, correlations were likewise pronounced with R alpha-2A sites (0.80) but less marked with H alpha-2A sites (0.73), alpha-2B sites (0.62) and alpha-2C sites (0.62).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Multiple alpha-2 adrenergic receptor subtypes. II. Evidence for a role of rat R alpha-2A adrenergic receptors in the control of nociception, motor behavior and hippocampal synthesis of noradrenaline. 793 8

This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.
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PMID:Sigma receptor ligands (+)-SKF10,047 and SA4503 improve dizocilpine-induced spatial memory deficits in rats. 975 32

1-(2-ethoxy-phenyl)-4-[3-(3-thiophen-2-yl-isoxazolin-5-yl)-propyl]-piperazine (KCH-1110), has a high affinity for human dopamine D3 (hD3) receptor (Ki=1.28 nM) with about 90-fold selectivity over the human dopamine D2L (hD2L) receptor. Antipsychotic or antidopaminergic activity of KCH-1110 was investigated in the models for the positive symptoms of schizophrenia, apomorphine-induced climbing and cocaine-induced hyperlocomotion, in mice. Intraperitoneal (i.p.) or oral (p.o.) administration of KCH-1110 potently inhibited the apomorphine-induced cage climbing without any rotarod ataxia in mice. Cocaine-induced hyperactivity was also antagonised by KCH-1110. In addition, KCH-1110 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT in mice. KCH-1110 did not induce catalepsy in mice, but at much higher doses only a slight catalepsy response was shown. Although high doses of KCH-1110 significantly enhanced serum prolactin secretion in rats, low dose of KCH-1110 did not increase prolactin levels in rats. The present studies, therefore, suggest that KCH-1110 is a potent and relatively selective dopamine D3 receptor antagonist with antipsychotic actions.
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PMID:Pharmacological actions of a novel and selective dopamine D3 receptor antagonist, KCH-1110. 1452 27


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