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)

Ganaxolone (CCD 1042) is a 3beta-methyl-substituted analog of the endogenous neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one. Ganaxolone inhibited binding of the gamma-aminobutyric acid (GABA)A receptor-chloride channel ligand t-[35S]butylbicyclophosphorothionate (IC50 of 80 nM) and enhanced binding of the benzodiazepine site ligand [3H]flunitrazepam (EC50 of 125 nM) and the GABA site ligand [3H]muscimol (EC50 of 86 nM), consistent with activity as a positive allosteric modulator of the GABA(A) receptor. Electrophysiological recordings showed that, whereas nanomolar concentrations of ganaxolone potentiated GABA-evoked chloride currents in Xenopus oocytes expressing the human GABA(A) receptor subunits alpha1beta1gamma2L, alpha2beta1gamma2L or alpha3beta1gamma2L, direct activation of chloride flux occurred to a limited extent only at micromolar concentrations. Ganaxolone was effective in nontoxic doses against clonic convulsions induced by s.c. pentylenetetrazol administration in mice and rats (ED50 values of 4.3 and 7.8 mg/kg i.p., respectively). Ganaxolone also exhibited potent anticonvulsant activity against seizures induced by s.c. bicuculline (ED50 of 4.6 mg/kg i.p.), i.p. TBPS (ED50 of 11.7 mg/kg i.p.) and i.p. aminophylline (ED50 of 11.5 mg/kg i.p.) in mice. Although ganaxolone effectively blocked tonic seizures induced by maximal electroshock in mice (ED50 of 29.7 mg/kg i.p.), it did so only at doses that produced ataxia on the Rotorod (TD50 of 33.4 mg/kg i.p.). Conversely, ganaxolone was a potent anticonvulsant against fully kindled stage 5 seizures induced by corneal kindling in rats (ED50 of 4.5 mg/kg i.p.), producing these effects at doses well below those that resulted in ataxia (TD50 of 14.2 mg/kg i.p.). The seizure threshold, as determined by an increase in the dose of i.v. infused pentylenetetrazol required to induce clonus, was also significantly elevated by nontoxic doses of ganaxolone in mice. In summary, these data indicate that ganaxolone is a high-affinity, stereoselective, positive allosteric modulator of the GABA(A) receptor complex that exhibits potent anticonvulsant activity across a range of animal procedures. The profile of anticonvulsant activity obtained for ganaxolone supports clinical evaluation of this drug as an antiepileptic therapy with potential utility in the treatment of generalized absence seizures as well as simple and complex partial seizures.
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PMID:Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor. 906 15

The purpose of the present study was to determine whether the motor impairment (myorelaxation/ataxia) induced by excitatory amino acid receptor antagonists was exaggerated by pretreatment with ethanol. The results were compared with those of gamma-aminobutyric acid(A) (GABA(A)) receptor positive modulators alone and in combination with ethanol. The excitatory amino acid receptor antagonists, dizocilpine [(+)-MK-801; (5R,1OS)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten+ ++-5,10-imine], (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), LY 326325 [(-)-(3S,4aR,6R,8R)-6-[2-(1(2)H-tetrazol-5-yl)-ethyl]-dec ahydroisoquinaline-3-carboxylic acid], LY 300164 [7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3- benzodiazepine], and ACEA 1011 (5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione) produced dose-dependent myorelaxation/ataxia in mice as determined using the horizontal wire assay. Their behaviorally toxic doses (TD(50)s) were 0.41, 5.8, 33.0, 5.9, and 31.0 mg/kg, respectively, when administered alone i.p. In the presence of a sub-ataxic dose of ethanol (1.5 g/kg, i.p.), the TD(50)s of the excitatory amino acid antagonists were 0.13, 1.8, 10.4, 1.3, and 14.0 mg/kg, respectively. Similarly, the GABA(A) receptor positive modulators, pregnanolone, chlordiazepoxide, and pentobarbital exhibited TD(50)s of 20.8, 4.6, and 29.7 mg/kg, respectively, when administered alone and 2.7, 0.3, and 11.4 mg/kg, respectively, when administered in the presence of ethanol. Thus, similar to the GABA(A) receptor positive modulators, excitatory amino acid receptor antagonists exhibit the propensity to interact with ethanol and to have their motor side-effects exaggerated.
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PMID:Interaction of ethanol with excitatory amino acid receptor antagonists in mice. 1019 49

1. Several derivatives and analogues of the general anaesthetic 2,6-diisopropylphenol (propofol) have been recently synthesised with the aim of exploring the structure-activity relationships. 2. In the present study, the effects of one such compound, 4-iodo-2,6-diisopropylphenol (4-I-Pro), on gamma-aminobutyric acid type A (GABA(A)) receptors in vitro were compared with its in vivo effects in rodents. Human GABA(A) receptors were expressed in Xenopus oocytes, and the actions of 4-I-Pro on receptor function were compared with those of propofol by two-electrode voltage-clamp recording. 3. Similar to propofol, 4-I-Pro directly activated Cl- currents in the absence of GABA at all combinations of receptor subunits tested. However, the efficacy of 4-I-Pro in inducing direct activation of alpha1beta2gamma2S receptors was markedly less than that of propofol. 4. Similarly to propofol, 4-I-Pro potentiated in a concentration-dependent manner GABA-evoked Cl- currents measured at different GABA(A) receptor constructs. 5. As expected, intraperitoneal injection of propofol induced sedation, ataxia, and loss of the righting reflex in rats. In contrast, administration of 4-I-Pro failed to produce any of these behavioural effects. 6. Administration of 4-I-Pro to rats reduced in a dose-dependent manner the incidence of tonic-clonic seizures induced by pentylenetetrazol and induced an anticonflict effect as measured in the Vogel test. 7. Microdialysis revealed that, like propofol, administration of 4-I-Pro reduced acetylcholine release in the hippocampus of freely moving rats. 8. These results demonstrate that para-substitution of the phenol ring of propofol with iodine yields a compound that exhibits anticonvulsant and anticonflict effects, but is devoid of sedative-hypnotic and anaesthetic properties. Thus, 4-I-Pro possesses pharmacological characteristics more similar to anxiolytic and anticonvulsant drugs than to general anaesthetics.
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PMID:Characterization of the electrophysiological and pharmacological effects of 4-iodo-2,6-diisopropylphenol, a propofol analogue devoid of sedative-anaesthetic properties. 1021 39

Electrophysiological investigation of cultured cerebellar murine granule cells revealed differences between the GABA(A) receptors at inhibitory synapses and those on the cell body. Specifically, mIPSCs decayed more rapidly than cell body receptors deactivated, the mean single channel conductance at the synapse (32 pS) was greater than that at cell body (21 pS) and only cell body receptors were sensitive to Zn(2+) (150 microM), which depressed response amplitude by 82+/-5% and almost doubled the rate of channel deactivation. The GABA(A) receptor alpha6 subunit is selectively expressed in cerebellar granule cells. Although concentrated at synapses, it is also found on extrasynaptic membranes. Using a mouse line (Deltaalpha6lacZ) lacking this subunit, we investigated its role in the somato-synaptic differences in GABA(A) receptor function. All differences between cell body and synaptic GABA(A) receptors observed in wild-type (WT) granule cells persisted in Deltaalpha6lacZ cells, thus demonstrating that they are not specifically due to the cellular distribution of the alpha6 subunit. However, mIPSCs from WT and Deltaalpha6lacZ cells differed in both their kinetics (faster decay in WT cells) and underlying single channel conductance (32 pS WT, 25 pS Deltaalpha6lacZ). This provides good evidence for a functional contribution of the alpha6 subunit to postsynaptic GABA(A) receptors in these cells. Despite this, deactivation kinetics of mIPSCs in WT and Deltaalpha6lacZ granule cells exhibited similar benzodiazepene (BDZ) sensitivity. This suggests that the enhanced BDZ-induced ataxia seen in Deltaalpha6lacZ mice may reflect physiological activity at extrasynaptic receptors which, unlike those at synapses, display differential BDZ-sensitivity in WT and Deltaalpha6lacZ granule cells (Jones, A.M., Korpi, E.R., McKernan, R.M., Nusser, Z., Pelz, R., Makela, R., Mellor, J.R., Pollard, S., Bahn, S., Stephenson, F.A., Randall, A.D., Sieghart, W., Somogyi, P., Smith, A.J.H., Wisden, W., 1997. Ligand-gated ion channel partnerships: GABA(A) receptor alpha(6) subunit inactivation inhibits delta subunit expression. Journal of Neuroscience 17, 1350-1362).
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PMID:Somato-synaptic variation of GABA(A) receptors in cultured murine cerebellar granule cells: investigation of the role of the alpha6 subunit. 1085 95

SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one] is a novel pyridoindole derivative that displays high affinity for rat native GABA(A) receptors containing alpha(1) (K(i) = 6.8 nM) and alpha2 (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5-containing GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat GABA(A) receptors confirm these data (K(i), alpha1beta2gamma2 = 17, alpha2beta2gamma2 = 73, alpha5beta3gamma2 = 215 nM) and indicate intermediate affinity for the alpha3beta2gamma2 subtype (K(i) = 80 nM). SL651498 behaves as a full agonist at recombinant rat GABA(A) receptors containing alpha2 and alpha3 subunits and as a partial agonist at recombinant GABA(A) receptors expressing alpha1 and alpha5 subunits. SL651498 elicited anxiolytic-like activity similar to that of diazepam [minimal effective dose (MED): 1-10 mg/kg, i.p.] in three conflict models, in the elevated plus-maze, the light/dark test, and the defense test battery in rats and mice. Results from activity tests and electroencephalogram analysis indicated that SL651498 induced muscle weakness, ataxia, or sedation at doses much higher than those producing anxiolytic-like activity (MED > or = 30 mg/kg, i.p.). Repeated treatment for 10 days with SL651498 (30 mg/kg, i.p., b.i.d.) in mice was not associated with the development of tolerance to its anticonvulsant effects or physical dependence. Furthermore, SL651498 was much less active than diazepam in potentiating the depressant effects of ethanol in mice. The "anxioselective" profile of SL651498 points to a major role for GABA(A) alpha2 subtype in regulating anxiety and suggests that selectively targeting GABA(A) receptor subtypes can lead to drugs with increased clinical specificity.
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PMID:SL651498: an anxioselective compound with functional selectivity for alpha2- and alpha3-containing gamma-aminobutyric acid(A) (GABA(A)) receptors. 1145 40

Ion channels provide the basis for the regulation of excitability in the central nervous system and in other excitable tissues such as skeletal and heart muscle. Consequently, mutations in ion channel encoding genes are found in a variety of inherited diseases associated with hyper- or hypoexcitability of the affected tissue, the so-called 'channelopathies.' An increasing number of epileptic syndromes belongs to this group of rare disorders: Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in a neuronal nicotinic acetylcholine receptor (affected genes: CHRNA4, CHRNB2), benign familial neonatal convulsions by mutations in potassium channels constituting the M-current (KCNQ2, KCNQ3), generalized epilepsy with febrile seizures plus by mutations in subunits of the voltage-gated sodium channel or the GABA(A) receptor (SCN1B, SCN1A, GABRG2), and episodic ataxia type 1-which is associated with epilepsy in a few patients--by mutations within another voltage-gated potassium channel (KCNA1). These rare disorders provide interesting models to study the etiology and pathophysiology of disturbed excitability in molecular detail. On the basis of genetic and electrophysiologic studies of the channelopathies, novel therapeutic strategies can be developed, as has been shown recently for the antiepileptic drug retigabine activating neuronal KCNQ potassium channels.
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PMID:Ion channels and epilepsy. 1157 35

Anxiety disorders are among the most common psychiatric disorders that affect all age groups of the general population. Currently, the preferred treatment is with pharmacological drugs that have antidepressant or anti-anxiety properties. However, these agents have numerous and often serious adverse effects, including sedation, impaired cognition, ataxia, aggression, sexual dysfunction, tolerance and dependence. Withdrawal reactions on termination after long-term administration are also a major limiting factor in the use of these agents. Herbal remedies, including kava (Piper methysticum), have been shown to be effective as alternative treatments, at least in mild to moderate cases of anxiety. Kava is a social and ceremonial herb from the South Pacific. It is available in the west as an over-the-counter preparation. Its biological effects, due to a mixture of compounds called kavalactones, are reported to include sedative, anxiolytic, antistress, analgesic, local anaesthetic, anticonvulsant and neuroprotective properties. The pharmacological properties of kava are postulated to include blockade of voltage-gated sodium ion channels, enhanced ligand binding to gamma-aminobutyric acid (GABA) type A receptors, diminished excitatory neurotransmitter release due to calcium ion channel blockade, reduced neuronal reuptake of noradrenaline (norepinephrine), reversible inhibition of monoamine oxidase B and suppression of the synthesis of the eicosanoid thromboxane A(2), which antagonises GABA(A) receptor function. Clinical studies have shown that kava and kavalactones are effective in the treatment of anxiety at subclinical and clinical levels, anxiety associated with menopause and anxiety due to various medical conditions. Until recently, the adverse effects attributed to kava use were considered mild or negligible, except for the occurrence of a skin lesion. This disorder, called kava dermopathy, occurs only with prolonged use of large amounts of kava and is reversible on reduced intake or cessation. Rare cases of interactions have occurred with pharmaceutical drugs that share one or more mechanisms of action with the kavalactones. In the past few years, about 35 cases of severe liver toxicity associated with kava intake have been reported in Europe and the US. However, a direct causal relationship with kava use has been difficult to establish in the majority of the cases, and there is insufficient evidence to implicate kava as the responsible agent. Nevertheless, until further research clarifies any causality, kava should be used with caution.
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PMID:Therapeutic potential of kava in the treatment of anxiety disorders. 1238 29

The roles of inhibitory interneurons in the cerebellar cortex were investigated. First, Golgi cells were specifically eliminated in transgenic mice in which Golgi cells expressed human interleukin-2 receptor alpha subunit (IL2Ralpha). Injection of exotoxin coupled to anti-IL2Ralpha antibody in the cerebellum of the transgenic mouse eliminated Golgi cells and abolished GABA and synaptic inhibition in the granular layer. After elimination of Golgi cells, acute severe ataxia and subsequent mild motor discoordination were observed. In the latter chronic phase, NMDA receptor-mediated synaptic response was reduced in granule cells. Our findings indicate that elimination of GABAergic inhibition in the granular layer caused overexcitation of granule cells resulting in severe ataxia, and then NMDA receptors in granule cells were downregulated, compensating for the reduction of GABAergic inhibition and improving motor control. In the second part, we report on the regulation mechanism of synaptic plasticity at inhibitory synapses on Purkinje cells (PCs). Inhibitory synaptic transmission on a PC is potentiated after repetitive PC depolarization. This synaptic plasticity (rebound potentiation, RP) was suppressed when a presynaptic neuron was activated during the PC depolarization. This synaptic regulation is unique in the sense that the homosynaptic activity suppresses the induction of synaptic plasticity. The mechanism of how presynaptic activity suppresses RP was examined. GABA released from the presynaptic terminal activated not only GABA(A) receptor but also GABA(B) receptor. The latter was coupled to Gi/o proteins, which downregulated adenylyl cyclase reducing cAMP and inactivated cAMP-dependent protein kinase (PKA). Downregulation of PKA suppressed RP induction.
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PMID:Roles of inhibitory interneurons in the cerebellar cortex. 1258 69

SL651498 (6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one) was identified as a drug development candidate from a research program designed to discover subtype-selective GABA(A) receptor agonists for the treatment of generalized anxiety disorder and muscle spasms. The drug displays high affinity for rat native GABA(A) receptors containing alpha(1) (K(i) = 6.8 nM) and alpha(2) (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5-containing GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat GABA(A) receptors confirm these findings and indicate intermediate affinity for the alpha(3)beta(2)gamma(2) subtype. SL651498 behaves as a full agonist at recombinant rat GABA(A) receptors containing alpha(2) and alpha(3) subunits, and as a partial agonist at recombinant GABA(A) receptors expressing alpha(1) and alpha(5) subunits. SL651498 produced anxiolytic-like and skeletal muscle relaxant effects qualitatively similar to those of benzodiazepines (BZs) [minimal effective dose (MED): 1 to 10 mg/kg, i.p. and 3 to 10 mg/kg, p.o.]. However, unlike these latter drugs, SL651498 induced muscle weakness, ataxia or sedation at doses much higher than those having anxiolytic-like activity (MED: 30 to 100 mg/kg, i.p. or p.o.). Moreover, in contrast to BZs, SL651498 did not produce tolerance to its anticonvulsant activity or physical dependence. It was much less active than BZs in potentiating the depressant effects of ethanol or impairing cognitive processes in rodents. The differential profile of SL651498 as compared to BZs may be related to its selective efficacy at the alpha(2)- and alpha(3)-containing GABA(A) receptors. This suggests that selectively targeting GABA(A) receptor subtypes can lead to drugs with increased clinical specificity. SL651498 represents a promising alternative to agents currently used for the treatment of anxiety disorders and muscle spasms without the major side effects seen with classical BZs.
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PMID:SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms. 1259 9

GABA(A) receptors have been implicated in mediating several acute effects of ethanol including anxiolysis, ataxia, sedation/hypnosis, and anticonvulsant activity. Ethanol sensitivity of neurons has been associated with expression of alpha1 subunit-containing receptors. The objective of this study was to determine the contribution of alpha1 subunit containing receptors to ethanol responses in comparison to neurosteroids and other anesthetics using GABA(A) receptor alpha1 subunit knockout mice. Deletion of alpha1 subunit-containing receptors did not alter the anxiolytic, ataxic, anticonvulsant, or hypnotic effects of ethanol or acute functional tolerance to ethanol but did increase sensitivity to the locomotor-stimulating effects of ethanol. The ability of ethanol to potentiate muscimol-stimulated chloride uptake and ethanol clearance was also not altered following alpha1 subunit deletion. The anticonvulsant and hypnotic effects of neurosteroids as well as their potentiating effect on GABA-mediated Cl(-) uptake were unaltered in alpha1(-/-) mice. The hypnotic effect of pentobarbital, etomidate, and midazolam were reduced, whereas the effect of ketamine was enhanced in alpha1(-/-) mice. Thus, GABA(A) receptor alpha1 subunit-containing receptors appear to influence the motor-stimulating effect of ethanol and the sedative/hypnotic effects of some anesthetics, but not ethanol. These receptors do not appear to be necessary for most ethanol responses, suggesting involvement of other GABA(A) receptor subtypes or other targets altogether.
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PMID:Deletion of GABAA receptor alpha 1 subunit-containing receptors alters responses to ethanol and other anesthetics. 1260 32


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