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)

Hyperalgesia and allodynia following peripheral tissue or nerve injury are not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depend on NMDA receptor-mediated central changes in synaptic excitability. Functional inhibition of NMDA receptors can be achieved through actions at different recognition sites such as the primary transmitter site (competitive), strychnine-insensitive glycine site (glycine(B)), polyamine site (NR2B selective) and phencyclidine site located inside the cationic channel. Unfortunately, most agents which completely block NMDA receptors cause numerous side effects such as memory impairment, psychotomimetic effects, ataxia and motor incoordination. There is now, however, considerable evidence that moderate affinity channel blockers, glycine(B) and NR2B selective antagonists show a much better profile in animal models than high affinity channel blockers and competitive NMDA receptor antagonists. These "therapeutically" safe NMDA receptor antagonists are also able to slow or prevent the development of opioid tolerance, indicating the utility of their combination with opioids in the treatment of chronic pain. The antinociceptive effects of NMDA receptor antagonists and opioids could be predicted to be synergistic and the presence of an NMDA receptor antagonist should block both the development of chronic pain states and inhibit the development of tolerance to the analgesic effects of morphine. Peripheral NMDA receptors offer a very attractive target for NMDA receptor antagonists that do not cross the blood brain barrier in inflammatory and visceral pain. Such agents might be predicted to be devoid of CNS side effects at doses producing powerful antinociception at peripheral NMDA receptors.
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PMID:NMDA receptors as targets for drug action in neuropathic pain. 1169 28

The glutamatergic system has received considerable attention over recent years as a potential target for anxiolytic drugs. In spite of the pronounced anxiolytic-like effects of competitive and non-competitive antagonists of NMDA receptors in animal models of anxiety, these substances can not be regarded as potential anxiolytic drugs, mainly due to their side-effect profiles (eg, ataxia, myorelaxation, impairment of learning and memory processes and psychotomimetic effects). Antagonists and partial agonists of the glycine, receptor inhibit function of the NMDA receptor complex and evoke in animals an anxiolytic-like response. Although data concerning anti-anxiety-like effects of glycine, receptor antagonists are not very promising, studies are underway to develop new, brain-penetrating agents devoid of side effects. Further developments are necessary to more fully elucidate the possible involvement of AMPA/kainate receptors in anxiety. The recent discovery of metabotropic glutamate receptors, which modulate the function of the glutamatergic system, offers new hope for discovery of a new generation of anxiolytics. MPEP, a highly selective, brain penetrable, noncompetitive mGlu5 receptor antagonist, evokes anxiolytic-like effects in several animal models of anxiety, remaining remarkably free of side effects. LY-354740, a selective brain-penetrable group II mGlu receptor agonist, evokes marked anxiolytic-like effects in animal models of anxiety. LY-354740 causes mild sedation in mice, does not disturb motor coordination and has no potential to cause dependence. Therefore mGlu receptor ligands may become the anxiolytics of the future, free from the side effects characteristic of benzodiazepines.
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PMID:Glutamate receptor ligands as anxiolytics. 1189 23

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

Exposing the developing brain to the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) has been shown to cause deficits in neurobehavioral functions, particularly on learning and memory and seizure sensitivity. Besides acting as a noncompetitive NMDA antagonist, PCP at high doses is known to affect the dopaminergic system. The present study assessed the effect of postnatal PCP treatment on locomotor activity and striatal dopamine (DA) D(2) receptor. Male and female rat pups were injected intraperitoneally (i.p.) with one of three doses of PCP (1, 3 and 5 mg/kg) or saline from postnatal day (PD) 5 to PD 15. Control and PCP-treated rats were given a challenge dose of PCP (10 mg/kg) as adults, and their locomotor behaviors--locomotion, stereotypy and ataxia--were scored. Postnatal PCP treatment did not have any significant effect in either sex on any of the PCP-induced locomotor behavioral paradigms studied. Separate groups of male and female rats were treated daily with saline or PCP (5 mg/kg i.p.) from PD 5 to PD 15 and sacrificed either as juveniles (PD 21) or adults, and D(2) receptor binding was measured in their striata. Striatal D(2) receptor density in juvenile and adult male postnatal PCP-treated rats did not differ from saline-treated controls. Adult female PCP-treated rats showed a slight but significant reduction in the maximal binding of striatal D(2) receptors. There was no effect of postnatal PCP on striatal D(2) receptor binding in female juvenile rats. These results support the hypothesis that blocking the developing NMDA receptor minimally affects PCP-induced locomotor behavior and the striatal D(2) receptor.
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PMID:Effects of postnatal PCP treatment on locomotor behavior and striatal D2 receptor. 1266 9

We studied the effects of D-cycloserine, a partial NMDA receptor allosteric agonist, on ataxia in patients with spinocerebellar degeneration. Fifteen Japanese ataxic patients enrolled in a 14-day single-blind trial of D-cycloserine (daily oral dose of 50 mg) following a 14-day single-blind placebo phase. At the end of the D-cycloserine administration, there was a significant reduction in the posture, gait and total score of the international cooperative ataxia rating scale and in the time for walking and speech tasks. D-Cycloserine was well-tolerated and no adverse effect was observed. D-Cycloserine may have therapeutic efficacy for spinocerebellar ataxia.
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PMID:D-cycloserine for the treatment of ataxia in spinocerebellar degeneration. 1273 88

Magnesium is a physiological N-methyl-D-aspartate (NMDA) antagonist. The NMDA receptor may be involved in the pathogenesis of acute mountain sickness (AMS). In the present study, healthy subjects were randomized to receive either 400 mg of oral magnesium citrate (16 mmol) or matching placebo every 8 h for 5 days (prevention trial). Subjects then climbed to 4559 m in approx. 24 h and stayed there for 48 h. A Lake Louise Score <3 at any time was defined as the absence of AMS, whereas a score >6 (with ataxia, headache and nausea) was defined as a prevention failure. In a subsequent trial (treatment trial), subjects with a Lake Louise Score >6 (with ataxia, headache and/or nausea) were randomized to receive either 4 g of intravenous magnesium sulphate (16 mmol) or matching placebo. A decrease in the score >50% within 60 min was regarded as a treatment success. Dichotomous data were analysed using relative risk (RR) or odds ratio (OR), and continuous data using Student's t test or Wilcoxon's rank-sum test. In the prevention trial, data from 61 subjects (30 receiving magnesium and 31 placebo) were analysed. With oral magnesium, 20% of subjects had no AMS compared with 16.1% in the placebo group [RR (95% CI), 1.2 (0.4-3.6); where CI is confidence interval]. With magnesium, 40% were prevention failures compared with 35.5% in the placebo group [RR (95% CI), 1.13 (0.59-2.15)]. The mean time to failure and severity of AMS was similar between the two groups. With magnesium, 38.2% had loose stools compared with 11.8% in placebo group [RR (95% CI), 3.25 (1.18-8.97)]. In the treatment trial, 12 subjects received magnesium and 13 received the placebo. With intravenous magnesium, 25% were regarded as treatment successes compared with none in the placebo group [OR (95% CI), 9.71 (0.91-103.4)]. With magnesium, mean (+/- S.D.) scores decreased from 11.6 +/- 1.7 before treatment to 9.0 +/- 3.5 after treatment (P=0.009); scores remained unchanged in the placebo group. With magnesium, 75% of subjects experienced a transient flushing compared with 7.7% in the placebo group [RR (95% CI), 0.05 (0.01-0.25)]. In conclusion, oral magnesium does not prevent AMS. In subjects with established AMS, intravenous magnesium reduces the severity of symptoms to some extent, but this effect is of no clinical importance.
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PMID:Magnesium for the prevention and treatment of acute mountain sickness. 1457 5

N-methyl-D-aspartate (NMDA) receptor antagonists have antiakinetic and antidyskinetic effects in animals models of Parkinson's disease (PD). However, non-selective inhibition of NMDA receptors throughout the central nervous system may result in undesired effects such as ataxia and psychosis. We therefore studied Ro 25-6981, an activity-dependent antagonist of NMDA receptors containing the NR2B subunit which are predominantly expressed in the striatum. Ro 25-6981 induced contraversive rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats without stimulating locomotion in normal rats and reversed parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-treated common marmosets. Due to the small number of marmosets, there were no significant differences between Ro 25-6981 and vehicle though there was a significant trend toward differences, as shown by the Page test. Furthermore, Ro 25-6981 potentiated the action of levodopa in both species and attenuated the maximal levodopa response in 6-OHDA-lesioned rats chronically treated with levodopa without reducing the overall response. Ro 25-6981 also potentiated the action of the dopamine receptor agonists apomorphine, A68930 and quinpirole in 6-OHDA-lesioned rats. The present observations suggest a therapeutic potential of NR2B-selective NMDA receptor antagonists in the management of PD.
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PMID:Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson's disease. 1508 91

Inasmuch as glutamate is the main excitatory neurotransmitter in the central nervous system, strategies aimed at counteracting glutamate excitotoxicity, which is at least partially involved in many acute neurologic, chronic neurodegenerative and psychiatric diseases, are challenging. Blockade of the NMDA receptor was identified as one way of achieving selective antagonism and overcoming glutamate neurotoxicity, yet not without liabilities. Glycine site antagonism of the NMDA receptor in 1987 offered a significant advance in blocking this receptor because such drugs were shown to lack most of the side effects, such as memory impairment, ataxia, lack of motor coordination and psychotomimetic effects, which accompanied competitive and non-competitive NMDA receptor antagonists. To date, much has been done to improve the structure-activity relationship (SAR) of compounds resulting in the synthesis of ACEA 1021. It is unclear, however, whether further chemical substitutions will lead to an improved compound. Many studies have been performed with ACEA 1021 and although there are much in vitro and in vivo data to support its neuroprotective effects and improved safety profile, there is very little published information regarding its clinical pharmacology. In order to properly evaluate the true potential for ACEA 1021 in acute and chronic CNS disorders additional longer term safety and efficacy data in humans are needed.
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PMID:ACEA 1021: flip or flop? 1559 82

N-Methyl-D-aspartate (NMDA) receptor antagonists cause hyperlocomotion and cognitive deficits in rodents, and caffeine-tolerant mice show diminished locomotor response to NMDA receptor antagonists. The aim of this study was to evaluate the effect of subchronic caffeine treatment on MK-801-induced hyperlocomotion, ataxia and cognitive deficits, as well as amphetamine-induced hyperlocomotion in mice. Mice were treated subchronically with caffeine (0, 0.1, 0.3 and 1 mg/ml and 1, 3 and 7 days) and evaluated for locomotor activity, working memory (delayed alternation test), long-term memory (inhibitory avoidance task) and ataxia. Hyperlocomotion induced by MK-801 (0.25 mg/kg i.p.) was diminished after 3 days and almost abolished after 7 days of caffeine treatment at the 1 mg/ml dose, and this effect was also dose-dependent. Ataxia induced by 0.5 mg/kg MK-801 was not affected by caffeine treatment, but a short-lived hyperlocomotor effect was observed. Performance deficit in the inhibitory avoidance task induced by MK-801 (0.01 mg/kg) was prevented in mice treated with caffeine for 7 days at 1 mg/ml, and perseverative errors in the T-maze by MK-801 (0.4 mg/kg) were attenuated. The locomotor effect of amphetamine (5 mg/kg) was unaffected by subchronic caffeine treatment. The findings that hyperlocomotion and cognitive effects induced by MK-801 can be specifically influenced by reduced adenosinergic activity agree with a model of adenosine hypofunction in schizophrenia, since NMDA receptor antagonists are pharmacological models for this disorder.
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PMID:Effect of subchronic caffeine treatment on MK-801-induced changes in locomotion, cognition and ataxia in mice. 1576 42

Hypoglutamatergic theory of schizophrenia is substantiated by observation that high affinity uncompetitive antagonists of NMDA receptors such as PCP can induce psychotic symptoms in humans. Recently, metabotropic glutamate receptors of the mGluR5 type have also been discussed as possible players in this disease. However, less is known about the potential contribution of mGluR1 in schizophrenia. Therefore, the aim of the present study was to compare the effect of selective mGluR1 antagonist EMQMCM, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist (MTEP ([(2-methyl-1, 3-thiazol-4-yl) ethynyl] pyridine) either alone or in combination with (+)MK-801 in a prepulse inhibition (PPI) model and locomotor activity tests. Additionally, the effect of both mGluR1 and mGluR5 antagonists on (+)MK-801-evoked ataxia was tested. In contrast to (+)MK-801, which induced disruption of PPI, neither MTEP (1.25-5 mg/kg) nor EMQMCM (0.5-4 mg/kg) altered the PPI. However, MTEP, but not EMQMCM, enhanced disruption of PPI induced by (+)MK-801. Although neither mGluR1 nor mGluR5 antagonists given alone changed locomotor activity of rats, MTEP at 5 mg/kg potentiated the effect of (+)MK-801 while EMQMCM (up to 4 mg/kg) turned out to be ineffective. On the other hand, EMQMCM, but not MTEP, enhanced ataxia evoked by MK-801. The present results demonstrate that blockade of mGluR1 and mGluR5 evokes different effects on behavior induced by NMDA receptor antagonists.
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PMID:mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition. 1599 82


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