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)

Male Sprague-Dawley rats injected sc with a single sublethal dose of the organophosphate nerve agent, soman (100 micrograms/kg), had motor limbic seizures within 5-15 min. Pretreatment with a single dose of memantine HCl (MEM, 18 mg/kg, sc), alone or in combination with atropine sulfate (ATS, 16 mg/kg, sc), before soman prevented seizures without sedation or ataxia. Rats appeared normal or demonstrated increased exploratory activity. Excessive salivation, a peripheral manifestation of soman intoxication, was decreased by ATS, but pretreatment with ATS alone did not prevent seizures. After seizure onset, MEM +/- ATS, but not ATS, abolished seizures. Acetylcholinesterase (AChE) activity in several brain regions (cortex, stem, striatum, and hippocampus) was markedly reduced by soman, but not by MEM, ATS, or MEM + ATS. Preadministration of MEM + ATS in vivo significantly protected AChE from inhibition by soman. Memantine reduced inhibition of AChE activity in crude brain homogenates by soman, but not by edrophonium (anionic site inhibitor) or decamethonium (peripheral site inhibitor). Thus, MEM may bind to a different modulatory site, not yet characterized, to protect AChE. When given after onset of soman-induced seizures, treatment with MEM +/- ATS did not reactivate AChE although seizures were controlled, suggesting additional anticonvulsant mechanisms of action. At concentrations (10(-4) to 5 x 10(-4) M) which did not significantly alter the spontaneous firing of action potentials (APs), MEM limited sustained high frequency repetitive firing (SRF) induced by depolarization of spinal cord (mouse and rat) and neocortical (mouse) neurons in monolayer-dissociated cell culture. In the same range of concentrations, ATS both limited SRF and suppressed spontaneous activity, suggesting toxicity. In addition, MEM and ATS reversibly produced use-dependent block of depolarizing responses to acetylcholine (ACh) applied by pressure ejection to spinal cord neurons. Thus, the anticonvulsant efficacy of MEM, with or without ATS, may have resulted from a combination of actions, including protection of AChE from inhibition by soman, limitation of high frequency firing of APs, and blockade of excitatory postsynaptic responses to ACh.
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PMID:Prophylactic and therapeutic efficacy of memantine against seizures produced by soman in the rat. 173 53

Memantine (1-amino-3,5-dimethyladamantane) has previously been shown to attenuate or block chemically or electrically induced seizures in rodents at doses of 5-20 mg/kg i.p., suggesting that the drug might have potential utility in the treatment of seizures. In the present study, the effects of memantine were examined in amygdala-kindled and non-kindled rats. In fully kindled rats, i.e. a model of focal seizures with secondary generalization, memantine exerted no effects on seizure parameters at 5 mg/kg i.p., but reduced seizure severity and duration at 10 mg/kg. The threshold for induction of afterdischarges recorded from the amygdala was not altered after administration of 10 mg/kg. At 20 mg/kg, memantine induced spontaneous motor seizures in amygdala-kindled rats. No motor seizures were observed in non-kindled rats, but in both kindled and non-kindled animals memantine, 20 mg/kg, induced spikes in the electroencephalogram. Additional dose-dependent behavioural alterations observed after memantine included hyperactivity, ataxia and stereotypies, which may relate to the dopaminomimetic properties of the drug. The results demonstrate that kindled rats are more sensitive to central nervous system stimulating effects of memantine than non-kindled rats, which could relate to an impairment of inhibitory processes and/or alterations in synaptic transmission mediated by excitatory amino acids in the kindled brain.
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PMID:High doses of memantine (1-amino-3,5-dimethyladamantane) induce seizures in kindled but not in non-kindled rats. 236 81

Recent studies have provided evidence that excitatory amino acid antagonists can exert analgesic effects in animals. These studies, however, have focused primarily on phasic pain or hyperalgesia rather than tonic pain. The present study evaluates the effects of systemic administration of Memantine (1-amino-3,5-dimethyl-adamantane), a clinically used N-methyl-D-aspartate (NMDA) receptor antagonist, on formalin-induced phasic and tonic pain behavior in the rat. Memantine (2.5, 5.0, 10.0 and 20.0 mg/kg) or normal saline was injected i.p. 1 h prior to a s.c. injection of formalin (5%, 50 microliters) into the vibrissal pad of adult rats (n = 5/group). Pain behavior was measured by the number of seconds of formalin-induced face grooming during a 42-min post-injection observation period. Saline-injected animals displayed a biphasic face-grooming response, consisting of an early, phasic phase (0-6 min) and a delayed, prolonged tonic phase (12-42 min). Memantine at doses of 2.5-10 mg/kg produced a significant dose-related inhibition of the second phase (65-93%) and a much smaller inhibition of the first phase (up to 52%). A higher dose (20 mg/kg) further inhibited both phases but also produced other motor effects (increased exploratory and decreased freezing behavior, hind-paw weakness and gait ataxia) which were not observed at the lower doses. These results suggest that the NMDA receptor antagonist Memantine can block formalin-induced tonic and, to a lesser extent, phasic pain, at doses that do not alter observed motor behaviors.
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PMID:The NMDA antagonist Memantine blocks pain behavior in a rat model of formalin-induced facial pain. 823 44

Memantine (1-amino-3,5-dimethyl-adamantane) is the only clinically used NMDA (N-methyl-D-aspartate) glutamate receptor antagonist. The present experiments were carried out to compare the dose-response for memantine's predictive therapeutic and side-effects in a variety of tests in C57BL/6J/Han mice, and to elucidate if tolerance may develop to them. Memantine produced a dose-dependent (2.5-15 mg/kg) antidepressant-like effect in the tail-suspension test (TST); this anti-immobility effect of 15 mg/kg of memantine appeared to persist with its sub-chronic administration (3 days, twice daily). Treatment with the same doses of memantine produced no effects on locomotor activity, and sub-chronic treatment with 15 mg/kg did not affect locomotor activity. Exploratory activity was assessed in the open field. Given acutely 5 min before the test, memantine reduced rearing (1.875-30 mg/kg), ambulation (7.5 and 30 mg/kg) and grooming (30 mg/kg). These effects were more pronounced 35 min after its administration. As measured in three different tests, ataxia and stereotypy appeared only at the single dose of 30 mg/kg, 5 and 35 min after administration. In mice treated sub-chronically with 30 mg/kg, the dose of 30 mg/kg increased ambulation, and continued to decrease rearing and grooming, but no signs of ataxia and stereotypy were detected. The present data indicate that different doses of memantine are required for the purportedly therapeutic and side-effects, and that tolerance may develop to the ataxic, but not anti-immobility actions.
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PMID:A comparison of the predictive therapeutic and undesired side-effects of the NMDA receptor antagonist, memantine, in mice. 1586 70

Intramuscular injection of selective NMDA receptor antagonists memantine and arcaine 4-fold decreased the incidence of pentylenetetrazole-induced generalized tonic-clonic seizures in rats, while the incidence of clonic seizures decreased by 1.2-1.3 times. Memantine and arcaine are characterized by low therapeutic index, i.e. induced ataxia in rats in doses exceeding the effective anticonvulsant dose by only 3.5-10 times. Intramuscular injection of IEM-1913 (combined blockade of NMDA and AMPA receptors in the brain) decreased the incidence of pentylenetetrazole-induced clonic and tonic-clonic seizures in rats by 4-8 times. The therapeutic index of IEM-1913 surpassed that of memantine and arcaine by 200-600 times.
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PMID:Combined blockade of AMPA and NMDA receptors in the brain of rats prevents pentylenetetrazole-induced clonic and tonic-clonic seizures without ataxia. 1911 May 62

Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder manifesting cognitive deficits that often subsequently progress to dementia. To date, there is no specific treatment available for FXTAS. Studies have demonstrated the premutation-associated overactivation of glutamatergic receptors in neurons. Memantine, a NMDA receptor antagonist approved for treatment of Alzheimer's disease, thus was tested in the first placebo-controlled, double-blind, randomized clinical trial in FXTAS. Prior event-related brain potential (ERP) studies in FXTAS found reduced N400 repetition effect, a glutamate-related electrophysiological marker of semantic priming, and verbal memory processes. This substudy of the randomized clinical trial of memantine in FXTAS sought to use the N400 repetition effect to evaluate effects of chronic memantine treatment on verbal memory. Subsequent recall and recognition memory tests for the experimental stimuli were administered to characterize verbal memory. Data from 41 patients who completed the 1-year memantine trial (21 on memantine) and also completed longitudinal ERP studies were analyzed. Results showed treatment-associated benefits on both cued-recall memory and N400 repetition effect amplitude. Importantly, improvement in cued recall was positively correlated with amplitude increase of the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that memantine treatment may have beneficial effects on verbal memory in FXTAS. Additional studies of memantine, perhaps in combination with other therapeutic agents, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently recognized neurodegenerative disorder.
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PMID:Memantine effects on verbal memory in fragile X-associated tremor/ataxia syndrome (FXTAS): a double-blind brain potential study. 2487 47