Memantine was better than placebo in Alzheimer disease already being treated with donepezil.

University of California, Davis Medical Center, Sacramento, California, USA.
ACP journal club 01/2004; 141(2):38.
Source: PubMed

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    • "The role of NMDA receptors in the neuronal dysfunctions induced by mitochondrial toxins is still unclear. The uncompetitive NMDA receptor antagonist memantine (1-amino-3,5-dimethyladamantane) has been approved for the treatment of moderately severe to severe Alzheimer's disease because of significant efficacy (Finucane, 2004; Hirsch, 2004; Tariot et al., 2004). The interest for this compound is also high since it displays a good pharmacological tolerance in man (Rogawski and Wenk, 2003) and, even though it binds the NMDA receptor similarly to Mg 2+ ions, its less pronounced voltage dependency is more effective in blocking tonic pathological activation of the NMDA receptor (Lipton, 2006). "
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    ABSTRACT: Memantine, a low-affinity uncompetitive NMDA receptor antagonist, has been widely utilized for the treatment of Alzheimer's disease. A possible neuroprotective role of this drug in pathophysiological conditions involving an altered energetic metabolism of the basal ganglia has never been addressed. Thus, we have characterized the electrophysiological effect of memantine on striatal spiny neurons recorded under control conditions and after in vitro ischemia (oxygen and glucose deprivation). Memantine reduced in a dose-dependent manner (EC(50)=5 microM) the irreversible loss of field potential amplitude induced by in vitro ischemia. The neuroprotective effect of memantine against in vitro ischemia was even more potent (EC(50)=3.2 microM) in the absence of external magnesium, a condition enhancing NMDA-mediated glutamatergic transmission. Memantine was also able to block long-term potentiation recorded from spiny neurons following a brief ischemic episode. Moreover, memantine showed protection against irreversible field potential loss induced by 3-nitropropionic acid (3-NP), an inhibitor of the mitochondrial complex II, without influencing toxicity induced by rotenone, a complex I inhibitor. Memantine could represent a potential neuroprotective agent in pathophysiological conditions involving an altered energy metabolism of basal ganglia.
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    ABSTRACT: The blockade of NMDA receptors has been pursued as a strategy to reduce the consequences of acute ischemic stroke (AIS) and NMDA receptors remain a valid therapeutic target to treat AIS. Because the pharmacological and toxicity profile of memantine in Alzheimer's disease patients appears to be good, we determined whether memantine would be effective at improving behavioral performance following embolic strokes in rabbits. For these studies, we used a rabbit multiple infarct ischemia model with a well-defined behavioral endpoint. In this study, memantine dissolved in PBS was given intravenously either as a bolus injection (over 1 min) or infused over 60 min. The P(50) of the control groups measured 24 h after embolization were 1.12 +/- 0.18 mg and 1.08 +/- 0.23 mg for the bolus injected and infused groups, respectively. Bolus injections of memantine at 1 mg/kg and 10 mg/kg were not effective at altering the P(50) value and memantine at a dose of 25 mg/kg was lethal. However, slowly infused memantine (25 mg/kg) significantly increased the P(50) value to 2.31 +/- 0.48 mg and 3.13 +/- 1.13 mg when given 5 and 60 min following embolization, respectively. Memantine administered 180 min following embolization also increased the P(50) value to 2.69 +/- 2.21 mg, but the response was variable. These results suggest that uncompetitive NMDA antagonists, more specifically open channel blockers, which may be alternatives to high affinity NMDA antagonists, may have substantial therapeutic benefit for the treatment of AIS and memantine or new dual activity analogs of memantine should be further pursued as a useful therapy to treat the behavioral deficits associated with multiple-infarct ischemia.
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    ABSTRACT: There is accumulating evidence that excitotoxicity and oxidative stress resulting from excessive activation of glutamate (N-methyl-D-aspartate) NMDA receptors are major participants in striatal degeneration associated with 3-nitropropionic acid (3NP) administration. Although excitotoxic and oxidative mechanisms are implicated in 3NP toxicity, there are conflicting reports as to whether NMDA receptor antagonists attenuate or exacerbate the 3NP-induced neurodegeneration. In the present study, we investigated the involvement of NMDA receptors in striatal degeneration, protein oxidation and motor impairment following systemic 3NP administration. We examined whether NMDA receptor antagonists, memantine and ifenprodil, influence the neurotoxicity of 3NP. The development of striatal lesion and protein oxidation following 3NP administration is delayed by memantine but not affected by ifenprodil. However, in behavioral experiments, memantine failed to improve and ifenprodil exacerbated the motor deficits associated with 3NP toxicity. Together, these findings suggest caution in the application of NMDA receptor antagonists as a neuroprotective agent in neurodegenerative disorders associated with metabolic impairment.
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