Objective: Glutamate neurotoxicity has been suggested to be involved in the pathogenesis of Alzheimer's disease (AD), and clinical data support the use of the NMDA receptor antagonist memantine for AD treatment. This presentation discusses various in vivo models that demonstrate the neuroprotective activity of memantine at doses in rats (5 mg/kg for acute injections or 20 mg/kg/day using ALZET minipump infusion) that are therapeutically relevant in humans.
Design/Methods/Results: To test neuroprotective activity, the endogenous NMDA receptor agonist quinolinic acid (QA) was infused for 2 weeks directly into the brain while a second pump delivered either saline or memantine. Rats previously infused with QA alone showed learning deficits in the T-maze while those infused in parallel with memantine acquired the task normally. Similarly, a decrease in choline uptake sites (an indicator of the density of cholinergic terminals) was seen in the cortex of rats treated with QA but not in those also receiving memantine. Of relevance to the clinical use of memantine are preclinical studies on neurodegeneration in structures important for learning and affected in AD such as the cholinergic nucleus basalis of Meynert (NBM). NMDA-induced neurodegeneration of this structure caused a considerable decrease in levels of the acetylcholine synthesizing enzyme choline acetyltransferase in target cortical areas. Memantine given i.p. before NMDA microinjection produced clear protection with an ED50 of 2.8 mg/kg. Similarly, NBM lesion produced by direct injection of the mitochondrial toxin 3-nitropropionic acid was inhibited by memantine.
Conclusion: The ability of memantine to protect neurons from glutamate neurotoxicity at therapeutically relevant doses provides a mechanistic basis for the clinical experience with memantine in treating AD.
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