Publikation: Neuroprotective properties of memantine in different models of excitotoxicity
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Neuronal dysfunction in Alzheimer's disease (AD) may result, in part, from sustained elevations of glutamate levels and increased sensitivity to glutamate, leading to low-level influx of calcium into neurons, impaired neuronal homeostasis and eventually neurodegeneration. Agents that specifically block the pathological stimulation of glutamate receptors, mainly the N-methyl-D-asparate receptor (NMDA-R) might be anticipated to restore physiological function of neurons and thereby have diseasemodifying effects in AD. Previous attemps to use NMDA-R antagonists to retard the progression of AD have been hindered by the psychotomimetic and cardiovascular effects of these drugs. The tolerability of clinically used uncompetitive NMDA-R antagonist memantine is highly dependent on changes in membrane potential and the drug's fast channel unbloeking kinetics. Memantine blocks sustained NMDA-R activation under pathological conditions and rapidly leaves the NMDA-R channel upon transient physiological activation. Objective: We investigated the neuroprotective properties of memantine in cellular models of different complexity. Methods: Organotypic rat hippocampal slices and murine cerebellar granule cell cultures were exposed to different direct or indirect excitotoxins. Death was measured by counting neurons with condensed nuclei. Results: First, an established model was chosen based on the known pharmacological properties of memantine, in order to find relevant concentrations for cell culture expriments. Memantine protected rat neurons in organotypic hippocampal slices from NMDA-indueed excitotoxicity within micromolar range. Next, we tested memantine within the previously determined dose range in neuronal stress models, which are dependent on excitation of cells by endogenous glutamate. Memantine protected routine cerebellar granule cells from apoptosis induced by the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). Furthermore, neuronal apoptosis induced by the pathophysiologicai mediator nitric oxide (NO) released from S-nitrosoglutathione (GSNO) was inhibited by memantine. Additionally, memantine prevented apoptosis induced by oxygen-glucose deprivation (OGD), a model of cerebral isehemia, in cerebellar granule cells. Conclusion: These findings support a beneficial effect of NMDA-R inhibition by memantine in different apoptotic models.
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VOLBRACHT, Christiane, Johan VAN BEEK, Marcel LEIST, 2004. Neuroprotective properties of memantine in different models of excitotoxicity. In: Neurobiology of Aging. Elsevier. 2004, 25(Suppl 2), pp. S412-S413. ISSN 0197-4580. eISSN 1558-1497. Available under: doi: 10.1016/S0197-4580(04)81352-6BibTex
@article{Volbracht2004Neuro-52216, year={2004}, doi={10.1016/S0197-4580(04)81352-6}, title={Neuroprotective properties of memantine in different models of excitotoxicity}, number={Suppl 2}, volume={25}, issn={0197-4580}, journal={Neurobiology of Aging}, pages={S412--S413}, author={Volbracht, Christiane and van Beek, Johan and Leist, Marcel}, note={Meeting Abstract} }
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