Elsevier

Neuroscience

Volume 86, Issue 4, 18 June 1998, Pages 1121-1132
Neuroscience

Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation

https://doi.org/10.1016/S0306-4522(98)00163-8Get rights and content

Abstract

The potential of most N-methyl-D-aspartate antagonists as neuroprotectants is limited by side effects. We previously reported that memantine is an open-channel N-methyl-D-aspartate blocker with a faster off-rate than many uncompetitive N-methyl-D-aspartate antagonists such as dizocilpine maleate. This parameter correlated with memantine's known clinical tolerability in humans with Parkinson's disease. Memantine is the only N-methyl-D-aspartate antagonist that has been used clinically for excitotoxic disorders at neuroprotective doses. Therefore, we wanted to investigate further the basis of its clinical efficacy, safety, and tolerability. Here we show for the first time for any clinically-tolerated N-methyl-D-aspartate antagonist that memantine significantly reduces infarct size when administered up to 2 h after induction of hypoxia/ischemia in immature and adult rats. We found that at neuroprotective concentrations memantine results in few adverse side effects. Compared to dizocilpine maleate, memantine displayed virtually no effects on Morris water maze performance or on neuronal vacuolization. At concentrations similar to those in brain following clinical administration, memantine (6–10 μM) did not attenuate long-term potentiation in hippocampal slices and substantially spared the N-methyl-D-aspartate component of excitatory postsynaptic currents, while dizocilpine maleate (6–10 μM) or D-APV (50 μM) completely blocked these phenomena.

We suggest that the favorable kinetics of memantine interaction with N-methyl-D-aspartate channels may be partly responsible for its high index of therapeutic safety, and make memantine a candidate drug for use in many N-methyl-D-aspartate receptor-mediated human CNS disorders.

Section snippets

In vivo hypoxia/ischemia

Two separate protocols were employed to induce hypoxia/ischemia in immature versus adult rats. For the immature studies, 12-day-old rats (Long–Evans, ??) underwent bilateral carotid ligation followed by hypoxia modified from Jensen et al.[26]Adult rats underwent unilateral middle cerebral artery occlusion using a modification of the filament model described by Longa et al.[39]All rats were housed in the institutional animal facility on a 12-h light/dark cycle, and all surgical and handling

Protective effect of memantine administered 1 h after hypoxia/ischemia in immature rats

The rat pup model yielded severe infarction in the control group at 48 h following hypoxia. Infarction was seen bilaterally in the neocortex, with necrosis involving the frontal and parietal regions of cortex. The occipital cortex showed milder effects, ranging from sheets of reactive astrocytes, macrophages and pyknotic neurons to clusters of pyknotic neurons at the occipitoparietal border. Hippocampal structures were less affected, with pyknotic granule cells in the dentate gyrus and variable

Discussion

This study demonstrates that the NMDA open-channel blocker, memantine, is neuroprotective when administered up to 2 h after the onset of hypoxia/ischemia. Furthermore, this agent is effective when systemically administered in both immature and adult rat stroke models, even up to 2 h after the onset of ischemia. The efficacy was comparable to MK-801, but most importantly our studies reveal that memantine lacks many of the adverse effects that have been reported for other NMDA antagonists,

Conclusions

In summary, our findings provide a behavioral, ultrastructural, and electrophysiological basis for the observed clinical safety of memantine, a drug that has been used clinically in Europe for over 15 years. However, given that memantine was only recently been recognized as an NMDA receptor antagonist,[5]which works via open-channel block,3, 7, 8it is not surprising that its full clinical potential for treatment of NMDA receptor-mediated neurologic diseases has not yet been realized. Our

Unlinked References

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Acknowledgements

This work was supported by Public Health Service Grants R29 NS31718 and P20 NS32570 (FEJ), P01 HD5987, R01 EY05477, and R01 EY09024 (SAL), and by an NIH-NICHD Mental Retardation Research Center Grant (P30 HD18655). Additional support was provided by an AHA Grant-In-Aid (FEJ). We wish to thank Dr James Larrick at Panorama, Inc., and Dr Gunter Quack at Merz and Co. GmbH & Co. for the kind gifts of memantine. This work was supported in part by a Sponsored Research Agreement and Consulting

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