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
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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These authors contributed equally to the work.