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Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond

Key Points

  • Excessive NMDA-type glutamate receptor activity is thought to contribute to a wide range of neurologic disorders, but multiple antagonists of this target have all failed in human trials because of poor clinical tolerability.

  • It became clear that therapeutic strategies had to change if the NMDA receptor was to be approached clinically. This review highlights the recent realization that uncompetitive, low-affinity (weakly binding) yet specific antagonists with fast off rates can block excessive NMDA receptor activity while sparing normal activity. This concept has led to successful clinical trials with the drug memantine. The action of an uncompetitive antagonist is contingent upon prior activation of the receptor by the agonist, and, as a result, uncompetitive antagonists, such as memantine, preferentially block increasing (pathological) levels of activity, while relatively sparing normal activity.

  • Studies in both human and rodent models have shown that Vascular dementia, Alzheimer's disease, stroke, HIV-associated dementia, glaucoma, multiple sclerosis, epilepsy, Parkinson's disease, Huntington's disease, motor neuron disease, neuropathic pain, and other neurologic disorders may all manifest a component of NMDA receptor-mediated cell damage.

  • Clinical trials have shown that the NMDA receptor antagonist, memantine, an open-channel blocker, can be helpful for moderate-to-severe Alzheimer's disease. Other clinical trials have suggested that the drug is also effective in Vascular dementia, and a series of additional trials are in progress for other indications.

  • Second-generation drugs, represented by the Nitro Memantines, may prove even more effective than memantine by manifesting a second site of action at redox-active thiols on critical regulatory cysteine residues, where nitric oxide (NO) can react via a mechanism designated S-nitrosylation.

  • Perhaps the most promising aspect of such NMDA receptor drugs is that the simple concept of uncompetitive inhibition could be extended to other neuroprotective targets and, more generally, even to other pharmaceutical targets. This approach can enhance clinical tolerability of drugs by avoiding effects on normal activity of the target, and thus may well represent the future of drug development

Abstract

Neuroprotective drugs tested in clinical trials, particularly those that block N-methyl-D-aspartate-sensitive glutamate receptors (NMDARs), have failed miserably in large part because of intolerable side effects. However, one such drug, memantine, was recently approved by the European Union and the US FDA for the treatment of dementia following our group's discovery of its clinically tolerated mechanism of action. Here, we review the molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca2+ influx through the receptor's associated ion channel and consequent free-radical formation.

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Figure 1: Schema of the apoptotic-like cell injury and death pathways triggered by excessive NMDAR activity.
Figure 2: NMDAR model illustrating important binding and modulatory sites.
Figure 3: Chemical structure of memantine.
Figure 4: Blockade of NMDA current by memantine.
Figure 5: Uncompetitive inhibition by memantine.
Figure 6: Effect of memantine on single-channel recordings.
Figure 7: Relative lack of effect of memantine on NMDA receptor component of excitatory postsynaptic currents (EPSCs).

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Acknowledgements

I would like to thank my colleagues for their contributions to this work, which is updated here with respect to the effects of memantine on Alzheimer's disease and vascular dementia. I am especially grateful to J. Bormann, H. -S. V. Chen, Y.-B. Choi and J. S. Stamler for their discussions or collaborations. This work was supported in part by National Institutes of Health grants.

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S.A.L. is the named inventor on a series of patents for the use of memantine for neurodegenerative disorders. When these patents were filed, Lipton was a faculty member at Harvard Medical School. Hence patents are assigned to Harvard-affiliated institutions, including Children's Hospital of Boston. In accordance with university conflict-of-interest policies, the inventor will derive no direct benefit and has no stock ownership in any company involved with memantine. He does participate in a royalty-sharing plan with the hospital, as per university guidelines, which began in early 2004 after memantine was approved by the FDA and sold for the treatment of Alzheimer's disease. The inventor has also served as a consultant to clinical studies involving memantine but did not participate in direct patient care, collection of data, or data analysis in accord with Nationa Institutes of Health conflict-of-interest guidelines.

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Amyotrophic lateral sclerosis

Alzheimer's disease

Huntington's disease

Multiple slcerosis

Parkinson's disease

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Lipton, S. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nat Rev Drug Discov 5, 160–170 (2006). https://doi.org/10.1038/nrd1958

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