Many drugs that have been developed to treat neurodegenerative diseases fail to gain approval for clinical use because they are not well tolerated in humans. In this article, I describe a series of strategies for the development of neuroprotective therapeutics that are both effective and well tolerated. These strategies are based on the principle that drugs should be activated by the pathological state that they are intended to inhibit. This approach has already met with success, and has led to the development of the potentially neuroprotective drug memantine, an N-methyl-D-aspartate (NMDA)-type and glutamate receptor antagonist.
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Quantitative proteomic analyses of dynamic signalling events in cortical neurons undergoing excitotoxic cell death
Cell Death & Disease Open Access 01 March 2019
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This article would not have been possible without the insightful work of my colleagues, present and former, H.-S. V. Chen, Y.-B. Choi, D. Zhang, N. Nakanishi, M. Digicaylioglu, T. Satoh, Z. Gu, S. Mobashery and J. S. Stamler, to whom I am extremely grateful. The work was supported in part by grants from the NIH, the Institute for the Study of Aging, and a Senior Scholar Award in Aging Research from the Ellison Medical Foundation.
S.A.L. is the named inventor on patents for the use of the clinically approved and marketed drug memantine (Namenda), in the treatment of neurodegenerative diseases. He has no direct ownership in memantine, but under the rules of the institution where this work was performed, Harvard University, he participates in a royalty sharing plan administered by Harvard Medical School and Children's Hospital, Boston. S.A.L. is also a named inventor on patents for the use of erythropoietin, matrix metalloproteinase inhibitors, and electrophilic compounds for the treatment of neurodegenerative and related disorders. These patents are assigned to the Burnham Institute for Medical Research in La Jolla, California, USA.
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Lipton, S. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 8, 803–808 (2007). https://doi.org/10.1038/nrn2229
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