New Therapeutic Strategies and Drug Candidates for Neurodegenerative Diseases: p53 and TNF-α Inhibitors, and GLP-1 Receptor Agonists

Authors

  • NIGEL H. GREIG,

    Corresponding author
    1. Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • MARK P. MATTSON,

    1. Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • TRACYANN PERRY,

    1. Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • SIC L. CHAN,

    1. Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • TONY GIORDANO,

    1. Department of Molecular Biology and Biochemistry, Louisiana State University, Shreveport, Louisiana 71130, USA
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  • KUMAR SAMBAMURTI,

    1. Department of Physiology and Neuroscience, Medical University South Carolina, Charleston, South Carolina 29425, USA
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  • JACK T. ROGERS,

    1. Genetics and Aging Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
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  • HAIM OVADIA,

    1. Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Hospital, Jerusalem, Israel
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  • DEBOMOY K. LAHIRI

    1. Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
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Address for correspondence: Nigel H. Greig, Drug Design and Development Section, Laboratory of Neurosciences, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224. greign@grc.nia.nih.gov

Abstract

Abstract: Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate-limiting steps within the pathological cascade. Such targets include TNF-α, p53, and GLP-1 receptor. The cytokine TNF-α is elevated in Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimer's disease toxic peptide, Aβ, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzothiazole and -oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon-like peptide-1 receptor (GLP-1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults.

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