New therapeutic strategies and drug candidates for neurodegenerative diseases

p53 and TNF-α inhibitors, and GLP-1 receptor agonists

Nigel H. Greig, Mark P. Mattson, Tracyann Perry, Sic L. Chan, Tony Giordano, Kumar Sambamurti, Jack T. Rogers, Haim Ovadia, Debomoy Lahiri

Research output: Contribution to journalArticle

82 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)290-315
Number of pages26
JournalAnnals of the New York Academy of Sciences
Volume1035
DOIs
StatePublished - 2004

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Neurodegenerative diseases
Neurodegenerative Diseases
Alzheimer Disease
Poisons
Parkinson Disease
Glutamic Acid
Stroke
Oxazoles
Pharmaceutical Preparations
Thalidomide
Amyotrophic Lateral Sclerosis
Glutamate Receptors
Brain
DNA Damage
Homeostasis
Cell Death
Transcription Factors
Cardiovascular Diseases
Therapeutics
Apoptosis

Keywords

  • GLP-1 receptor (GLP-1R)
  • p53
  • TNF-α

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

New therapeutic strategies and drug candidates for neurodegenerative diseases : p53 and TNF-α inhibitors, and GLP-1 receptor agonists. / Greig, Nigel H.; Mattson, Mark P.; Perry, Tracyann; Chan, Sic L.; Giordano, Tony; Sambamurti, Kumar; Rogers, Jack T.; Ovadia, Haim; Lahiri, Debomoy.

In: Annals of the New York Academy of Sciences, Vol. 1035, 2004, p. 290-315.

Research output: Contribution to journalArticle

Greig, Nigel H. ; Mattson, Mark P. ; Perry, Tracyann ; Chan, Sic L. ; Giordano, Tony ; Sambamurti, Kumar ; Rogers, Jack T. ; Ovadia, Haim ; Lahiri, Debomoy. / New therapeutic strategies and drug candidates for neurodegenerative diseases : p53 and TNF-α inhibitors, and GLP-1 receptor agonists. In: Annals of the New York Academy of Sciences. 2004 ; Vol. 1035. pp. 290-315.
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