title: New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists.
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-alpha, p53, and GLP-1 receptor. The cytokine TNF-alpha 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, Abeta, 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.
authors.affiliation: Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. greign@grc.nia.nih.gov
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Tracyann
authors.initials: T
authors.lastname: Perry
authors.forename: Sic L
authors.initials: SL
authors.lastname: Chan
authors.forename: Tony
authors.initials: T
authors.lastname: Giordano
authors.forename: Kumar
authors.initials: K
authors.lastname: Sambamurti
authors.forename: Jack T
authors.initials: JT
authors.lastname: Rogers
authors.forename: Haim
authors.initials: H
authors.lastname: Ovadia
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D008959:Models, Neurological; D009363:Neoplasm Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000150:complications / Q000188:drug therapy*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000737:chemistry; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053319:Tumor Necrosis Factor Decoy Receptors; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D009363:Neoplasm Proteins; D018027:Receptors, Glucagon; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D016159:Tumor Suppressor Protein p53