title: p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism.
abstract: Drugs currently used for patients with Parkinson's disease provide temporary relief of symptoms but do not halt or slow the underlying neurodegenerative disease process. Increasing evidence suggests that neurons die in Parkinson's disease by a process called apoptosis, which may be triggered by mitochondrial impairment and oxidative stress. We report that two novel synthetic inhibitors of the tumor suppressor protein p53, pifithrin-alpha (PFT-alpha) and Z-1-117, are highly effective in protecting midbrain dopaminergic neurons and improving behavioral outcome in a mouse model of Parkinson's disease. Mice given intraperitoneal injections of PFT-alpha or Z-1-117 exhibited improved motor function, reduced damage to nigrostriatal dopaminergic neurons and reduced depletion of dopamine and its metabolites after exposure to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP caused an increase in the level of the proapoptotic protein Bax, which was prevented by giving mice PFT-alpha and Z-1-117. PFT-alpha and Z-1-117 also suppressed Bax production and apoptosis in cultured dopaminergic cells exposed to MPP(+). Our findings demonstrate a pivotal role for p53 in experimental parkinsonism and identify a novel class of synthetic p53 inhibitors with clinical potential.
authors.affiliation: Laboratory of Neurosciences, Gerontology Research Center 4F01, National Institute on Aging/NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Zhu
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Qian-sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Guo
authors.forename: Jon
authors.initials: J
authors.lastname: Oyler
authors.forename: Roy G
authors.initials: RG
authors.lastname: Cutler
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D052160:Benzothiazoles; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology* / Q000523:psychology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D052160:Benzothiazoles; D015259:Dopamine Agents; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C468560:Z-1-117; D051028:bcl-2-Associated X Protein; D014050:Toluene; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C121565:pifithrin; D004298:Dopamine