p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism.
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.
Duan
Wenzhen
W
Laboratory of Neurosciences, Gerontology Research Center 4F01, National Institute on Aging/NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Zhu
Xiaoxiang
X
Ladenheim
Bruce
B
Yu
Qian-sheng
QS
Guo
Zhihong
Z
Oyler
Jon
J
Cutler
Roy G
RG
Cadet
Jean Lud
JL
Greig
Nigel H
NH
Mattson
Mark P
MP
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
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