p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism

Wenzhen Duan, Xiaoxiang Zhu, Bruce Ladenheim, Qian Sheng Yu, Zhihong Guo, Jon Oyler, Roy G. Cutler, Jean Lud Cadet, Nigel H. Greig, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

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-α (PFT-α) 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-α 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-α and Z-1-117. PFT-α 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.

Original languageEnglish (US)
Pages (from-to)597-606
Number of pages10
JournalAnnals of neurology
Volume52
Issue number5
DOIs
StatePublished - Nov 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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