Sepiapterin attenuates 1-methyl-4-phenylpyridinium-induced apoptosis in neuroblastoma cells transfected with neuronal NOS: Role of tetrahydrobiopterin, nitric oxide, and proteasome activation

Tiesong Shang, Srigiridhar Kotamraju, Hongtao Zhao, Shasi V. Kalivendi, Cecilia J. Hillard, B. Kalyanaraman

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26 Scopus citations

Abstract

In this study, we investigated the molecular mechanism of toxicity of 1-methyl-4-phenylpyridinium (MPP+), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes parkinsonism in experimental animals and humans. Using wild-type and human neuronal nitric oxide synthase (nNOS) stably transfected neuroblastoma cells (SH-SY5Y), we showed that nNOS overexpression in SH-SY5Y cells greatly enhanced proteasome activity and mitigated MPP+-induced apoptosis. During MPP+-induced oxidative stress, intracellular BH4 levels decreased, resulting in nNOS "uncoupling" (i.e., switching from nitric oxide to superoxide generation). Increasing the intracellular BH 4 levels by sepiapterin supplementation restored the nNOS activity, inhibited superoxide formation, increased proteasome activity, decreased protein ubiquitination, and attenuated apoptosis in MPP+-treated cells. Implications of BH4 depletion in dopaminergic cells and sepiapterin supplementation to augment the striatal nNOS activity in the pathogenesis mechanism and treatment of Parkinson disease are discussed.

Original languageEnglish (US)
Pages (from-to)1059-1074
Number of pages16
JournalFree Radical Biology and Medicine
Volume39
Issue number8
DOIs
Publication statusPublished - Oct 15 2005

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Keywords

  • Free radicals
  • Nitric oxide
  • Parkinson disease
  • Proteasome
  • Superoxide
  • Ubiquitination

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

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