Sepiapterin attenuates 1-methyl-4-phenylpyridinium-induced apoptosis in neuroblastoma cells transfected with neuronal NOS: role of tetrahydrobiopterin, nitric oxide, and proteasome activation. Free Radic Biol Med 2005 Oct 15;39(8):1059-74
Date
10/04/2005Pubmed ID
16198233DOI
10.1016/j.freeradbiomed.2005.05.022Scopus ID
2-s2.0-25144483746 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
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 BH4 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.
Author List
Shang T, Kotamraju S, Zhao H, Kalivendi SV, Hillard CJ, Kalyanaraman BAuthors
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of WisconsinBalaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
1-Methyl-4-phenylpyridiniumAconitate Hydratase
Apoptosis
Dimerization
Electron Transport Complex I
Enzyme Activation
Humans
Neuroblastoma
Nitric Oxide
Nitric Oxide Synthase Type I
Proteasome Endopeptidase Complex
Pterins
Superoxides
Transfection
Tumor Cells, Cultured
