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Botanical drug puerarin attenuates 6‐hydroxydopamine (6‐OHDA)‐induced neurotoxicity via upregulating mitochondrial enzyme arginase‐2
Author(s) -
Zhao Jia,
Rong Jianhui,
Lao Lixing
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb496
Subject(s) - arginase , puerarin , neurotoxicity , nitric oxide , chemistry , pharmacology , arginine , downregulation and upregulation , biochemistry , biology , toxicity , medicine , alternative medicine , organic chemistry , amino acid , pathology , gene
Inhibition of nitric oxide synthases (NOS) shows promise to halt the progression of neurodegenerative diseases. The present study was designed to explore whether botanical isoflavone puerarin could attenuate nitric oxide (NO)‐mediated neurotoxicity via modulating the enzymes in the L‐arginine‐NO pathway. Neurotoxin 6‐hydroxydopamine (6‐OHDA) is well known to induce neurodegeneration via a NO‐dependent mechanism. We first validated that puerarin protected rat dopamingeric PC12 cells against 6‐OHDA‐induced neurotoxicity in a concentration‐dependent manner. We subsequently profiled the cellular responses to puerarin by a proteomic response fingerprinting approach. A total of sixteen protein spots with > 1.5‐fold change of intensity were selected and identified by mass spectrometry. As one of puerarin‐upregulated proteins, mitochondrial arginase‐2 hydrolyzes L‐arginine to L‐ornithine, thereby competing with neuronal NOS for substrate L‐arginine in mitochondria. Thus, we hypothesize that puerain may attenuate nitric oxide (NO)‐mediated mitochondrial injury via increasing arginase‐2 expression. Western blot and RT‐PCR analyses confirmed that puerarin increased arginase‐2 expression in a concentration‐ and time‐dependent manner. Accordingly, puerarin suppressed 6‐OHDA‐induced NO production and neurotoxicity in PC12 cells and primary rat midbrain neurons. Arginase inhibitor BEC diminished the effect of puerarin on 6‐OHDA‐induced NO production and neurotoxicity. The activation of arginase‐2 by puerarin represents an endogenous mechanism for specific control of NO‐mediated mitochondrial damage. Thus, puerarin is useful lead for suppressing NO‐mediated neurotoxicity in neurodegenerative diseases.