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Green tea polyphenols potentiate the action of nerve growth factor to induce neuritogenesis: Possible role of reactive oxygen species
Author(s) -
Gundimeda Usha,
McNeill Thomas H.,
Schiffman Jason E.,
Hinton David R.,
Gopalakrishna Rayudu
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22519
Subject(s) - nerve growth factor , mapk/erk pathway , neurite , reactive oxygen species , tropomyosin receptor kinase a , chemistry , kinase , pharmacology , extracellular , microbiology and biotechnology , neuroprotection , biochemistry , biology , receptor , in vitro
Exogenously administered nerve growth factor (NGF) repairs injured axons, but it does not cross the blood–brain barrier. Thus, agents that could potentiate the neuritogenic ability of endogenous NGF would be of great utility in treating neurological injuries. Using the PC12 cell model, we show here that unfractionated green tea polyphenols (GTPP) at low concentrations (0.1 μg/ml) potentiate the ability of low concentrations of NGF (2 ng/ml) to induce neuritogenesis at a level comparable to that induced by optimally high concentrations of NGF (50 ng/ml) alone. In our experiments, GTPP by itself did not induce neuritogenesis or increase immunofluorescent staining for β‐tubulin III; however, it increased expression of mRNA and proteins for the neuronal markers neurofilament‐L and GAP‐43. Among the polyphenols present in GTPP, epigallocatechin‐3‐gallate (EGCG) alone appreciably potentiated NGF‐induced neurite outgrowth. Although other polyphenols present in GTPP, particularly epigallocatechin and epicatechin, lack this activity, they synergistically promoted this action of EGCG. GTPP also induced an activation of extracellular signal‐regulated kinases (ERKs). PD98059, an inhibitor of the ERK pathway, blocked the expression of GAP‐43. K252a, an inhibitor of TrkA‐associated tyrosine kinase, partially blocked the expression of these genes and ERK activation. Antioxidants, catalase (cell‐permeable form), and N‐acetylcysteine (both L and D‐forms) inhibited these events and abolished the GTPP potentiation of NGF‐induced neuritogenesis. Taken together, these results show for the first time that GTPP potentiates NGF‐induced neuritogenesis, likely through the involvement of sublethal levels of reactive oxygen species, and suggest that unfractionated GTPP is more effective in this respect than its fractionated polyphenols. © 2010 Wiley‐Liss, Inc.