Dual contradictory effect of H-89 on neuronal retraction, death and inflammation in differentiated PC12 cells subjected to oxidative stress.
Interrelation between oxidative stress and neuro-inflammation has been discussed extensively to contribute to neuronal dysfunction in neurodegenerative disorders. In this manner, it seems that there is an intriguing link between protein kinase A (PKA), neuronal apoptosis and inflammation. Rat PC12 pheochromocytoma cell can be induced to differentiate into neuron-like cells possessing elongated neurites by nerve growth factor. In this study, we investigated the effect of H-89, a selective inhibitor of PKA, on the neurite retraction along with evaluation of cell death and inflammatory markers in the differentiated PC12 cells, exposed to H2O2. We found that dose-dependent inhibition of PKA by low and medium concentrations of H-89 (5, 7 and 10 μM) enhanced the parameters of neurite outgrowth and complexity in the cells co-treated with H2O2 as an oxidative stress. Similar concentrations of H-89 significantly inhibited cell death and neurite retraction induced by oxidative stress. Components of TNF-α-NFκB-COX-2 axis, a discussed pathway in neuroinflammation, downregulated dose-dependently by administration of H-89 in H2O2-induced PC12 cells. In this condition, PKA inhibition by the high concentrations of H-89 (15 and 20 μM) led to enhanced cell death and inflammation with decreased neurite outgrowth. These findings indicate that H-89 has a dual contradictory effect on oxidative stress and inflammation that affect neurite outgrowth and complexity in differentiated PC12 cells.
NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Shabnam Zeighamy
SZ
Alamdary
Hadi
H
Digaleh
Fariba
F
Khodagholi
D000818:Animals; D017209:Apoptosis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000633:toxicity; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases