Neuroprotective effects of quercetin in chemical hypoxia: in silico evaluation of the hypothesis exploring PKC inhibitio
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Med Chem Res (2013) 22:4836–4841 DOI 10.1007/s00044-013-0503-x
ORIGINAL RESEARCH
Neuroprotective effects of quercetin in chemical hypoxia: in silico evaluation of the hypothesis exploring PKC inhibition-mediated pharmacotherapy Anand Kumar Pandey • Pallab Bhattacharya • Swet Chand Shukla • Sudip Paul • Ranjana Patnaik
Received: 5 October 2012 / Accepted: 17 January 2013 / Published online: 29 January 2013 Ó Springer Science+Business Media New York 2013
Abstract The effect of chemical hypoxia, i.e., KCNinduced hypoxia on protein kinase C (PKC) translocation and cell injury was well reported. It has been well documented that activation of PKC is regulated by calcium and unsaturated free fatty acids which are actively involved in the phosphorylation of various cellular proteins, thereby initiating a variety of physiologic as well as cellular processes. The involvement of PKC has been reported in the regulation of neuronal excitability, neurotransmitter release, cellular proliferation, and gene expression. PKC can affect Ca2? homeostasis by increasing the activity of Na?/Ca2? exchanger and Ca2?-ATPase. These effects are most probably neuroprotective since they promote Ca2? sequestration, thereby decreasing free cytosolic Ca2? level. On the other side, PKC-mediated phosphorylation of NMDA receptor increases the probability of the channel opening and reduces the Mg2? block increasing the channel’s conductivity. It has been proposed that sustained elevation of free cytosolic Ca2? levels could result in prolonged activation of PKC which, in turn, may decrease neuronal energy due to excessive utilization of ATP by the Anand Kumar Pandey, Pallab Bhattacharya and Swet Chand Shukla contributed equally to this study. A. K. Pandey (&) P. Bhattacharya S. Paul R. Patnaik (&) School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, UP, India e-mail: [email protected] R. Patnaik e-mail: [email protected] S. C. Shukla School of Biochemical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, UP, India
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activated enzyme. However, all known protein kinase inhibitors target the ATP-binding site. Owing to this reason, search for strong natural inhibitors that selectively target the protein kinase domains continues to be a daunting challenge. Past studies reiterated that quercetin being a dietary flavonoid of plant origin which has antioxidant, antiinflammatory properties, and capability to cross the blood brain barrier. The binding energy of quercetin with PKCh was -9.28 kcal/mol. Thus, we hypothesized that Quercetin, a plant-originated natural polyphenolic compound that can act as a neuroprotective agent in chemical hypoxia-induced injury due to its inhibitory effects on PKC. The aim of our proposed hypothesis is to find out a successful modality of effective natural and dietary compound for the treatment of chemical hypoxia available till date. Hence, we have tried to put forward a hypothesis on the basis of our in silico s
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