Neuroprotective effects of quercetin in chemical hypoxia: in silico evaluation of the hypothesis exploring PKC inhibition-mediated pharmacotherapy

Abstract

The effect of chemical hypoxia, i.e., KCN-induced 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 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, anti-inflammatory properties, and capability to cross the blood brain barrier. The binding energy of quercetin with PKCθ 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 studies which involves the clue for regulation of PKC by quercetin.