This is a Phase 1 research proposal. Several recent studies including our own have demonstrated that resveratrol can protect the heart from ischemia reperfusion injury. Studies in our laboratory have shown that Protykin, a natural extract of 50 percent trans-resveratrol from Polygonum cuspidatum, possesses potential cardioprotective ability in vivo. More recently, we have shown that resveratrol possesses potential for use as a pharmacological preconditioning agent. Ishemic preconditioning represents a state-of-the-art technique for cardioprotection; however, a pharmacological preconditioning agent has yet to be identified. There is a continuous search for a pharmacological preconditioning agent, which can be clinically used for cardioprotection. Resveratrol may fill this gap. However, more studies are required to determine if indeed resveratrol can function as a pharmacological preconditioning agent. The research will be accomplished by addressing three Specific Aims: i) whether resveratrol mediated cardioprotection is achieved through adenosine A1 receptor activation; ii) whether resveratrol function through translocation and activation of protein kinase C (PKC) isoforms delta or zeta and/or MAP kinase and tyrosine kinase receptors and iii) whether resveratrol potentiates mitochondrial KAT P channel opening. Since, preconditioning occurs through adenosine A1 receptors, PKC delta or zeta and/or MAP kinase and tyrosine kinase receptors and mitochondrial KATPchannel, the results will determine if resveratrol fulfills the criteria of a preconditioning agent. In the Phase 1 study, we will conduct a dose and time response study, and determine the required dose to induce such an affect. There is a great need for the development of a pharmacological preconditioning agent, because the application of ischemic preconditioning, the most powerful cardioprotective stimulus ever known, is only limited to the laboratory. Since, resveratrol is a naturally occurring compound with antioxidant potential, it can be readily used for human clinical testing. We have developed a novel, cost effective, patent-pending technique to isolate and purify a 50 percent trans-resveratrol extract from Polygonum cuspidatum. Also, we have conducted acute oral, acute dermal, primary dermal irritation, and primary eye irritation studies in rats, which demonstrated the safety of this novel extract. Upon successful completion of the Phase 1 feasibility study, we will coordinate a Phase 2 human clinical trial.
Thesaurus Terms: antioxidant, cardiovascular pharmacology, drug design /synthesis /production, ischemic preconditioning, plant extract dosage, growth factor receptor, isozyme, mitochondria, mitogen activated protein kinase, pharmacokinetics, potassium channel, protein kinase C, protein tyrosine kinase, purinergic receptor, receptor expression genetically modified animal, laboratory mouse, laboratory rat
