Stroke is a major cause of disability and a leading cause of death. Chronic stroke therapy requires a functional recovery by overcoming axonal growth inhibitors such as Nogo-A. Although drugs are being developed, currently, there are no clinically proven drugs for recovery from stroke and other neuronal injuries. Evaluating the efficacy of natural products that are safe, neuroprotective, neuroregenerative, and inexpensive would complement ongoing efforts. Following ischemic injury, axonal growth is enhanced by the conventional approach of ?extrinsically? blocking axonal growth inhibitors. Our hypothesis is that axonal growth can also be achieved by ?intrinsically? decreasing the susceptibility of neurons to axonal growth inhibitors. Combining this intrinsic approach with neurotrophic activity could be even more effective. At low nanomolar concentrations, green tea polyphenols, such as epigallocatechin-3-gallate (EGCG), elevate the cAMP-Epac (exchange protein directly activated by cAMP) pathway and induce internalization of Nogo-A receptor (NgR1) and other related receptors. EGCG thereby blocks the actions of not only Nogo-A, but also diverse axonal growth inhibitors. In parallel, EGCG also activates the reactive oxygen species (ROS)-protein kinase Ce pathway and potentiates the actions of neurotrophins, such as brain-derived neurotrophic factor (BDNF). The combined effects of EGCG (desensitization of neurons to axonal growth inhibitors and potentiation of neurotrophins) lead to long axonal growth and functional recovery, which may be exploited for chronic stroke therapy. In the first aim, we will use primary cortical neurons to determine whether the EGCG-induced cAMP- Epac pathway can cause internalization and degradation of NgR1 and its coreceptors as well as other related receptors. We will ascertain whether this correlates with the EGCG-induced decrease in the action of Nogo-A and other axonal growth inhibitors. We will also determine if EGCG-induced parallel activation of the ROS- PKCe pathway can potentiate the actions of neurotrophins, such as BDNF, and enhance long neurite growth. In the second aim, we will use the mouse model of MCAO (middle cerebral artery occlusion/reperfusion) to induce stroke. For chronic stroke therapy, we will administer a safe dose of EGCG daily through drinking water. We will determine whether EGCG decreases the neuronal surface-associated NgR1 and other related receptors in the brain. We will then ascertain whether this decrease correlates with a reduction in the Nogo-A inhibitory pathway as well as with an increase in cAMP, axonal growth, BDNF, neuroplasticity, and functional recovery as assessed by behavioral studies. We will determine whether the approach of using EGCG (which blocks axonal growth inhibitors as well as potentiates neurotrophins) can be as efficient as or even more efficient than the NgR1 antagonistic peptide NEP1-40 (intranasal delivery to the brain). The successful outcome of this preclinical exploration may prove that the internalization of cell-surface NgR1, induced by EGCG or other agents, desensitizes neurons to axonal growth inhibitors.
Stroke is a leading cause of death and the most common cause of adult neurological disability in the USA. Green tea polyphenols, which have demonstrated potential in the prevention and treatment of stroke, are inexpensive and safe for long-term therapy. Therefore, there is an utmost need to understand the neuroregenerative mechanisms of green tea polyphenols and exploit such mechanisms to optimize therapy of stroke.
