Atherosclerosis of the cerebral vasculature can produce occlusion and cerebral infarction. Although the tissue in the ischemia core dies within minutes, the surrounding tissue, termed the ischemic penumbra, sustains damage from cytotoxic factors including cytokines, reactive oxygen and nitrogen species and other biochemical processes that destroy cells within the penumbra in a time-dependent manner. Therapeutic angiogenesis, i.e. stimulation of localized neovascularization by angiogenic growth factors, has the potential to reduce ischemia and consequent tissue injury. Scatter factor (SF), also know as hepatocyte growth factor (HGF), has documented angiogenic and protective effects in cerebral, myocardial, hepatic, renal and peripheral ischemia, and holds significant potential as a therapeutic approach to ischemic diseases. ? However, treatment modalities that employ gene- or protein-based formulations are characteristically ? expensive and difficult to administer. Therapeutic approaches that employ small molecule mimetics of natural angiogenic and protective factors may be powerful alternatives to gene- and protein-based therapies. We have recently identified a small molecule, Refanalin that recapitulates the biologic activity of SF/HGF by activating the SF/HGF receptor, c-met. In vitro, Refanalin activates the same intracellular signaling cascades as SF/HGF, scatters renal cells, induces endothelial and epithelial cell proliferation, and protects against apoptotic and necrotic cell death. In vivo, Refanalin is as effective as SF/HGF in protecting against ischemic and toxic organ damage, and inducing angiogenesis in peripheral ischemia and full thickness wounds, with no overt signs of toxicity. Importantly, Refanalin crosses the blood-brain barrier and intraperitoneal administration of Refanalin reduces infarct size in the setting of stroke. This Phase I SBIR proposal is designed to make a detailed analysis of the neuroprotective effects of Refanalin and determine whether delayed administration of this agent after induction of cerebral ischemia is protective. These experiments are expected to provide sufficient data for in-depth, pre-clinical Phase II studies examining Refanalin efficacy in stroke. ? ? ?
| McNeal, David W; Brandner, Dieter D; Gong, Xi et al. (2016) Unbiased Stereological Analysis of Reactive Astrogliosis to Estimate Age-Associated Cerebral White Matter Injury. J Neuropathol Exp Neurol 75:539-54 |
