Abstract TP260: A Novel Neurogenic-Stem Cell Stimulating Curcumin Analog to Treat Acute Ischemic Stroke

Abstract

While nerve cells rapidly die in stroke, and patients do initiate a neurogenic response to replace these cells, there has been no attempt to develop pleiotropic cytoprotective compounds to further promote neurogenesis in stroke patients, and there are no neurogenic or cytoprotective drugs approved by the FDA. In this study, we focused on the parent compound J-147, a curcumin derivative that is a 5-LOX inhibitor, and has potent neuroprotective and neurogenic activities. J-147 rescues HT22 cells from iodoacetic acid challenge (EC 50 50 nM), and oxytosis (EC 50 115 nM). J-147 is neuroprotective against glutamate excitotoxcity in E18 cortical neuron culture (EC 50 27 nM), and prevents cell death in an embryonic cortical cell trophic factor withdrawal assay (EC 50 25 nM). J-147 can rescue a clone of the hippocampal nerve cell line HT22 expressing TrkB, from serum starvation under conditions where the cells can be protected by BDNF (EC 50 50 nM). In mice, J-147 is neurogenic and can stimulate cell division in germinal regions of the brain (increase BrdU + DCX + labeled cells), enhances endogenous neurotrophic factors and energy metabolism. With this basis, we tested J-147 in 2 translational stroke models. First, using a rodent intraluminal suture model, in combination with a quantal analysis method to determine the effect of increasing ischemia duration (5-90 minutes) on behavioral deficits, IV J-147 treatment (10 mg/kg) administered 5 minutes following the end of occlusion (5-90 minutes), significantly (P=0.045) reduced stroke-induced behavioral deficits and increased the P 50 value to 36.37 ± 1.72 (n=19) minutes from P 50 = 20.1 ± 4.07 minutes (n=19) for the control group. J-147 also reduced infarct volume following IV administration (p<0.05). Second, using the standardized rabbit small clot embolic stroke model, IV J-147 treatment (10mg/kg) administered 1 hour post-embolization increased the P 50 value (behavior) to 1.88 ± 0.10 mg (n=20) compared to P 50 = 1.07 ± 0.07 (n=19) for control(p<0.05). Additional studies showed that J-147 was not mitogenic, or cytotoxic using the CeeTox assay (Raking 90μM) and had a good IV PK profile in rabbits/rats (t 1/2 5.89-8.56 hours). These data support the development of J-147 and neurogenic analogs as a novel class of drug to treat stroke.