Abstract WP123: Neuroprotective Efficacy of P7C3-A20 After Ischemic Stroke

Abstract

Ischemic stroke is a devastating condition with few therapeutics available. The recently identified neuroprotective compound P7C3-A20 (A20) inhibits mature neuronal apoptosis while increasing the net magnitude of postnatal neurogenesis. P7C3 compounds enhance flux of NAD in the salvage pathway, a proposed therapeutic utility in treating stroke patients. P7C3 has demonstrated efficacy in several preclinical neurodegenerative models, yet it has never been tested in focal cerebral ischemia. Implementing STAIR recommendations, a 90min rat middle cerebral artery occlusion was performed followed by immediate injection of A20 or vehicle and then twice daily injections for 7 days. The therapeutic window was assessed using the same experimental paradigm, with rats injected at a delayed time point (6hrs). Acutely (n=12/group), A20-treated rats had significantly fewer missteps in the sensorimotor grid-walk task (A20 mean (AM)=16.8±3; Vehicle mean (VM)=33.%±7.4), and chronically (28 days post-injury) had significantly reduced escape latencies on day 4 in the water maze task (AM=16.7±1.6; VM=24.2±1.7) than vehicle-treated controls. Behavioral improvements were associated with significantly decreased cortical (AM=0.44±0.03; VM=0.35±0.01) and hippocampal atrophy (AM =0.94±0.05; VM=0.81±0.03) and increased neurogenesis in the subventricular zone (AM=513±29; VM=356±31). Furthermore, normalized NAD levels decreased in vehicle-treated rats (VM=0.2±0.03) and this was rescued with A20 treatment (AM=0.35±0.04). A20 continued to demonstrate efficacy in sensorimotor and working memory behavior tasks when administered at 6hrs. Both A20-treated rat time points showed the most improvement with asymmetry in the cylinder task (Immediate AM=34.5±3.3; Delayed AM=40.7±3; Immediate VM=26.5±3.9; delayed VM=30.3±6.1) and working memory (Immediate AM=39.4±7.1; Delayed AM=41.9±6.5; Immediate VM=35.9±8.1; delayed VM=6.36±7.9) compared with vehicle controls (n=4-5/group). In conclusion, these studies demonstrate that treatment with A20 produces benefits on both degenerative and reparative processes after focal ischemia, which translates into behavioral improvement and suggests new therapeutic approaches to treat stroke patients.