Abstract WP156: Poly-arginine Peptides R18 and R18D Improve Functional Outcomes After Endothelin-1-induced Stroke in the Sprague Dawley Rat

Abstract

Aims: We have previously demonstrated that the poly-arginine peptides R18 and R18D are neuroprotective at 24 hours following intraluminal middle cerebral artery occlusion (MCAO) in the rat. Therefore, using an independent laboratory we examined the ability of R18 and R18D to improve functional outcomes after endothelin-1 (ET-1) induced MCAO in rats over 56 days post-stroke. Methods: Peptides were administered intravenously at 100, 300 or 1000 nmol/kg, 60 minutes after ET-1 induced MCAO. Multiple forelimb placing tests and horizontal ladder tests were performed post-stroke, and the neuroprotective peptide NA-1 (TAT-NR2Bpc), which is being assessed in Phase 3 clinical stroke trials, was used as a benchmark. Results: R18 (300 and 1000nmol/kg, respectively) was the most effective peptide to improve functional outcomes, followed by R18D (300 and 1000 nmol/kg, respectively), and NA-1 (300 and 100 nmol/kg, respectively). Furthermore, R18 at 300 and 1000 nmol/kg was the most effective treatment to restore pre-stroke animal body weight (post-stroke day 4 versus day 7 for saline, and days 5-7 for all other treatments), while R18 and R18D at 300 and 1000 nmol/kg, but not NA-1 also significantly reduced the number of animals requiring special care (hand feeding) 48 hours after stroke. Conclusion: In conclusion, this study confirms that R18 and R18D can improve long-term functional outcomes after stroke, and given the superior effectiveness of R18 over NA-1 in the present, as well as in our previous studies, justifies further evaluation in a non-human primate stroke model and in a clinical stroke trial.