Poly-Arginine Peptides R18 and R18D Improve Functional Outcomes After Endothelin-1-Induced Stroke in the Sprague Dawley Rat

Abstract We have previously demonstrated that R18 and its d-enantiomer, R18D, are neuroprotective at 24 hours following intraluminal filament occlusion of the middle cerebral artery (MCAO) in the rat. This study examined R18 and R18D effectiveness in improving functional outcomes at up to 56 days poststroke following endothelin-1-induced MCAO. Peptides were administered intravenously at doses of 100, 300, or 1000 nmol/kg, 60 minutes after MCAO. Functional recovery poststroke was assessed using multiple forelimb placing tests and horizontal ladder test, and NA-1 (TAT-NR2B9c), a neuroprotective currently in phase 3 clinical stroke trials, was used as a benchmark. The study demonstrated that R18 (300 and 1000 nmol/kg) was the most effective peptide in improving functional outcomes, followed by R18D (300 and 1000 nmol/kg), and NA-1 (300 and 100 nmol/kg). Furthermore, R18 at doses of 300 and 1000 nmol/kg was the most effective agent in restoring pre-stroke body weight, while R18 and R18D at doses of 300 and 1000 nmol/kg, but not NA-1 also significantly reduced the number of animals requiring hand feeding 48 hours after stroke. This study confirms that R18 and R18D are effective in improving long-term functional outcomes after stroke, and suggests that R18 may be more effective than NA-1.