Pharmacokinetics and Neuroprotective Efficacy of Poly‐Arginine Peptide R18D in Sprague Dawley Rats Subjected to Transient Intraluminal Filament Middle Cerebral Artery Occlusion Stroke

BACKGROUND: This study examined the dose-dependent efficacy and pharmacokinetics of R18D in a rat transient middle cerebral artery occlusion (MCAO) stroke model. METHODS: R18D was intravenously administered 60 min after the onset of a 90-min MCAO induced by intraluminal filament insertion. For pharmacokinetic profiling, blood samples were collected 10, 15, 30 and 60 min, and at 2, 4 and 8 h after the start of a 10-min intravenous infusion of R18D. Infarct volume and body weight were assessed at 24 h after MCAO. RESULTS: R18D reduced mean total infarct volume by 47.2% (p = 0.0003), 28.4% (p = 0.008), and 27.9% (p = 0.003) at doses of 325, 650 and 1100 nmol/kg, respectively. The 650 nmol/kg dose significantly reduced cerebral hemisphere swelling by 8.3% (p = 0.01), whereas the 325 nmol/kg (5.6%; p = 0.15) and 1100 nmol/kg (4.5%; p = 0.14) doses produced non-significant reductions in swelling. R18D did not significantly affect post-stroke weight loss, however rats treated with the lowest dose (325 nmol/kg) exhibited the smallest reduction in body weight compared with vehicle-treated animals (7.35% vs. 9.35). Pharmacokinetic analysis of the three R18D doses after stroke demonstrated a half-life of 72 to 78 min, with dose-dependent plasma Cmax values of 5.3 μg/mL, 11.9 μg/mL and 17.3 μg/mL for the low-, medium- and high-dose groups, respectively. CONCLUSIONS: These results further support the neuroprotective properties of R18D and provide strong justification for its continued development as a neuroprotective treatment for ischemic stroke.