The R18 Polyarginine Peptide Is More Effective Than the TAT-NR2B9c (NA-1) Peptide When Administered 60 Minutes after Permanent Middle Cerebral Artery Occlusion in the Rat

Abstract

We examined the dose responsiveness of polyarginine R18 (100, 300, and 1000 nmol/kg) when administered 60 minutes after permanent middle cerebral artery occlusion (MCAO). The TAT-NR2B9c peptide, which is known to be neuroprotective in rodent and nonhuman primate stroke models, served as a positive control. At 24 hours after MCAO, there was reduced total infarct volume in R18 treated animals at all doses, but this reduction only reached statistical significance at doses of 100 and 1000 nmol/kg. The TAT-NR2B9c peptide reduced infarct volume at doses of 300 and 1000 nmol/kg, but not to a statistically significant extent, while the 100 nmol/kg dose was ineffective. The reduction in infarct volume with R18 and TAT-NR2B9c peptide treatments was mirrored by improvements in one or more functional outcomes (namely, neurological score, adhesive tape removal, and rota-rod), but not to a statistically significant extent. These findings further confirm the neuroprotective properties of polyarginine peptides and for R18 extend its therapeutic time window and dose range, as well as demonstrating its greater efficacy compared to TAT-NR2B9c in a severe stroke model. The superior neuroprotective efficacy of R18 over TAT-NR2B9c highlights the potential of this polyarginine peptide as a lead candidate for studies in human stroke.

Assessment of therapeutic window for poly‐arginine‐18D (R18D) in a P7 rat model of perinatal hypoxic‐ischaemic encephalopathy

“…The present study adds to our previous findings which demonstrate the neuroprotective effectiveness of R18 and R18D in a P7 rat model of perinatal HIE (Edwards et al, ), and other acute neuronal injury models (Chiu et al, ; Edwards et al, ; Meloni et al, ; Meloni, Brookes, et al, ; Meloni, Milani, et al, ; Milani et al, ; Milani, Clark, et al, ; Milani, Cross, et al, ; Milani, Knuckey, et al, ). Importantly, the present study examined the neuroprotective efficacy of R18D when administered 30, 60 or 120 min after HI.…”

“…Importantly, we have demonstrated that the poly‐arginine peptides R18 and its D‐enantiomer R18D, can reduce brain injury in P7 rats when administered immediately after HI (Edwards, Cross, Anderton, Knuckey, & Meloni, ). The positive findings with R18 and R18D in HI are in line with previous studies from our laboratory demonstrating efficacy of these peptides in adult rat models of stroke due to middle cerebral artery occlusion (MCAO) and traumatic brain injury (Chiu et al, ; Edwards et al, ; Milani, Clark, et al, ; Milani, Cross, et al, ; Milani, Knuckey, et al, ; Meloni et al, , ).…”

Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents With a Multimodal Mechanism of Action

“…Consistent with in vitro findings, CARPs (e.g., R9D, R12, R18, R18D, protamine; Tables 1, 3) were also demonstrated to provide significant neuroprotection and improve functional outcomes in rat models of permanent and/or transient middle cerebral artery occlusion (MCAO), perinatal hypoxia-ischemia and traumatic brain injury (15,16,(18)(19)(20)(21)(22)(23)(24)212) and a non-human primate MCAO stroke model (26). Positive neuroprotective effects with R9D and R18D, which are the D-enantiomers of R9 and R18, also confirmed the lack of stereo-specificity for CARP efficacy in vivo.…”

Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

“…perinatal hypoxia-ischaemia, and also reduce the severity of traumatic brain injury [162,[265][266][267][268][269], further confirming the efficacy of CARPs in a pre-clinical stroke setting.…”