Research Article 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 D. Milani, 1,2,3 N. W. Knuckey, 2,3,4 R. S. Anderton, 1,2 J. L. Cross, 2,3,4 and B. P. Meloni 2,3,4 1 School of Health Sciences, Te University of Notre Dame Australia, Fremantle, WA 6160, Australia 2 Western Australian Neuroscience Research Institute, Nedlands, WA 6009, Australia 3 Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, WA 6009, Australia 4 Centre for Neuromuscular and Neurological Disorders, Te University of Western Australia, Nedlands, WA 6009, Australia Correspondence should be addressed to D. Milani; diemilani@gmail.com Received 24 February 2016; Accepted 11 April 2016 Academic Editor: David S. Liebeskind Copyright © 2016 D. Milani et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We examined the dose responsiveness of polyarginine R18 (100, 300, and 1000nmol/kg) when administered 60 minutes afer permanent middle cerebral artery occlusion (MCAO). Te TAT-NR2B9c peptide, which is known to be neuroprotective in rodent and nonhuman primate stroke models, served as a positive control. At 24 hours afer MCAO, there was reduced total infarct volume in R18 treated animals at all doses, but this reduction only reached statistical signifcance at doses of 100 and 1000 nmol/kg. Te TAT-NR2B9c peptide reduced infarct volume at doses of 300 and 1000nmol/kg, but not to a statistically signifcant extent, while the 100 nmol/kg dose was inefective. Te 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 signifcant extent. Tese fndings further confrm the neuroprotective properties of polyarginine peptides and for R18 extend its therapeutic time window and dose range, as well as demonstrating its greater efcacy compared to TAT-NR2B9c in a severe stroke model. Te superior neuroprotective efcacy of R18 over TAT-NR2B9c highlights the potential of this polyarginine peptide as a lead candidate for studies in human stroke. 1. Introduction While the incidence of stroke is falling in developed coun- tries, it remains a leading cause of death and disability worldwide, with an increasing global disease burden due to an aging population, as well as the ongoing epidemics of diabetes, hypertension, and obesity [1]. In terms of acute therapies, for ischaemic stroke, reperfusion therapy using tPA (tissue plasminogen activator) alone or more recently in combination with thrombectomy is by far the most efective treatment intervention currently available [2–6]. However, despite the success of tPA/thrombectomy therapy, the num- ber of stroke patients that receive this treatment is relatively small. Tis is due to a combination of factors including the narrow therapeutic time window for tPA/thrombectomy (3–4.5 h afer stroke), delays in patients obtaining medical care, the requirement for a brain scan to exclude haemor- ragic stroke, and the need for highly trained personnel and specialised equipment to perform the intervention. Given these limitations, the search continues for a neuroprotective agent that can be safely administered early afer stroke onset to limit the extent of brain injury afer stroke and that can be used when reperfusion interventions cannot be implemented. Additionally, any neuroprotective treatment that improves the efcacy, safety, and therapeutic window for tPA/thrombectomy would be of great clinical signifcance. In terms of neuroprotective agents, our laboratory has recently demonstrated that polyarginine and arginine-rich peptides have potent neuroprotective properties in in vitro injury models that mimic the efects of stroke [7–9]. More- over, we have extended these in vitro fndings by demon- strating that the polyarginine peptides R9, R12, and R18 Hindawi Publishing Corporation Stroke Research and Treatment Volume 2016, Article ID 2372710, 9 pages http://dx.doi.org/10.1155/2016/2372710