Short Communication Brain penetration of the novel free radical trapping neuroprotectant NXY-059 in rats subjected to permanent focal ischemia A. Richard Green a, ⁎ , Kerstin Lanbeck-Vallén b , Tim Ashwood b , Stefan Lundquist b , Éva Lindström Böö b , Hallgrimur Jonasson b , Mark Campbell c a AstraZeneca R&D Charnwood, Bakewell Rd., Loughborough LE11 5RH, Sweden b AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden c MDS Pharma Services, 22011 30th Drive SE, Bothell, WA 98021-4444, USA ARTICLE INFO ABSTRACT Article history: Accepted 5 December 2005 Available online 30 January 2006 The penetration of the free radical trapping neuroprotectant NXY-059 into the brain has been examined in rats subjected to permanent middle cerebral artery occlusion (pMCAO). NXY-059 (125 mg/kg bolus followed by 125 mg/kg/h) was infused for 4 h 45 min starting 15 min after right pMCAO or sham operation. At 5 h, there was a similar plasma total NXY-059 concentration (μmol/L) in both groups [sham: 623 ± 44 (6); pMCAO: 605 ± 43 (5)] and a similar drug concentration (nmol/g) in the right cortex [sham: 6.92 ± 1.05 (6); pMCAO: 6.14 ± 2.18 (6)]. A subsequent experiment in normal rats, infusing NXY-059 at both a similar and higher concentration (252 mg/kg bolus and 252 mg/kg/h), demonstrated that the concentration of NXY-059 in cortex increased linearly with respect to the plasma concentration. These data demonstrate that NXY-059 does penetrate brain tissue in control animals and ischemic tissue of animals subjected to pMCAO. © 2005 Elsevier B.V. All rights reserved. Keywords: NXY-059 Blood brain barrier Cerebral ischemia Neuroprotection Stroke NXY-059 is a novel free radical trapping (Maples et al., 2001) neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke (Green and Ashwood, 2005; Kuroda et al., 1999; Sydserff et al., 2002). It is in clinical development for the treatment of acute ischemic stroke. Neuroprotection has been demonstrated in both transient and permanent focal ischemia, but in vitro studies (Dehouck et al., 2002) and in vivo studies in a transient ischemia model (Kuroda et al., 1999) suggested that NXY-059 has limited brain penetration. Efficacy in rat transient ische- mia models (Kuroda et al., 1999; Sydserff et al., 2002) may be explained by NXY-059 trapping free radicals produced during reperfusion in the vasculature from endothelial cells and circulating inflammatory cells such as polymorpholeukocytes and macrophages (Betz, 1996; Hallenbeck, 1996; Matsuo et al., 1995). However, NXY-059 also exhibits a high degree of efficacy in permanent MCA occlusion (pMCAO) models in rats (Sydserff et al., 2002; Zhao et al., 2001) and marmosets (Marshall et al., 2001, 2003) where interactions at the blood endothelial interface play a minor role (Prieto et al., 1988; Zhang et al., 1994). The current study was undertaken to examine whether NXY-059 was present in the brain of rats subjected to pMCAO. Male Sprague–Dawley rats (225–300 g) obtained from Harlan Sprague–Dawley, Indianapolis, IN, USA or Scanbur BK AB, Sollentuna, Sweden were used. They were housed in controlled conditions of heating, lighting and humidity and allowed free access to feed and water. NXY-059 (disodium 4- [(tert-butylamino)methyl] benzene-1,3-disulfonate N oxide) BRAIN RESEARCH 1072 (2006) 224 – 226 ⁎ Corresponding author. 0006-8993/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2005.12.035 available at www.sciencedirect.com www.elsevier.com/locate/brainres