Research Report Multimodal assessment of neuroprotection applied to the use of MK-801 in the endothelin-1 model of transient focal brain ischemia Slavianka Georgieva Moyanova a, ⁎ , Lidia Vasileva Kortenska a , Rumiana Gesheva Mitreva a , Vyara Dincova Pashova a , Richard Teke Ngomba b , Ferdinando Nicoletti b,c, ⁎ a Department of Neurobiology of Adaptation, Laboratory of Integrative Neuropharmacology, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria b Istituto Neurologico Mediterraneo, Neuromed, Pozzilli, Italy c University of Rome bLa SapienzaQ, Department of Human Physiology and Pharmacology P.le Aldo Moro, 5, 00185 Rome, Italy ARTICLE INFO ABSTRACT Article history: Accepted 24 March 2007 Available online 28 March 2007 Transient focal ischemia produced by local infusion of endothelin-1 (ET1) in the territory of the middle cerebral artery has been proposed as a potentially useful model for the screening of drugs developed for the treatment of thrombo-embolic stroke. However, most of the data rely exclusively on the assessment of the infarct volume, which is only a partial predictor of the neurological outcome of stroke. Here, we have validated the model using a multimodal approach for the assessment of neuroprotection, which includes (i) determination of the infarct volume by 2,3,5-triphenyltetrazolium chloride staining; (ii) an in-depth behavioral analysis of the neurological deficit; and (iii) an EEG analysis of electrophysiological abnormalities in the peri-infarct somatosensory forelimb cortical area, S1FL. The non- competitive NMDA receptor antagonist, MK-801 (3 mg/kg, injected i.p. 20 min after ET1 infusion in conscious rats) could reduce the infarct volume, reverse the EEG changes occurring at early times post-ET1, and markedly improve the neurological deficit in ischemic animals. The latter effect, however, was visible at day 3 post-ET1, because the drug itself produced substantial behavioral abnormalities at earlier times. We conclude that a multimodal approach can be applied to the ET1 model of focal ischemia, and that MK-801 can be used as a reference compound to which the activity of safer neuroprotective drugs should be compared. © 2007 Elsevier B.V. All rights reserved. Keywords: Endothelin-1 model of ischemia MK-801 Electrophysiological outcome Neurological deficit Neuroprotection 1. Introduction Despite years of extensive research, there are no effective neuroprotective strategies in the treatment of stroke, with the exception of hypothermia (Coimbra and Wieloch, 1994; Krieger, 2006), which, however, is seldom used in clinical practice. This reflects the intrinsic limitations of most animal models of brain ischemia, which, at best, incorporate only some features of ischemic stroke in humans. For example, models of global ischemia that are frequently used for the BRAIN RESEARCH 1153 (2007) 58 – 67 ⁎ Corresponding authors: S.G. Moyanova can be contacted at Department of Neurobiology of Adaptation, Laboratory of Integrative Neuropharmacology, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria. Fax: +359 2 8719 109. F. Nicoletti can be contacted at Department of Human Physiology and Pharmacology, University of Rome bLa SapienzaQ P.le Aldo Moro, 5, 00185 Rome, Italy. Fax: +39 06 49912969. E-mail addresses: slav@bio.bas.bg (S.G. Moyanova)., nicoletti@neuromed.it (F. Nicoletti). 0006-8993/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2007.03.070 available at www.sciencedirect.com www.elsevier.com/locate/brainres