Research Report The neuroprotective effects of NMDAR antagonist, ifenprodil and ASIC1a inhibitor, flurbiprofen on post-ischemic cerebral injury ☆ Vikas Mishra, Rajkumar Verma, Neetu Singh, Ram Raghubir ⁎ Division of Pharmacology, Central Drug Research Institute (CSIR), P.O. Box 173, Lucknow (U.P.) 226001, India ARTICLE INFO ABSTRACT Article history: Accepted 3 March 2011 Available online 10 March 2011 Owing to the complex and multifactorial pathology of cerebral stroke, multiple drug therapy had long been advocated by STAIR committee for stroke successful treatment. In this context, we analyzed the effect of Ifenprodil, an NR2b selective NMDAR antagonist and its combination at lower doses with flurbiprofen, a selective ASIC1a inhibitor on rat model of focal cerebral ischemia. We found that the combination produced significant neuroprotective effect as produced by ifenprodil at higher doses, which was evidenced by reduction in infarct volume, neurological deficit and MDA levels. Further, histopathological studies revealed that, the combination not only attenuated the cell damage in striatal regions of ischemic brain, but also significantly inhibited apoptotic cell death, which was more pronounced than monotherapy with ifenprodil or flurbiprofen. Thus, it appears that the combination therapy will be more efficacious in offering neuroprotection on one hand and also lower the risks associated by mono-therapy with ifenprodil at higher doses. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. Keywords: Cerebral ischemia NMDA ASIC1a Neuroprotection 1. Introduction Cerebral stroke is a major cause for mortality and morbidity worldwide. Despite tremendous research efforts for develop- ment of neuroprotectants, the only drug therapy available for stroke is rt-PA, which has a narrow therapeutic window with hemorrhagic complications. Among various reasons cited, a major reason for the failure of neuroprotectants in clinical trials was attributed to research focused on single drug intervention therapies for cerebral ischemia, despite the complex and multifactorial pathology of stroke (Mehta et al, 2007; Doyle et al, 2008). Brain injury following stroke results from the complex interplay of multiple pathways including excitotoxicity, acidotoxicity, oxidative stress, inflammation and apoptosis. Each of the above pathophysiological processes, though are overlapping but occur at distinct time frames following ischemia (Doyle et al, 2008). Excitotoxicity, the earliest one, results from the over activity of excitatory neurotransmitter glutamate on NMDA receptors, which causes Ca 2+ ions overload in ischemic brain thus triggering multiple cell death signaling pathways. However, clinical trials in humans to prevent brain injury by the use of NMDA receptor antagonists have been disappointing owing to lack of efficacy and adverse effects (Ikonomidou and Turski, 2002; Birmingham 2002). Lately, NR2b selective antagonists (ifenprodil and traxoprodil) were reported to be significant neuroprotective with lesser side effects as compared to conventional NMDA receptor blockers BRAIN RESEARCH 1389 (2011) 152 – 160 ☆ CDRI communication no: 8030. ⁎ Corresponding author. Fax: +91 0522 2623405. E-mail address: raghubirr@yahoo.com (R. Raghubir). 0006-8993/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2011.03.011 available at www.sciencedirect.com www.elsevier.com/locate/brainres