Licofelone attenuates quinolinic acid induced Huntington like symptoms: Possible behavioral, biochemical and cellular alterations Harikesh Kalonia, Puneet Kumar, Anil Kumar ⁎ Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh-160014, India abstract article info Article history: Received 18 September 2010 Received in revised form 8 December 2010 Accepted 5 January 2011 Available online 13 January 2011 Keywords: Antioxidant Licofelone Mitochondrial dysfunction Neurotoxicity Oxidative stress Cyclo-oxygenase and lipoxygenase enzymes are involved in archidonic acid metabolism. Emerging evidence indicates that cyclo-oxygenase and lipoxygenase inhibitors prevent neurodegenerative processes and related complications. Therefore, the present study has been designed to explore the neuroprotective potential of licofelone (dual COX-2/5-LOX inhibitor) against quinolinic acid induced Huntington like symptom in rats. Intrastriatal administration of quinolinic acid significantly caused reduction in body weight and motor function (locomotor activity, rotarod performance and beam walk test), oxidative defense (as evidenced by increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidant enzymes), alteration in mitochondrial enzyme complex (I, II and IV) activities, raised TNF-α level and striatal lesion volume as compared to sham treated animals. Licofelone (2.5, 5 and 10 mg/kg) treatment significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, mitochondrial enzyme complex activities and attenuated TNF-α level and striatal lesion as compared to control (quinolinic acid). The present study highlights that licofelone attenuates behavioral, biochemical and cellular alterations against quinolinic acid induced neurotoxicity and this could be an important therapeutic avenue to ameliorate the Huntington like symptoms. © 2011 Elsevier Inc. All rights reserved. 1. Introduction Quinolinic acid (QA) is an endogenous metabolite of tryptophan at the kynurenine pathway (Amori et al., 2009), causes early low-grade neuroinflammation (Braidy et al., 2009). QA induced alterations are very much similar to the etiology of Huntington disease (HD) patients. One of the first steps in QA induced neuronal damage involves hyper stimulation of N-methyl-D-aspartate receptors (Choi, 1994) leading to a massive Ca 2+ influx that activates Ca 2+ dependent phospholipases A2. These phospholipases A2 cleave membrane phospholipid to yield arachidonic acid, which is then converted into prostaglandin (PG) G2 by cyclooxygenases (Hurley et al., 2002). PGG2 is then subsequently reduced to PGH2 with the production of a free radical intermediate that rapidly converts into reactive hydroxyl radicals (Kukreja et al., 1986). COX-2 expression is constitutive in some neurons (Seibert et al., 1999) and induced by glutamate (Manev et al., 2005) and proinflammatory stimuli (Bazan et al., 1994) in migratory immune, glia cells (Hurley et al., 2002; Luo et al., 1998; Nogawa et al., 1997). This results in an increased COX-2 activity that contribute to neurodegeneration either by oxidative stress, or by cytotoxic actions of prostaglandins such as PGA1 and PGE1 (Kukreja et al., 1986; Bezzi et al., 1998). Increased COX-2 expression has been reported in a number of acute and chronic neurodegenerative states, including seizures, ischemia/stroke, Alzheimer's disease (Hurley et al., 2002), Parkinson's disease (Knott et al., 2000), amyotrophic lateral sclerosis etc. (Yasojima et al., 2001). Another enzymes involved in the arachidonic acid metabolism are lipoxygenases (LOXs). Three major types of mammalian lipoxygenases are capable of inserting oxygen into liberated arachidonic acid: 5-LOX, 12-lipoxygenase (12-LOX), and 15-lipoxygenase (15-LOX). Thus, these enzymes metabolize arachidonic acid (but also other fatty acids) into a number of biologically active metabolites. The primary products of lipoxygenase action are hydroperoxyeicosatetraenoic acids (HPETEs). Manev and coworkers reported that both 5-LOX and 5-LOX-activating protein are expressed in different areas of the brain (Manev et al., 2005). Therefore, we indicate a link between neuroinflammation and gluta- mate-mediated excitotoxicity in Huntington disease that could be mediated through the inducible isoform of the enzyme cyclooxygenase (COX, especially COX-2) and lipoxygenase (LOX). Published report suggests alteration in COX-2 expression by genetic manipulation can alter neuronal susceptibility to excitotoxicity. Over expression of neuronal COX-2 renders neurons more susceptible to excitotoxicity (Kelley et al., 1999) and neuronal loss in aged mice (Andreasson et al., 2001). Conversely, loss of COX-2 in knockout mice decreases neuronal Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 607–615 Abbreviations: COX, cyclo-oxygenase; LOX, lipoxygenase; HD, Huntington disease; PG, Prostaglandin; QA, Quinolinic acid; SOD, Super oxide dismutase; SDH, Succinate dehydrogenase; TNF, Tumor necrosis factor. ⁎ Corresponding author. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India. Tel.: + 91 172 2534106; fax: + 91 172 2541142. E-mail address: kumaruips@yahoo.com (A. Kumar). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2011.01.003 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp