Targeting Neuro-Inflammatory Cytokines and Oxidative Stress by Minocycline Attenuates Quinolinic-Acid-Induced Huntington’s Disease-Like Symptoms in Rats Harikesh Kalonia • Jitendriya Mishra • Anil Kumar Received: 5 July 2011 / Revised: 17 February 2012 / Accepted: 18 February 2012 Ó Springer Science+Business Media, LLC 2012 Abstract Recent experimental and clinical reports sup- port the fact that the minocycline exhibits significant neuroprotective activity in neurodegenerative diseases. However, its mechanism of neuroprotection is still far from our understanding. Besides, minocycline does not always produce neuroprotective effect. Therefore, this study has been designed to explore the possible mechanism of min- ocycline in experimental model of HD in rats. Intrastriatal administration of quinolinic acid caused a significant reduction in body weight, motor dysfunction (impaired locomotor activity, rotarod performance, and beam walk test), oxidative damage (as evidenced by increase in lipid peroxidation, nitrite concentration, and depletion of super oxide dismutase and catalase), increased TNF-a and IL-6 levels as compared to the sham-treated animals. Minocy- cline (25, 50, and 100 mg/kg) treatment (for 21 days) significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, attenuated TNF-a and IL-6 levels as compared to quinolinic-acid (QA)-treated animals. This study provides evidence that minocycline might have neuroprotective effect against QA-induced Huntington-like behavioral, biochemical alterations, and neuroinflamma- tion in rats. Keywords Minocycline Á Neurotoxicity Á Oxidative stress Á Proinflammatory cytokines Á Quinolinic acid Introduction Huntington’s disease (HD) is a complex neurodegenerative disorder caused significant neuronal degeneration within the striatum, characterized by motor and cognitive dysfunction (Blum et al. 2003; Brouillet et al. 1999). Currently, HD is being treated symptomatically because of its complex pathophysiology. The mutation involved produces a poly- glutamine expansion within the N terminal part of the Huntingtin protein, which leads to many neuronal alterations such as impairments in transcription (Cha 2000; Zuccato et al. 2003), calcium signaling (Tang et al. 2003), or axonal transport (Gunawardena et al. 2003; Szebenyi et al. 2003). It has also been reported to promote mitochondrial complex II dysfunction (Beal 2000), mitochondrial Ca 2? defects (Panov et al. 2002), NMDA receptor sensitization (Song et al. 2003; Zeron et al. 2002), proapoptotic and pronecrotic protease activation (Wellington et al. 2003). Minocycline is a second generation tetracycline, cur- rently being investigated in various neurodegenerative conditions (Chen et al. 2000; Zhu et al. 2002; Diguet et al. 2004; Tsuji et al. 2004; Yang et al. 2003). Beneficial activity of minocycline has been related to its ability to inhibit both mitochondrial enzyme complex activity lead- ing to cell death and neuroinflammatory cascades (Blum et al. 2004; Scarabelli et al. 2004; Tikka et al. 2002; Wang et al. 2003, 2004; Zhu et al. 2002). However, the potential neuroprotective mechanisms of minocycline for treating HD are far from our understand- ing. Chen and his group demonstrated that intraperitoneal injection of minocycline improves motor alterations in the R6/2 transgenic mouse model of HD (Chen et al. 2000; Turmaine et al. 2000; Smith et al. 2003). Although, the inhibitory effect of minocycline on caspase activation has been well described (Wang et al. 2003); however, it is still H. Kalonia Á J. Mishra Á A. Kumar (&) Pharmacology Division, UGC Centre of Advanced Study, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India e-mail: kumaruips@yahoo.com 123 Neurotox Res DOI 10.1007/s12640-012-9315-x