ORIGINAL ARTICLE Improvement of Mitochondrial Function by Paliperidone Attenuates Quinolinic Acid-Induced Behavioural and Neurochemical Alterations in Rats: Implications in Huntington’s Disease Jitendriya Mishra • Anil Kumar Received: 8 February 2014 / Revised: 8 April 2014 / Accepted: 8 April 2014 Ó Springer Science+Business Media New York 2014 Abstract Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as increased calcium concentration in cytoplasm, exhaustive ATP depletion, oxidative stress, as well as selective GABAergic, dopa- minergic, and cholinergic neuronal death. Clinical data hint towards the connection between signalling of dopaminer- gic system and efficient amelioration of chorea following a tetrabenazine administration in Huntington’s disease patients. Therefore, the present study has been designed to explore the neuroprotective potential of paliperidone, an active metabolite of risperidone (a dopaminergic antago- nist) against QA-induced neurotoxicity and related com- plications in rats. QA (200 nmol) was administered bilaterally to the striatum over a period of 2 min by means of a 28-gauge stainless steel needle attached to a Hamilton syringe. The study protocol involves seven treatment groups (n = 12): naı ¨ve, sham, control (QA), paliperidone (0.5, 1 and 2 mg/kg) and paliperidone (2) per se. Single bilateral intrastriatal injection of QA (200 nmol/2 ll sal- ine) significantly caused motor incordination, memory impairment, oxidative damage, decrease in biogenic amines levels, cellular alterations (TNF-a, IL-6, PGE2, PGF2a, caspase-3, BDNF, mitochondrial function) and damage of striatal neurons compared to the sham treat- ment. Treatment with paliperidone (0.5, 1 and 2 mg/kg) for 21 days significantly attenuated the QA-induced behav- ioural (motor and memory function), neurochemical (antioxidant enzymes and biogenic amines) and cellular alterations, as well as striatal neurodegeneration. The study indicated that modulation of dopaminergic pathway by paliperidone treatment could be a useful approach in the management of motor and memory abnormality in HD patients. Keywords Apoptosis  BDNF  Biogenic amines  Mitochondrial respiration  Neuroinflammation Introduction Huntington’s disease (HD) is a dominant autosomal inherited disorder characterized by chorea, cognitive impairment and psychiatric disturbances. Neuropathologi- cal analysis indicates that HD results from abnormal CAG repeat expansion leading to an expanded polyglutamine (polyQ) tail in the N terminus of Huntingtin protein (mhtt), as well as selective and progressive neuronal loss of the GABAergic medium spiny neurons (MSNs) in the striatum (Vonsattel and DiFiglia 1998). Quinolinic acid (QA), a tryptophan metabolite of kynurenine pathway (Amori et al. 2009), is a well-known excitotoxin and reported to cause neuroinflammation (Braidy et al. 2009), mitochondrial dysfunction (Kumar et al. 2013a; Mishra et al. 2014) and apoptosis (Cao et al. 2005). QA-induced neurotoxicity involves a cascade of events such as increased calcium concentration in cytoplasm, exhaustive ATP depletion, oxidative stress, as well as selective GABAergic, dopa- minergic and cholinergic neuronal death (Miranda et al. 1997; Araujo et al. 2000; Santamaria and Rios 1993). Several study results also revealed that abnormal cal- cium signalling plays an important role in HD pathogene- sis. A recent study on an HD mouse model suggested about the existence of a connection between glutamate receptor activation, apoptosis of MSNs and calcium overload (Tang J. Mishra  A. Kumar (&) Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh 160014, India e-mail: kumaruips@yahoo.com 123 Neurotox Res DOI 10.1007/s12640-014-9469-9