BACKGROUND AND PURPOSEHuntington's disease (HD) is a progressive neurodegenerative disorder characterized by a degeneration of striatal neurons. The possible role of COX and lipoxygenase (LOX) pathways has been well-documented in the pathology of several neurodegenerative disorders including HD. Licofelone is a competitive inhibitor of COX-1-and COX-2 and 5-LOX isoenzymes. Therefore, the present study was designed to investigate possible neuroinflammatory and apoptotic mechanisms in the neuroprotective effect of licofelone against 3-nitropropionic acid (3-NP)-induced HD-like symptoms in rats.
EXPERIMENTAL APPROACHRats were administered 3-NP (10 mg·kg , p.o.) was given once a day, 1 h before 3-NP treatment for 14 days. Body weight and behavioural parameters (locomotor and rotarod activity) were assessed on the 1st, 5th, 10th and 15th day post-3-NP administration. Malondialdehyde, nitrite concentration, endogenous antioxidant enzymes (superoxide dismutase and catalase levels), mitochondrial enzyme complexes, pro-inflammatory compounds (TNF-a, IL-6, NF-kB), PGs (PGE2 and PGF2a) and caspase-3 activity were measured on day 15 in the striatum.
KEY RESULTSSystemic 3-NP treatment significantly reduced body weight, locomotor activity, oxidative defence, mitochondrial enzyme complex activities and increased TNF-a, IL-6, caspase-3 activity, NF-kB and PGE2 and PGF2a levels in the striatum. Licofelone (2.5, 5 and 10 mg·kg -1 ) significantly attenuated the impairment in behavioural, biochemical and mitochondrial, pro-inflammatory and pro-apoptotic markers as compared with vehicle-treated group.
CONCLUSIONS AND IMPLICATIONSThe results demonstrate the involvement of pro-inflammatory compounds and the apoptotic cascade in the neuroprotective effect of licofelone against 3-NP-induced neurotoxicity.Abbreviations 3-NP, 3-nitropropionic acid; BDNF; brain-derived neurotropic factor; CMC, sodium carboxymethyl cellulose; CREB, cAMP response element binding protein; DMSO, dimethyl sulphoxide; DTT, dithiothreitol; HD, Huntington's disease; LDH, lactate dehydrogenase; LOX, lipoxygenase; MDA, malondialdehyde; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole; NBT, nitrazobluetetrazolium; ROS, reactive oxygen species; SDH, succinate dehydrogenase; SOD, superoxide dismutase BJP British Journal of Pharmacology