title: Mitochondrial modulators in experimental Huntington's disease: reversal of mitochondrial dysfunctions and cognitive deficits.
abstract: Huntington's disease (HD) is a chronic neurodegenerative condition involving impaired mitochondrial functions. The present study evaluates the therapeutic potential of combined administration of mitochondrial modulators: alpha-lipoic acid and acetyl-l-carnitine on mitochondrial dysfunctions in 3-NP-induced HD. Our results reveal 3-NP administration resulted in compromise of mitochondrial functions in terms of: (1) impaired activity of mitochondrial respiratory chain enzymes, altered cytochrome levels, reduced histochemical staining of complex-II and IV, reduced in-gel activity of complex-I to V, and reduced mRNA expression of respiratory chain complexes; (2) enhanced mitochondrial oxidative stress indicated by increased malondialdehyde, protein carbonyls, reactive oxygen species and nitrite levels, along with decreased Mn-superoxide dismutase and catalase activity; (3) mitochondrial structural changes measured by mitochondrial swelling, reduced mitochondrial membrane potential and ultra-structure changes; (4) increased cytosolic cytochrome c levels, caspase-3 and -9 activity along with altered expression of apoptotic proteins (AIF, Bim, Bad, and Bax); and (5) impaired cognitive functions assessed using Morris water maze and Y-maze. Combination of mitochondrial modulators (alpha-lipoic acid + acetyl-l-carnitine) on the other hand ameliorated 3-NP-induced mitochondrial dysfunctions, oxidative stress, histologic alterations, and behavioral deficits, suggesting their therapeutic efficacy in the management of HD.
authors.affiliation: Department of Biochemistry, Basic Medical Science Building, Panjab University, Chandigarh, India.
authors.forename: Arpit
authors.initials: A
authors.lastname: Mehrotra
authors.affiliation: Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Kanwal
authors.affiliation: Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, India.
authors.forename: Sanjay Kumar
authors.initials: SK
authors.lastname: Banerjee
authors.affiliation: Department of Biochemistry, Basic Medical Science Building, Panjab University, Chandigarh, India. Electronic address: sandhir@pu.ac.in.
authors.forename: Rajat
authors.initials: R
authors.lastname: Sandhir
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000235:genetics; D008933:Mitochondrial Swelling / Q000187:drug effects; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates; D017208:Rats, Wistar; D008063:Thioctic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D009574:Nitro Compounds; D011422:Propionates; D000108:Acetylcarnitine; D008063:Thioctic Acid; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; Acetyl-L-carnitine; Alpha-lipoic acid; Huntington's disease; Mitochondria; Oxidative stress