title: Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington's disease.
abstract: 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces neuropathological changes similar to those observed in Huntington's disease (HD). The objective of the present study was to investigate neuroprotective effect of mitochondrial modulators; alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) on 3-NP-induced alterations in mitochondrial lipid composition, mitochondrial structure and memory functions. Experimental model of HD was developed by administering 3-NP at sub-chronic doses, twice daily for 17 days. The levels of conjugated dienes, cholesterol and glycolipids were significantly increased, whereas the levels of phospholipids (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine) including cardiolipin were significantly decreased in the mitochondria isolated from the striatum of 3-NP-treated animals. In addition, the difference in molecular composition of each phospholipid class was also evaluated using mass spectrometry. Mitochondria lipid from 3-NP-treated animals showed increased cholesterol to phospholipid ratio, suggesting decreased mitochondrial membrane fluidity. 3-NP administration also resulted in ultra-structural changes in mitochondria, accompanied by swelling as assessed by transmission electron microscopy. The 3-NP administered animals had impaired spatial memory evaluated using elevated plus maze test. However, combined supplementation with ALA + ALCAR for 21 days normalized mitochondrial lipid composition, improved mitochondrial structure and ameliorated memory impairments in 3-NP-treated animals, suggesting an imperative role of these two modulators in combination in the management of HD.
authors.affiliation: Department of Biochemistry, Panjab University, Chandigarh, 160014, India.
authors.forename: Arpit
authors.initials: A
authors.lastname: Mehrotra
authors.affiliation: Department of Biochemistry, Panjab University, Chandigarh, 160014, India.
authors.forename: Abhilasha
authors.initials: A
authors.lastname: Sood
authors.affiliation: Department of Biochemistry, Panjab University, Chandigarh, 160014, India. sandhir@pu.ac.in.
authors.forename: Rajat
authors.initials: R
authors.lastname: Sandhir
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism; D002855:Chromatography, Thin Layer; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D050356:Lipid Metabolism / Q000187:drug effects*; D008560:Membrane Fluidity / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009574:Nitro Compounds; D018697:Nootropic Agents / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D011422:Propionates; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D009574:Nitro Compounds; D018697:Nootropic Agents; D010743:Phospholipids; D011422:Propionates; D000108:Acetylcarnitine; D008063:Thioctic Acid; D002784:Cholesterol; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; Acetyl-L-carnitine; Alpha-lipoic acid; Huntington’s disease; Lipid composition; Mitochondria