title: Improvement of mitochondrial function by paliperidone attenuates quinolinic acid-induced behavioural and neurochemical alterations in rats: implications in Huntington's disease.
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, dopaminergic, and cholinergic neuronal death. Clinical data hint towards the connection between signalling of dopaminergic 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 antagonist) against QA-induced neurotoxicity and related complications 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): naïve, 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 μl saline) significantly caused motor incordination, memory impairment, oxidative damage, decrease in biogenic amines levels, cellular alterations (TNF-α, IL-6, PGE2, PGF2α, caspase-3, BDNF, mitochondrial function) and damage of striatal neurons compared to the sham treatment. Treatment with paliperidone (0.5, 1 and 2 mg/kg) for 21 days significantly attenuated the QA-induced behavioural (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.
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, 160014, India.
authors.forename: Jitendriya
authors.initials: J
authors.lastname: Mishra
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D006816:Huntington Disease; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009069:Movement Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000633:toxicity*; D017208:Rats, Wistar
chemical_list: D001679:Biogenic Amines; D007555:Isoxazoles; D018696:Neuroprotective Agents; D011743:Pyrimidines; D000110:Acetylcholinesterase; D017378:Quinolinic Acid; D000068882:Paliperidone Palmitate; D010100:Oxygen
references.citation: J Psychiatr Res. 2011 Sep;45(9):1194-201
references.pmid: 21440257
references.citation: Anal Biochem. 1982 Oct;126(1):131-8
references.pmid: 7181105
references.citation: Int J Psychiatry Clin Pract. 2014 Jan;18(1):58-62
references.pmid: 24047427
references.citation: J Biol Chem. 1970 Sep 25;245(18):4724-31
references.pmid: 4393961
references.citation: Brain Res. 2008 Oct 3;1233:8-19
references.pmid: 18657526
references.citation: Lancet. 1970 Dec 5;2(7684):1185-6
references.pmid: 4098454
references.citation: Prog Neurobiol. 2007 Apr;81(5-6):294-330
references.pmid: 17379385
references.citation: Behav Brain Res. 2007 Jan 25;176(2):216-21
references.pmid: 17123640
references.citation: J Neurochem. 1997 Aug;69(2):581-93
references.pmid: 9231715
references.citation: Neuroscience. 1997 Jun;78(4):967-75
references.pmid: 9174065
references.citation: Biochem J. 1966 Jun;99(3):667-76
references.pmid: 5964963
references.citation: Dev Neurosci. 1992;14(5-6):362-8
references.pmid: 1363970
references.citation: Exp Neurol. 2000 Dec;166(2):287-97
references.pmid: 11085894
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2012 Aug 7;38(2):107-15
references.pmid: 22507762
references.citation: Psychopharmacology (Berl). 1998 Oct;139(4):356-63
references.pmid: 9809856
references.citation: J Neurochem. 2003 Mar;84(5):1097-109
references.pmid: 12603833
references.citation: Cell Death Dis. 2011 Nov 10;2:e228
references.pmid: 22071633
references.citation: Arch Biochem Biophys. 1959 May;82(1):70-7
references.pmid: 13650640
references.citation: Eur J Pharmacol. 2013 Nov 15;720(1-3):16-28
references.pmid: 24211676
references.citation: PLoS One. 2013 May 14;8(5):e52147
references.pmid: 23690912
references.citation: Drug Metab Dispos. 2008 Apr;36(4):769-79
references.pmid: 18227146
references.citation: Eur J Neurosci. 2007 Jun;25(12):3513-25
references.pmid: 17610571
references.citation: Neurotox Res. 2012 Nov;22(4):310-20
references.pmid: 22392362
references.citation: Can J Physiol Pharmacol. 2013 Dec;91(12):1119-26
references.pmid: 24289084
references.citation: J Neurosci Methods. 1997 Jul 18;75(1):49-54
references.pmid: 9262143
references.citation: J Int Neuropsychol Soc. 2007 May;13(3):539-43
references.pmid: 17445303
references.citation: Can J Physiol Pharmacol. 2004 Aug-Sep;82(8-9):732-9
references.pmid: 15523530
references.citation: J Biol Chem. 1968 Feb 25;243(4):716-9
references.pmid: 5638587
references.citation: Neurotox Res. 2014 Aug;26(2):130-51
references.pmid: 24566814
references.citation: Acta Pharmacol Sin. 2005 Feb;26(2):150-4
references.pmid: 15663890
references.citation: Neurotox Res. 2009 Jul;16(1):77-86
references.pmid: 19526301
references.citation: Neurosci Lett. 1993 Sep 3;159(1-2):51-4
references.pmid: 8264978
references.citation: J Neurochem. 2007 Mar;100(5):1375-86
references.pmid: 17254027
references.citation: Life Sci. 2000 Nov 24;68(1):29-39
references.pmid: 11132243
references.citation: Psychopharmacology (Berl). 2011 Oct;217(3):397-410
references.pmid: 21523348
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12218-23
references.pmid: 16103364
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1998 Oct;22(7):1217-40
references.pmid: 9829299
references.citation: Schizophr Res. 2013 Jun;147(1):14-23
references.pmid: 23583326
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Apr 25;818(2):269-76
references.pmid: 15734169
references.citation: Neurosci Res. 2006 Aug;55(4):397-402
references.pmid: 16766071
references.citation: Cell Death Dis. 2010 Jul 15;1:e54
references.pmid: 21364659
references.citation: J Cell Biol. 1967 Feb;32(2):415-38
references.pmid: 10976232
references.citation: Neuroscience. 2009 Mar 3;159(1):196-203
references.pmid: 19138730
references.citation: Biochem Pharmacol. 1961 Jul;7:88-95
references.pmid: 13726518
references.citation: J Pharmacol Exp Ther. 1997 Jan;280(1):105-13
references.pmid: 8996187
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jan 10;36(1):71-7
references.pmid: 21878360
references.citation: Arch Biochem Biophys. 1978 Feb;186(1):189-95
references.pmid: 24422
references.citation: Neurosci Lett. 2002 Feb 1;318(3):137-40
references.pmid: 11803118
references.citation: Trends Neurosci. 1992 Apr;15(4):133-9
references.pmid: 1374971
references.citation: Neuron. 1995 Oct;15(4):961-73
references.pmid: 7576644
references.citation: Trends Neurosci. 2000 Jun;23(6):239-45
references.pmid: 10838590
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2602-7
references.pmid: 15695335
references.citation: J Neuropathol Exp Neurol. 1998 May;57(5):369-84
references.pmid: 9596408
references.citation: Neurosci Lett. 2011 Aug 18;500(3):167-71
references.pmid: 21699956
references.citation: J Neurochem. 1999 Sep;73(3):1127-37
references.pmid: 10461904
references.citation: Int J Mol Sci. 2013 Nov 15;14(11):22558-603
references.pmid: 24248060
references.citation: J Biol Chem. 1949 Feb;177(2):751-66
references.pmid: 18110453
references.citation: Brain Res. 1985 Aug 19;341(1):57-65
references.pmid: 2412634
references.citation: Neurology. 2006 Feb 14;66(3):366-72
references.pmid: 16476934
references.citation: ILAR J. 2007;48(4):356-73
references.pmid: 17712222
references.citation: Eur J Pharmacol. 2013 Jun 5;709(1-3):1-12
references.pmid: 23562615
references.citation: Brain Res. 2000 Jun 2;866(1-2):257-61
references.pmid: 10825501