title: Neuroprotective effect of hemeoxygenase-1/glycogen synthase kinase-3β modulators in 3-nitropropionic acid-induced neurotoxicity in rats.
abstract: The present study has been designed to explore the possible interaction between hemeoxygenase-1 (HO-1) and glycogen synthase kinase-3β (GSK-3β) pathway in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. 3-NP produces neurotoxicity by inhibition of the mitochondrial complex II (enzyme succinate dehydrogenase) and by sensitizing the N-methyl-D-aspartate receptor. Recent studies have reported the therapeutic potential of HO-1/GSK-3β modulators in different neurodegenerative disorders. However, their exact role is yet to be explored. The present study is an attempt to investigate the effect of pharmacological modulation of HO-1/GSK-3β pathway against 3-NP-induced behavioral, biochemical and molecular alterations in rat. Behavioral observation, oxidative stress, pro-inflammatory [tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)], HO-1 and GSK-3β activity were evaluated post 3-NP treatment. Findings of the present study demonstrate a significant alteration in the locomotor activity, motor coordination, oxidative burden (increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidants), pro-inflammatory mediators [TNF-α, IL-1β], HO-1 and GSK-3β activity in 3-NP-treated animals. Further, administration of hemin (10- and 30-mg/kg; i.p.) and lithium chloride (LiCl) (25- and 50-mg/kg; i.p.) prevented the alteration in body weight, motor impairments, oxidative stress and cellular markers. In addition, combined administration of hemin (10-mg/kg) and LiCl (25-mg/kg) showed synergistic effect on 3-NP-treated rats. Pretreatment with Tin (IV) protoporphyrin (40 μM/kg), HO-1 inhibitor reversed the beneficial effect of LiCl and hemin. Outcomes of the present study suggest that HO-1 and GSK-3β enzymes are involved in the pathophysiology of HD. The modulators of both the pathways might be used as adjuvants or prophylactic therapy for the treatment of HD-like symptoms.
authors.affiliation: Department of Pharmacology, I.S.F. College of Pharmacy, Ferozepur Road, Ghal Kalan, Moga 142001, Punjab, India.
authors.forename: A
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Pharmacology, I.S.F. College of Pharmacy, Ferozepur Road, Ghal Kalan, Moga 142001, Punjab, India; Research Scholar, Punjab Technical University, Jalandhar, India.
authors.forename: S
authors.initials: S
authors.lastname: Jamwal
authors.affiliation: Department of Pharmacology, I.S.F. College of Pharmacy, Ferozepur Road, Ghal Kalan, Moga 142001, Punjab, India.
authors.forename: K R V
authors.initials: KR
authors.lastname: Bijjem
authors.affiliation: Department of Pharmacology, I.S.F. College of Pharmacy, Ferozepur Road, Ghal Kalan, Moga 142001, Punjab, India.
authors.forename: A
authors.initials: A
authors.lastname: Prakash
authors.affiliation: Department of Pharmacology, I.S.F. College of Pharmacy, Ferozepur Road, Ghal Kalan, Moga 142001, Punjab, India. Electronic address: punnubansal79@gmail.com.
authors.forename: P
authors.initials: P
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism / Q000517:prevention & control; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D051547:Heme Oxygenase-1 / Q000378:metabolism / Q000502:physiology*; D006427:Hemin / Q000008:administration & dosage; D015227:Lipid Peroxidation / Q000187:drug effects; D018021:Lithium Chloride / Q000008:administration & dosage; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D009573:Nitrites / Q000032:analysis; D009574:Nitro Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates / Q000633:toxicity*; D011524:Protoporphyrins / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008665:Metalloporphyrins; D018696:Neuroprotective Agents; D009573:Nitrites; D009574:Nitro Compounds; D011422:Propionates; D011524:Protoporphyrins; D006427:Hemin; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; C015392:3-nitropropionic acid
keywords: 3-nitropropionic acid; Huntington’s disease; glycogen synthase kinase-3β; hemeoxygenase-1; oxidative stress