The effects of PPAR-γ agonist pioglitazone on hippocampal cytokines, brain-derived neurotrophic factor, memory impairment, and oxidative stress status in lipopolysaccharide-treated rats

Document Type: Original Article

Authors

1 Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Basic Science and Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran

3 Iranshahr University of Medical Sciences, Iranshahr, Iran

4 Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

5 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

6 Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): The aim of current study was to evaluate improving effects of pioglitazone as an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), on brain-derived neurotrophic factor (BDNF) and cytokines as well as tissue oxidative damage criteria in the hippocampus in a rat model of lipopolysaccharide (LPS) induced memory impairment.
Materials and Methods: The rats were classified and treated as follows (10 rats per group): (1) vehicle, (2) vehicle before LPS (1 mg/kg, 120 min before memory tests), (3-5) pioglitazone 10, 20 or 30 mg/kg 30 min before LPS. Finally, the hippocampal tissues were collected for biomedical analyses.
Results: In the Morris water maze test, the LPS group, had a longer latency to find the platform while they spent a shorter time in the target quadrant in the probe trial. In the passive avoidance test, the animals of the LPS group had shorter delay times to enter the dark compartment than those of the control group. Treatment with 20 and 30 mg of pioglitazone corrected these parameters. In the hippocampus of LPS group interleukin-6, tumor necrosis factor-α, nitric oxide metabolites, and malondialdehyde were higher while  thiol, BDNF, and IL-10 concentrations and the activities of catalase (CAT) and superoxide dismutase (SOD) were lower than the control group. Treatment by both doses of 20 and 30 mg of pioglitazone corrected the biochemical parameters in the hippocampus.
Conclusion: The current findings revealed that pioglitazone protected the rats from learning and memory impairment induced by LPS. The effects were associated with improvement of cytokines, oxidative stress criteria, and BDNF.

Keywords

Main Subjects


1. Jiang LY, Tang SS, Wang XY, Liu LP, Long Y, Hu M, et al. PPARγ agonist pioglitazone reverses memory impairment and biochemical changes in a mouse model of type 2 diabetes mellitus. CNS Neurosci Ther 2012; 18:659-666.
2. Pathan AR, Viswanad B, Sonkusare SK, Ramarao P. Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats. Life sci 2006; 79:2209-2216.
3. Medhi B, Aggarwal R, Chakrabarti A. Neuroprotective effect of pioglitazone on acute phase changes induced by partial global cerebral ischemia in mice.  Indian J Exp Biol 2010; 48:793-799.
4. Prakash A, Kumar A, Ming LC, Mani V, Majeed ABA. Modulation of the nitrergic pathway via activation of PPAR-γ contributes to the neuroprotective effect of pioglitazone against streptozotocin-induced memory dysfunction. J Mol Neurosci 2015; 56:739-750.
5. Qiu D, Li XN. Pioglitazone inhibits the secretion of proinflammatory cytokines and chemokines in astrocytes stimulated with lipopolysaccharide. Int J Clin Pharmacol Ther 2015;53:746-752.
6. Semmler A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, et al. Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 2007; 204:733-740.
8. Swiergiel AH, Dunn AJ. Effects of interleukin-1beta and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests. Pharmacol Biochem Behav 2007; 86:651-659.
8. Sparkman NL, Martin LA, Calvert WS, Boehm GW. Effects of intraperitoneal lipopolysaccharide on Morris maze performance in year-old and 2-month-old female C57BL/6J mice. Behav Brain Res 2005; 159:145-151.
9. Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPARα in energy metabolism and vascular homeostasis. J Clin Inves 2006; 116: 571-580.
10. Houseknecht KL, Cole BM, Steele PJ. Peroxisome proliferator-activated receptor gamma (PPARγ) and its ligands: a review. Domest Anim Endocrinol 2002; 22:1-23.
11. Girnun GD, Domann FE, Moore SA, Robbins ME. Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter. Mol Endocrinol 2002; 16:2793-2801.
12. Villegas I, Martín AR, Toma W, de la Lastra CA. Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, protects against gastric ischemia–reperfusion damage in rats: role of oxygen free radicals generation. Eur J Pharmacol 2004; 505:195-203.
13. Yoo HY, Chang MS, Rho HM. Induction of the rat Cu/Zn superoxide dismutase gene through the peroxisome proliferator-responsive element by arachidonic acid. Gene 1999; 234:87-91.
14. Heneka MT, Galea E, Gavriluyk V, Dumitrescu-Ozimek L, Daeschner J, O’Banion MK, et al. Noradrenergic depletion potentiates β-amyloid-induced cortical inflammation: implications for Alzheimer’s disease. J Neurosci 2002; 22:2434-2442.
15. Feinstein DL. Therapeutic potential of peroxisome proliferator-activated receptor agonists for neurological disease. Diabetes Technol Ther 2003; 5:67-73.
16. Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 2006; 199:265-273.
17. Moreno S, Farioli-Vecchioli S, Ceru M. Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 2004; 123:131-145.
18. Baghcheghi Y, Beheshti F, Salmani H, Soukhtanloo M, Hosseini M. Protective effect of PPARgamma agonists on cerebellar tissues oxidative damage in hypothyroid rats. Neurol Res Int 2016; 2016: 1-9.
19. Bargi R, Asgharzadeh F, Beheshti F, Hosseini M, Sadeghnia HR, Khazaei M. The effects of thymoquinone on hippocampal cytokine level, brain oxidative stress status and memory deficits induced by lipopolysaccharide in rats. Cytokine 2017; 96:173-184.
20. Anaeigoudari A, Shafei MN, Soukhtanloo M, Sadeghnia HR, Reisi P, Beheshti F, Mohebbati R, Mousavi SM, Hosseini M. Lipopolysaccharide-induced memory impairment in rats is preventable using 7-nitroindazole. Arq Neuropsiquiatr 2015;73:784-790.
21. Beheshti F, Hosseini M, Vafaee F, Shafei MN, Soukhtanloo M. Feeding of Nigella sativa during neonatal and juvenile growth improves learning and memory of rats. J Tradit Complement Med 2015 17;6:146-152.
22. Faridkia Z, Yaghmaei P, Nassiri-Asl M. Protective effect of quinine on chemical kindling and passive avoidance test in rats. Iran Red Crescent Med J 2016; 21;18:1-5.
23. Nassiri-Asl M, Moghbelinejad S, Abbasi E, Yonesi F, Haghighi MR, Lotfizadeh M, Bazahang P. Effects of quercetin on oxidative stress and memory retrieval in kindled rats. Epilepsy Behav 2013;28:151-155.
24.Beheshti F, Hosseini M, Shafei MN, Soukhtanloo M, Ghasemi S, Vafaee F, et al. The effects of Nigella sativa extract on hypothyroidism-associated learning and memory impairment during neonatal and juvenile growth in rats. Nutr Neurosci 2017; 20:49-59.
25. Habeeb AF. Reaction of protein sulfhydryl groups with Ellman’s reagent. Methods Enzymol 1972; 25:457-464.
26. Madesh M, Balasubramanian KA. A microtiter plate assay for superoxide using MTT reduction method. Indian J Biochem Biophys 1997; 34:535-539.
27. Aebi H. Catalase in vitro. Methods in enzymology 1984; 105:121-126.
28. Płóciennikowska A, Hromada-Judycka A, Borzęcka K, Kwiatkowska K. Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling. Cell Mol Life Sci 2015; 72:557-581.
29. McGeer PL, Sibley J. Sparing of age-related macular degeneration in rheumatoid arthritis. Neurobiol Aging 2005;26:1199-1203.
30. Yamada K, Komori Y, Tanaka T, Senzaki K, Nikai T, Sugihara H, et al. Brain dysfunction associated with an induction of nitric oxide synthase following an intracerebral injection of lipopolysaccharide in rats. Neuroscience 1999; 88:281-294.
31. Valero J, Mastrella G, Neiva I, Sánchez S, Malva JO. Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory. Front neurosci 2014; 8:1-13.
32. Labouesse MA, Langhans W, Meyer U. Long-term pathological consequences of prenatal infection: beyond brain disorders. Am J Physiol Regul Integr Comp Physiol 2015; 309:R1-R12.
33. Rai S, Kamat PK, Nath C, Shukla R. Glial activation and post-synaptic neurotoxicity: the key events in Streptozotocin (ICV) induced memory impairment in rats. Pharmaco Biochem Behav 2014; 117:104-117.
34.Kishimoto T. The biology of interleukin-6. Blood 1989; 74:1-10.
35. de Waal Malefyt R, Haanen J, Spits H, Roncarolo M-G, Te Velde A, Figdor C, et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 1991; 174:915-924.
36. Cuhna FQ, Moncada S, Liew FY. Interleukin-10 inhibits the production of nitric oxide synthase by interferon-7 in murine macrophages. Biochem Biophys Res Comm 1992; 182:1155-1159.
37. Beckhauser TF, Francis-Oliveira J, De Pasquale R. Reactive oxygen species: physiological and physiopathological effects on synaptic plasticity. J Exp neurosci 2016; 10:23-48.
38. Kheir-Eldin AA, Motawi TK, Gad MZ, Abd-ElGawad HM. Protective effect of vitamin E, β-carotene and N-acetylcysteine from the brain oxidative stress induced in rats by lipopolysaccharide. Int J Biochem Cell Biol 2001; 33:475-482.
39. Hosseini M, Mohammadpour T, Karami R, Rajaei Z, Reza Sadeghnia H, Soukhtanloo M. Effects of the hydro-alcoholic extract of Nigella sativa on scopolamine-induced spatial memory impairment in rats and its possible mechanism. Chin J Integr Med 2015; 21:438-444.
40. Abareshi A, Anaeigoudari A, Norouzi F, Shafei MN, Boskabady MH, Khazaei M, et al. Lipopolysaccharide-induced spatial memory and synaptic plasticity impairment is preventable by captopril. Adv Med 2016; 2016:1-8.
41. Thomas K, Davies A. Neurotrophins: a ticket to ride for BDNF. Curr Biol 2005; 15:R262-R264.
42. Pitts AF, Miller MW. Expression of nerve growth factor, brain‐derived neurotrophic factor, and neurotrophin‐3 in the somatosensory cortex of the mature rat: Coexpression with high‐affinity neurotrophin receptors. J Compar Neurol 2000; 418:241-254.
43. Noga O, Peiser M, Altenähr M, Schmeck B, Wanner R, Dinh Q, et al. Selective induction of nerve growth factor and brain‐derived neurotrophic factor by LPS and allergen in dendritic cells. Clin Exp Allergy 2008; 38:473-479.
44. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 1991; 7:695-702.
45. Angelucci F, Spalletta G, Iulio Fd, Ciaramella A, Salani F, Varsi A, et al. Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients are characterized by increased BDNF serum levels. Curr Alzheimer Res 2010; 7:15-20.
46. Guan Z, Fang J. Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain, Behavi Immun 2006; 20:64-71.
47. Luperchio S, Tamir S, Tannenbaum SR. NO-induced oxidative stress and glutathione metabolism in rodent and human cells. Free Rad Biol Med 1996; 21:513-519.
48. Abdel-Zaher AO, Farghaly HSM, Farrag MMY, Abdel-Rahman MS, Abdel-Wahab BA. A potential mechanism for the ameliorative effect of thymoquinone on pentylenetetrazole-induced kindling and cognitive impairments in mice. Biomed Pharmacother 2017; 88:553-561.
49. Hosseini M, Dastghaib SS, Rafatpanah H, Hadjzadeh MA, Nahrevanian H, Farrokhi I. Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth. Clinics (Sao Paulo) 2010; 65:1175-1181.
50. Tabrizian K, Azami K, Belaran M, Soodi M, Abdi K, Fanoudi S, et al. Selective inducible nitric oxide synthase inhibitor reversed zinc chloride-induced spatial memory impairment via increasing cholinergic marker expression. Biol Trace Elem Res 2016; 173:443-451.
51. Anaeigoudari A, Soukhtanloo M, Reisi P, Beheshti F, Hosseini M. Inducible nitric oxide inhibitor aminoguanidine, ameliorates deleterious effects of lipopolysaccharide on memory and long term potentiation in rat. Life Scie 2016; 158:22-30.
52. Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 2015; 3:1-15.
53. Saha RN, Pahan K. Signals for the induction of nitric oxide synthase in astrocytes. Neurochem Int 2006; 49:154-163.
54. Saha RN, Pahan K. Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid Redox Signal 2006; 8:929-947.
55. Goodwin JL, Kehrli ME, Uemura E. Integrin Mac-1 and β-amyloid in microglial release of nitric oxide. Brain Res 1997; 768:279-286.
56. Meda L, Cassatella MA, Szendrei GI, Otvos L, Baron P, Villalba M, et al. Activation of microglial cells by β-amyloid protein and interferon-γ. Nature 1995; 374:647-650.
57. Akama KT, Albanese C, Pestell RG, Van Eldik LJ. Amyloid β-peptide stimulates nitric oxide production in astrocytes through an NFκB-dependent mechanism. Proc Natl Acad Sci 1998; 95:5795-5800.
58. Forloni G, Mangiarotti F, Angeretti N, Lucca E, De Simoni MG. β-amyloid fragment potentiates IL-6 and TNF-α secretion by LPS in astrocytes but not in microglia. Cytokine 1997; 9:759-762.
59. Murer MG, Raisman-Vozari R, Yan Q, Ruberg M, Agid Y, Michel PP. Survival factors promote BDNF protein expression in mesencephalic dopaminergic neurons. Neuroreport 1999; 10:801-805.
60. Rosa E, Mahendram S, Ke YD, Ittner LM, Ginsberg SD, Fahnestock M. Tau downregulates BDNF expression in animal and cellular models of Alzheimer’s disease. Neurobiol Aging 2016; 48:135-142.
61. Arancibia S, Silhol M, Mouliere F, Meffre J, Höllinger I, Maurice T, et al. Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol Dis 2008; 31:316-326.
62. Prakash A, Kumar A. Role of nuclear receptor on regulation of BDNF and neuroinflammation in hippocampus of β-amyloid animal model of Alzheimer’s disease. Neurotox Res 2014; 25:335-347.
63. Xiao Q, Wang C, Li J, Hou Q, Li J, Ma J, et al. Ginkgolide B protects hippocampal neurons from apoptosis induced by beta-amyloid 25–35 partly via up-regulation of brain-derived neurotrophic factor. Euro J Pharmaco 2010; 647:48-54.
64. Ghanizadeh A. Malondialdehyde, Bcl-2, superoxide dismutase and glutathione peroxidase may mediate the association of sonic hedgehog protein and oxidative stress in autism. Neurochem Res 2012; 37:899-901.