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Neurotoxicity Research

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01.04.2013 | Original Article

Gemfibrozil Pretreatment Affecting Antioxidant Defense System and Inflammatory, but not Nrf-2 Signaling Pathways Resulted in Female Neuroprotection and Male Neurotoxicity in the Rat Models of Global Cerebral Ischemia–Reperfusion

verfasst von: Fatemeh Mohagheghi, Leila Khalaj, Abolhassan Ahmadiani, Behrouz Rahmani

Erschienen in: Neurotoxicity Research | Ausgabe 3/2013

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Abstract

Two important pathophysiological mechanisms involved during cerebral ischemia are oxidative stress and inflammation. In pathological conditions such as brain ischemia the ability of free radicals production is greater than that of elimination by endogenous antioxidative systems, so brain is highly injured due to oxidation and neuroinflammation. Fibrates as peroxisome proliferator-activated receptor (PPAR)-α ligands, are reported to have antioxidant and anti-inflammatory actions. In this study, gemfibrozil, a fibrate is investigated for its therapeutic potential against global cerebral ischemia–reperfusion (I/R) injury of male and female rats. This study particularly has focused on inflammatory and antioxidant signaling pathways, such as nuclear factor erythroid-related factor (Nrf)-2, as well as the activity of some endogenous antioxidant agents. It was found that pretreatment of animals with gemfibrozil prior to I/R resulted in a sexually dimorphic outcome. Within females it proved to be protective, modulating inflammatory factors and inducing antioxidant defense system including superoxide dismutase (SOD), catalase, as well as glutathione level. However, Nrf-2 signaling pathway was not affected. It also decreased malondialdehyde level as an index of lipid peroxidation. In contrast, gemfibrozil pretreatment was toxic to males, enhancing the expression of inflammatory factors such as tumor necrosis factor-α, nuclear factor-κB, and cyclooxygenase-2, and decreasing Nrf-2 expression and SOD activity, leading to hippocampal neurodegeneration. Considering that gemfibrozil is a commonly used anti-hyperlipidemic agent in clinic, undoubtedly more investigations are crucial to exactly unravel its sex-dependent neuroprotective/neurodegenerative potential.

Abei H (1984) Catalase invitro. Methods Enzymol 105:121–126CrossRef

Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, Pilote L, Genest J, Eisenberg MJ (2009) Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review. Am J Med 122(10):962.e1–962.e8CrossRef

Azcoitia I, DonCarlos LL, Garcia Segura LM (2003) Are gonadal steroid hormones involved in disorders of brain aging? Aging Cell 2(1):31–37PubMedCrossRef

Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69PubMedCrossRef

Bordet R, Deplanque D, Maboudou P, Puisieux F, Pu Q, Robin E, Martin A, Bastide M, Leys D, Lhermitte M (2000) Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 20(8):1190–1196PubMedCrossRef

Bordet R, Ouk T, Petrault O, Gele P, Gautier S, Laprais M, Deplanque D, Duriez P, Staels B, Fruchart J (2006) PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem Soc Trans 34(Pt 6):1341–1346PubMed

Borges NC, Mendes GD, Barrientos-Astigarraga RE, Zappi E, Mendes FD, De Nucci G (2005) Comparative bioavailability study with two gemfibrozil tablet formulations in healthy volunteers. Arzneimittelforschung 55:382–386PubMed

Borrás C, Sastre J, García-Sala D, Lloret A, Pallardó FV, Viña J (2003) Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med 34(5):546–552PubMedCrossRef

Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1–2):248–254PubMedCrossRef

Candelario-Jalil E, Fiebich BL (2008) Cyclooxygenase inhibition in ischemic brain injury. Curr Pharm Des 14(14):1401–1418PubMedCrossRef

Carswell HVO, Anderson NH, Clark JS, Graham D, Jeffs B, Dominiczak AF, Macrae IM (1999) Genetic and gender influences on sensitivity to focal cerebral ischemia in the stroke-prone spontaneously hypertensive rat. Hypertension 33(2):681–685PubMedCrossRef

Cayen MN (1985) Disposition, metabolism and pharmacokinetics of hyperlipidemic agents in laboratory animals and man. Pharmacotherapy 29(2):157–204

Chen J, Simon R (1997) Ischemic tolerance in the brain. Neurology 48(2):306–311PubMedCrossRef

Crack PJ, Taylor JM, Ali U, Mansell A, Hertzog PJ (2006) Potential contribution of NF-κB in neuronal cell death in the glutathione peroxidase-1 knockout mouse in response to ischemia–reperfusion injury. Stroke 37(6):1533–1538PubMedCrossRef

Czlonkowska A, Ciesielska A, Gromadzka G, Kurkowska-Jastrzebska I (2005) Estrogen and cytokines production-the possible cause of gender differences in neurological diseases. Curr Pharm Des 11(8):1017–1030PubMedCrossRef

DeKosky ST (2003) Similar enzymes, different mechanisms: COX-1 and COX-2 enzymes in neurologic disease. Arch Neurol 60(4):632–633PubMedCrossRef

Delerive P, De Bosscher K, Besnard S, Berghe WV, Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, Staels B (1999) Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1. J Biol Chem 274(45):32048–32054PubMedCrossRef

Deplanque D, Gelé P, Pétrault O, Six I, Furman C, Bouly M, Nion S, Dupuis B, Leys D, Fruchart JC (2003) Peroxisome proliferator-activated receptor-α activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. J Neurosci 23(15):6264–6271PubMed

Diler A, Ziylan Y, Uzum G, Lefauconnier J, Seylaz J, Pinard E (2002) Passage of spermidine across the blood–brain barrier in short recirculation periods following global cerebral ischemia: effects of mild hyperthermia. Neurosci Res 43(4):335–342PubMedCrossRef

Dix KJ, Coleman DP, Jeffcoat AR (1999) Comparative metabolism and disposition of gemfibrozil in male and female Sprague-Dawley rats and Syrian golden hamsters. Drug Metab Dispos 27(1):138–146PubMed

Draper H, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431PubMedCrossRef

Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, Graham SH, Clark RSB (2004) Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem 279(37):38563–38570PubMedCrossRef

Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82(1):70–77PubMedCrossRef

Escher P, Wahli W (2000) Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 448(2):121–138PubMedCrossRef

Garcia-Bueno B, Madrigal JLM, Pérez-Nievas BG, Leza JC (2008) Stress mediators regulate brain prostaglandin synthesis and peroxisome proliferator-activated receptor-γ activation after stress in rats. Endocrinology 149(4):1969–1978PubMedCrossRef

Guo Q, Wang G, Liu X, Namura S (2009a) Effects of gemfibrozil on outcome after permanent middle cerebral artery occlusion in mice. Brain Res 1279:121–130PubMedCrossRef

Guo Q, Wang G, Namura S (2009b) Fenofibrate improves cerebral blood flow after middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 30(1):70–78PubMedCrossRef

Hallenbeck JM (2002) The many faces of tumor necrosis factor in stroke. Nat Med 8(12):1363–1368PubMedCrossRef

Hariz GM, Lindberg M, Hariz MI, Tommy Bergenheim A (2003) Gender differences in disability and health related quality of life in patients with Parkinson’s disease treated with stereotactic surgery. Acta Neurol Scand 108(1):28–37PubMedCrossRef

Hossmann KA (1998) Experimental models for the investigation of brain ischemia. Cardiovasc Res 39(1):106–120PubMedCrossRef

Huang CY, Fujimura M, Noshita N, Chang YY, Chan PH (2001) SOD1 down-regulates NF-κB and c-Myc expression in mice after transient focal cerebral ischemia. J Cereb Blood Flow Metab 21(2):163–173PubMedCrossRef

Hurn PD, Macrae IM (2000) Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab 20(4):631–652PubMedCrossRef

Innamorato NG, Rojo AI, García-Yagüe ÁJ, Yamamoto M, de Ceballos ML, Cuadrado A (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181(1):680–689PubMed

Inoue I, Goto S, Matsunaga T, Nakajima T, Awata T, Hokari S, Komoda T, Katayama S (2001) The ligands/activators for peroxisome proliferator-activated receptor α (PPARα) and PPARγ increase Cu²⁺, Zn²⁺-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism 50(1):3–11PubMedCrossRef

Intiso D, Zarrelli M, Lagioia G, Rienzo FD, Checchia De Ambrosio C, Simone P, Tonali P, Cioffi R (2004) Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients. Neurol Sci 24(6):390–396PubMedCrossRef

Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347(6294):645–650PubMedCrossRef

Jalalvand E, Javan M, Haeri-Rohani A, Ahmadiani A (2008) Stress- and non-stress-mediated mechanisms are involved in pain-induced apoptosis in hippocampus and dorsal lumbar spinal cord in rats. Neuroscience 157(2):446–452PubMedCrossRef

Jander S, Pohl J, Gillen C, Schroeter M, Stoll G (1996) Vascular cell adhesion molecule-1 mRNA is expressed in immune-mediated and ischemic injury of the rat nervous system. J Neuroimmunol 70(1):75–80PubMedCrossRef

Kakkar P, Das B, Viswanathan P (1984) A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys 21(2):130–132PubMed

Kaushal V, Schlichter LC (2008) Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci 28(9):2221–2230PubMedCrossRef

Knauf H, Kölle EU, Mutschler E (1990) Gemfibrozil absorption and elimination in kidney and liver disease. Klin Wochenschr 68(13):692–698PubMedCrossRef

Kraft AD, Lee JM, Johnson DA, Kan YW, Johnson JA (2006) Neuronal sensitivity to kainic acid is dependent on the Nrf2-mediated actions of the antioxidant response element. J Neurochem 98(6):1852–1865PubMedCrossRef

Kreisler A, Gelé P, Wiart JF, Lhermitte M, Destée A, Bordet R (2007) Lipid-lowering drugs in the MPTP mouse model of Parkinson’s disease: fenofibrate has a neuroprotective effect, whereas bezafibrate and HMG-CoA reductase inhibitors do not. Brain Res 1135:77–84PubMedCrossRef

Kurtz SM, Fitzgerald JE, Fisken RA, Schardein JL, Reutner TH, Lucas JA (1976) Toxicological studies on gemfibrozil. Proc R Soc Med 69(Suppl 2):15–23PubMed

Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7(1):97PubMedCrossRef

Lang J, McCullough L (2008) Pathways to ischemic neuronal cell death: are sex differences relevant? J Transl Med 6(1):33PubMedCrossRef

Li M, Zhang X, Cui L, Yang R, Wang L, Liu L, Du W (2011) The neuroprotection of oxymatrine in cerebral ischemia/reperfusion is related to nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response: role of Nrf2 and hemeoxygenase-1 expression. Biol Pharm Bull 34(5):595–601PubMedCrossRef

Marcondes F, Bianchi F, Tanno A (2002) Determination of the estrous cycle phases of rats: some helpful considerations. Braz J Biol 62:609–614PubMedCrossRef

Marx N, Kehrle B, Kohlhammer K, Grüb M, Koenig W, Hombach V, Libby P, Plutzky J (2002) PPAR activators as antiinflammatory mediators in human T lymphocytes. Circ Res 90(6):703–710PubMedCrossRef

McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD (2005) Ischemic nitric oxide and poly(ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 25(4):502–512PubMedCrossRef

Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, Chan PH (1998) Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci 18(1):205–213PubMed

Nakano M, Sugioka K, Naito I, Takekoshi S, Niki E (1987) Novel and potent biological antioxidants on membrane phospholipid peroxidation: 2-hydroxy estrone and 2-hydroxy estradiol. Biochem Biophys Res Commun 142(3):919–924PubMedCrossRef

Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284(20):13291–13295PubMedCrossRef

Niimura M, Takagi N, Takagi K, Mizutani R, Ishihara N, Matsumoto K, Funakoshi H, Nakamura T, Takeo S (2006) Prevention of apoptosis-inducing factor translocation is a possible mechanism for protective effects of hepatocyte growth factor against neuronal cell death in the hippocampus after transient forebrain ischemia. J Cereb Blood Flow Metab 26(11):1354–1365PubMedCrossRef

Nuñez JL, Lauschke DM, Juraska JM (2001) Cell death in the development of the posterior cortex in male and female rats. J Comp Neurol 436(1):32–41PubMedCrossRef

Pawate S, Shen Q, Fan F, Bhat NR (2004) Redox regulation of glial inflammatory response to lipopolysaccharide and interferon-γ. J Neurosci Res 77(4):540–551PubMedCrossRef

Petito CK, Torres-Munoz J, Roberts B, Olarte JP, Nowak TS, Pulsinelli WA (1997) DNA fragmentation follows delayed neuronal death in CA1 neurons exposed to transient global ischemia in the rat. J Cereb Blood Flow Metab 17(9):967–976PubMedCrossRef

Poynter ME, Daynes RA (1998) Peroxisome proliferator-activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 273(49):32833–32841PubMedCrossRef

Proteggente AR, England TG, Rehman A, Rice-Evans CA, Halliwell B (2002) Gender differences in steady-state levels of oxidative damage to DNA in healthy individuals. Free Radic Res 36(2):157–162PubMedCrossRef

Pulsinelli WA, Brierley JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10(3):267–272PubMedCrossRef

Ridder D, Schwaninger M (2009) NF-[kappa] B signaling in cerebral ischemia. Neuroscience 158(3):995–1006PubMedCrossRef

Sacco RL (2001) Newer risk factors for stroke. Neurology 57(Suppl 2):S31–S34PubMedCrossRef

Saito K, Suyama K, Nishida K, Sei Y, Basile AS (1996) Early increases in TNF-[alpha], IL-6 and IL-1 [beta] levels following transient cerebral ischemia in gerbil brain. Neurosci Lett 206(2–3):149–152PubMedCrossRef

Sasaki T, Kitagawa K, Yamagata K, Takemiya T, Tanaka S, Omura-Matsuoka E, Sugiura S, Matsumoto M, Hori M (2004) Amelioration of hippocampal neuronal damage after transient forebrain ischemia in cyclooxygenase-2-deficient mice. J Cereb Blood Flow Metab 24(1):107–113PubMedCrossRef

Satoh T, Okamoto SI, Cui J, Watanabe Y, Furuta K, Suzuki M, Tohyama K, Lipton S (2006) Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic phase II inducers. Proc Nat Acad Sci USA 103(3):768–773PubMedCrossRef

Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10(8):2247–2258PubMed

Shah ZA, Li RC, Thimmulappa RK, Kensler TW, Yamamoto M, Biswal S, Doré S (2007) Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury. Neuroscience 147(1):53–59PubMedCrossRef

Shih AY, Li P, Murphy TH (2005) A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J Neurosci 25(44):10321–10335PubMedCrossRef

Soane L, Li Dai W, Fiskum G, Bambrick LL (2010) Sulforaphane protects immature hippocampal neurons against death caused by exposure to hemin or to oxygen and glucose deprivation. J Neurosci Res 88(6):1355–1363PubMed

Sriram K, O’Callaghan JP (2007) Divergent roles for tumor necrosis factor-α in the brain. J Neuroimmune Pharmacol 2(2):140–153PubMedCrossRef

Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP, Delerive P, Fadel A, Chinetti G, Fruchart JC (1998) Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 393(6687):790–793PubMedCrossRef

Sugioka K, Shimosegawa Y, Nakano M (1987) Estrogens as natural antioxidants of membrane phospholipid peroxidation. FEBS Lett 210(1):37–39PubMedCrossRef

Thiyagarajan M, Sharma SS (2004) Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci 74(8):969–985PubMedCrossRef

Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, Nelson LM (2003) Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 157(11):1015–1022CrossRef

Vila N, Castillo J, Dávalos A, Chamorro Á (2000) Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31(10):2325–2329PubMedCrossRef

Wang G, Liu X, Guo Q, Namura S (2010) Chronic treatment with fibrates elevates superoxide dismutase in adult mouse brain microvessels. Brain Res 1359(4):247–255PubMedCrossRef

Xiang Z, Thomas S, Pasinetti G (2007) Increased neuronal injury in transgenic mice with neuronal overexpression of human cyclooxygenase-2 is reversed by hypothermia and rofecoxib treatment. Curr Neurovasc Res 4(4):274–279PubMedCrossRef

Xu J, Racke MK, Drew PD (2007) Peroxisome proliferator activated receptor agonist fenofibrate regulates IL 12 family cytokine expression in the CNS: relevance to multiple sclerosis. J Neurochem 103(5):1801–1810PubMedCrossRef

Yamamoto T, Ohkuwa T, Itoh H, Sato Y, Naoi M (2002) Effect of gender differences and voluntary exercise on antioxidant capacity in rats. Comp Biochem Physiol C: Toxicol Pharmacol 132(4):437–444CrossRef

Titel: Gemfibrozil Pretreatment Affecting Antioxidant Defense System and Inflammatory, but not Nrf-2 Signaling Pathways Resulted in Female Neuroprotection and Male Neurotoxicity in the Rat Models of Global Cerebral Ischemia–Reperfusion
verfasst von: Fatemeh Mohagheghi
Leila Khalaj
Abolhassan Ahmadiani
Behrouz Rahmani
Publikationsdatum: 01.04.2013
Verlag: Springer-Verlag
Erschienen in: Neurotoxicity Research / Ausgabe 3/2013
Print ISSN: 1029-8428
Elektronische ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-012-9338-3

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