The PPAR-gamma agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function

Journal of Neuroinflammation

Alastair Wilkins¹  Neil Scolding¹  Kevin Kemp¹  Mark Ginty¹  Elizabeth Gray¹ 

[1]Multiple Sclerosis and Stem Cell Group, Burden Centre, Institute of Clinical Neurosciences, Frenchay Hospital, University of Bristol, Bristol BS16 1JB, UK

关键词: Peroxisome proliferator activated receptor;    Pioglitazone;    Nitric oxide;    Peroxisome;   

Others  :  1212698
DOI  :  10.1186/1742-2094-9-63

 received in 2011-11-03, accepted in 2012-04-05,  发布年份 2012

【 摘 要 】

Background

Inflammation is known to play a pivotal role in mediating neuronal damage and axonal injury in a variety of neurodegenerative disorders. Among the range of inflammatory mediators, nitric oxide and hydrogen peroxide are potent neurotoxic agents. Recent evidence has suggested that oligodendrocyte peroxisomes may play an important role in protecting neurons from inflammatory damage.

Methods

To assess the influence of peroxisomal activation on nitric oxide mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator activated receptor (PPAR) gamma agonist, pioglitazone in primary cortical neurons that were either exposed to a nitric oxide donor or co-cultured with activated microglia.

Results

Pioglitazone protected neurons and axons against both nitric-oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in the protein and gene expression of PPAR-gamma, which was associated with a concomitant increase in the enzymatic activity of catalase. In addition, the protection of neurons and axons against hydrogen peroxide-induced toxicity afforded by pioglitazone appeared to be dependent on catalase.

Conclusions

Collectively, these observations provide evidence that modulation of PPAR-gamma activity and peroxisomal function by pioglitazone attenuates both NO and hydrogen peroxide-mediated neuronal and axonal damage suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation.

【 授权许可】

   
2012 Gray et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Lassmann H: Axonal and neuronal pathology in multiple sclerosis: what have we learnt from animal models. Exp Neurol 2010, 225:2-8.
• [2]Di Filippo M, Chiasserini D, Tozzi A, Picconi B, Calabresi P: Mitochondria and the link between neuroinflammation and neurodegeneration. J Alzheimers Dis 2010, 20(Suppl 2):S369-S379.
• [3]van Horssen J, Witte ME, Schreibelt G, de Vries HE: Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta 2011, 1812:141-150.
• [4]Bal-Price A, Brown GC: Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 2001, 21:6480-6491.
• [5]Golde S, Chandran S, Brown GC, Compston A: Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression. J Neurochem 2002, 82:269-282.
• [6]Gray E, Ginty M, Kemp K, Scolding N, Wilkins A: Peroxisome proliferator-activated receptor-alpha agonists protect cortical neurons from inflammatory mediators and improve peroxisomal function. Eur J Neurosci 2011, 33:1421-1432.
• [7]Wilkins A, Compston A: Trophic factors attenuate nitric oxide mediated neuronal and axonal injury in vitro: roles and interactions of mitogen-activated protein kinase signalling pathways. J Neurochem 2005, 92:1487-1496.
• [8]Singh J, Khan M, Singh I: Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy. J Lipid Res 2009, 50:135-147.
• [9]Bottelbergs A, Verheijden S, Hulshagen L, Gutmann DH, Goebbels S, Nave KA, Kassmann C, Baes M: Axonal integrity in the absence of functional peroxisomes from projection neurons and astrocytes. Glia 2010, 58:1532-1543.
• [10]Kassmann CM, Lappe-Siefke C, Baes M, Brugger B, Mildner A, Werner HB, Natt O, Michaelis T, Prinz M, Frahm J, Nave KA: Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet 2007, 39:969-976.
• [11]Singh I, Paintlia AS, Khan M, Stanislaus R, Paintlia MK, Haq E, Singh AK, Contreras MA: Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment. Brain Res 2004, 1022:1-11.
• [12]Zhu Y, Alvares K, Huang Q, Rao MS, Reddy JK: Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J Biol Chem 1993, 268:26817-26820.
• [13]Burns KA, Vanden Heuvel JP: Modulation of PPAR activity via phosphorylation. Biochim Biophys Acta 2007, 1771:952-960.
• [14]Bernardo A, Ajmone-Cat MA, Gasparini L, Ongini E, Minghetti L: Nuclear receptor peroxisome proliferator-activated receptor-gamma is activated in rat microglial cells by the anti-inflammatory drug HCT1026, a derivative of flurbiprofen. J Neurochem 2005, 92:895-903.
• [15]Cimini A, Benedetti E, Cristiano L, Sebastiani P, D'Amico MA, D'Angelo B, Di Loreto S: Expression of peroxisome proliferator-activated receptors (PPARs) and retinoic acid receptors (RXRs) in rat cortical neurons. Neuroscience 2005, 130:325-337.
• [16]Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999, 20:649-688.
• [17]Escher P, Wahli W: Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 2000, 448:121-138.
• [18]Stumvoll M, Stefan N, Fritsche A, Madaus A, Tschritter O, Koch M, Machicao F, Haring H: Interaction effect between common polymorphisms in PPARgamma2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity. J Mol Med (Berl) 2002, 80:33-38.
• [19]Park SW, Yi JH, Miranpuri G, Satriotomo I, Bowen K, Resnick DK, Vemuganti R: Thiazolidinedione class of peroxisome proliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. J Pharmacol Exp Ther 2007, 320:1002-1012.
• [20]Ricote M, Huang J, Fajas L, Li A, Welch J, Najib J, Witztum JL, Auwerx J, Palinski W, Glass CK: Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA 1998, 95:7614-7619.
• [21]Bernardo A, Minghetti L: Regulation of Glial Cell Functions by PPAR-gamma Natural and Synthetic Agonists. PPAR Res 2008, 2008:864140.
• [22]Heneka MT, Landreth GE, Hull M: Drug insight: effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders. Nat Clin Pract Neurol 2007, 3:496-504.
• [23]Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB: Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 2004, 88:494-501.
• [24]Quinn LP, Crook B, Hows ME, Vidgeon-Hart M, Chapman H, Upton N, Medhurst AD, Virley DJ: The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B. Br J Pharmacol 2008, 154:226-233.
• [25]Quintanilla RA, Jin YN, Fuenzalida K, Bronfman M, Johnson GV: Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin-expressing cells: possible role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in the pathogenesis of Huntington disease. J Biol Chem 2008, 283:25628-25637.
• [26]Diab A, Deng C, Smith JD, Hussain RZ, Phanavanh B, Lovett-Racke AE, Drew PD, Racke MK: Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. J Immunol 2002, 168:2508-2515.
• [27]Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT: Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol 2002, 51:694-702.
• [28]Natarajan C, Bright JJ: Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation. Genes Immun 2002, 3:59-70.
• [29]Niino M, Iwabuchi K, Kikuchi S, Ato M, Morohashi T, Ogata A, Tashiro K, Onoe K: Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-gamma. J Neuroimmunol 2001, 116:40-48.
• [30]Peiris M, Monteith GR, Roberts-Thomson SJ, Cabot PJ: A model of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice for the characterisation of intervention therapies. J Neurosci Methods 2007, 163:245-254.
• [31]Raikwar HP, Muthian G, Rajasingh J, Johnson CN, Bright JJ: PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12,14-prostaglandin J2. J Neuroimmunol 2006, 178:76-86.
• [32]Bernardo A, Minghetti L: PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr Pharm Des 2006, 12:93-109.
• [33]Fuenzalida K, Quintanilla R, Ramos P, Piderit D, Fuentealba RA, Martinez G, Inestrosa NC, Bronfman M: Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis. J Biol Chem 2007, 282:37006-37015.
• [34]Heneka MT, Landreth GE: PPARs in the brain. Biochim Biophys Acta 2007, 1771:1031-1045.
• [35]Crosby MB, Svenson J, Gilkeson GS, Nowling TK: A novel PPAR response element in the murine iNOS promoter. Mol Immunol 2005, 42:1303-1310.
• [36]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.
• [37]Wilkins A, Chandran S, Compston A: A role for oligodendrocyte-derived IGF-1 in trophic support of cortical neurons. Glia 2001, 36:48-57.
• [38]Lee VM, Carden MJ, Schlaepfer WW, Trojanowski JQ: Monoclonal antibodies distinguish several differentially phosphorylated states of the two largest rat neurofilament subunits (NF-H and NF-M) and demonstrate their existence in the normal nervous system of adult rats. J Neurosci 1987, 7:3474-3488.
• [39]Amor S, Puentes F, Baker D, van der Valk P: Inflammation in neurodegenerative diseases. Immunology 2010, 129:154-169.
• [40]Colton CA, Gilbert DL: Microglia, an in vivo source of reactive oxygen species in the brain. Adv Neurol 1993, 59:321-326.
• [41]Barone FC, Feuerstein GZ: Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 1999, 19:819-834.
• [42]Ji H, Wang H, Zhang F, Li X, Xiang L, Aiguo S: PPARgamma agonist pioglitazone inhibits microglia inflammation by blocking p38 mitogen-activated protein kinase signaling pathways. Inflamm Res 2010, 59:921-929.
• [43]Storer PD, Xu J, Chavis J, Drew PD: Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis. J Neuroimmunol 2005, 161:113-122.
• [44]Xing B, Xin T, Hunter RL, Bing G: Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt. J Neuroinflammation 2008, 5:4. BioMed Central Full Text
• [45]Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzberg GW, Jones T, Cuzner ML, Myers R: The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000, 123:2321-2337.
• [46]Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W: Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 2000, 123:1174-1183.
• [47]Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L: Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998, 338:278-285.
• [48]Murphy S: Production of nitric oxide by glial cells: regulation and potential roles in the CNS. Glia 2000, 29:1-13.
• [49]Bernardo A, Bianchi D, Magnaghi V, Minghetti L: Peroxisome proliferator-activated receptor-gamma agonists promote differentiation and antioxidant defenses of oligodendrocyte progenitor cells. J Neuropathol Exp Neurol 2009, 68:797-808.
• [50]Hwang J, Kleinhenz DJ, Lassegue B, Griendling KK, Dikalov S, Hart CM: Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production. Am J Physiol Cell Physiol 2005, 288:C899-C905.
• [51]Shimazu T, Inoue I, Araki N, Asano Y, Sawada M, Furuya D, Nagoya H, Greenberg JH: A peroxisome proliferator-activated receptor-gamma agonist reduces infarct size in transient but not in permanent ischemia. Stroke 2005, 36:353-359.
• [52]Zhao X, Zhang Y, Strong R, Grotta JC, Aronowski J: 15d-Prostaglandin J2 activates peroxisome proliferator-activated receptor-gamma, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 2006, 26:811-820.