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Licensed Unlicensed Requires Authentication Published by De Gruyter September 6, 2013

Role of the peroxisome proliferator-activated receptors (PPAR)-α, β/δ and γ triad in regulation of reactive oxygen species signaling in brain

  • Stepan Aleshin

    Stepan Aleshin graduated in 2006 at Biological Department of Moscow State University (MSU), Russian Federation. In 2009 he received his PhD in Biochemistry and Molecular Biology at the Faculty of Bioengineering and Bioinformatics of MSU. Since 2010 he works at the Institute of Neurobiochemistry of Otto-von-Guericke University, Magdeburg as postdoctoral fellow. His main scientific interest is deciphering the mechanisms of roles of Peroxisome Proliferators Activated Receptors (PPAR) in brain diseases.

    and Georg Reiser

    Georg Reiser did his PhD at the Max-Planck Institute of Biochemistry in Martinsried and the Ludwig-Maximilians University in Munich under the supervision of B. Hamprecht in the Department of F. Lynen. After working as research fellow in the Institute for Physiological Chemistry in Wurzburg, he obtained a DFG-fellowship with further training in electrophysiology at the University College London, Department of Biophysics under R. Miledi. There, he studied nicotinic acetylcholine receptor ion channels. From 1984 he continued research in mechanisms of neural molecular signaling, focusing on calcium regulation and identification of the inositol(1,3,4,5)P4 receptor protein. From 1994 he is Professor of Neurochemistry in Magdeburg, Medical Faculty researching on various molecular mechanisms of neuroprotection in ischemia and stroke, covering functions of mitochondria, protease-activated receptors, P2Y nucleotide receptors, nuclear Peroxisome Proliferators Activated Receptors, and iPLA2isoforms.

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From the journal Biological Chemistry

Abstract

Overwhelming evidence shows that oxidative stress is a major cause in development of brain disorders. Low activity of the reactive oxygen species (ROS)-degrading system as well as high levels of oxidative damage markers have been observed in brain tissue of patients with neurodegenerative and other brain diseases to a larger extent than in healthy individuals. Many studies aimed to develop effective and safe antioxidant strategies for the therapy or prevention of brain diseases. Nevertheless, it became clear that rigorous suppression of ROS is deleterious for normal cell functioning. Thus, approaches that can regulate the ROS levels over a wide range, from inhibition to induction, will be a powerful tool for neuroprotection. A most prominent target for such ROS management is the family of peroxisome proliferator-activated receptors (PPARs). All three members (PPAR-α, -β/δ and -γ) of this nuclear receptor subfamily form a tightly connected triad. For individual PPAR isoforms, neuroprotective properties have been well proven. Their involvement in regulation of ROS production and degradation underlies the therapeutic effects. Nevertheless, the current paradigms of the involvement of PPAR in neuroprotective therapy ignore such interconnections of PPARs and aim at antioxidant effects of individual PPAR isoforms, but do not take into account the necessity of careful regulation of ROS levels. The present review (i) summarizes the data, which support the concept of the PPAR triad in brain, (ii) demonstrates that usage of the PPAR triad allows the regulation of PPAR-dependent genes over a wide range, from inhibition to upregulation, and (iii) summarizes the known data concerning the PPAR triad involvement in regulation of ROS. Our report opens new directions in the field of PPAR/ROS-related neuroscience research.


Corresponding author: Georg Reiser, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Straße 44, D-39120 Magdeburg, Germany, e-mail:

About the authors

Stepan Aleshin

Stepan Aleshin graduated in 2006 at Biological Department of Moscow State University (MSU), Russian Federation. In 2009 he received his PhD in Biochemistry and Molecular Biology at the Faculty of Bioengineering and Bioinformatics of MSU. Since 2010 he works at the Institute of Neurobiochemistry of Otto-von-Guericke University, Magdeburg as postdoctoral fellow. His main scientific interest is deciphering the mechanisms of roles of Peroxisome Proliferators Activated Receptors (PPAR) in brain diseases.

Georg Reiser

Georg Reiser did his PhD at the Max-Planck Institute of Biochemistry in Martinsried and the Ludwig-Maximilians University in Munich under the supervision of B. Hamprecht in the Department of F. Lynen. After working as research fellow in the Institute for Physiological Chemistry in Wurzburg, he obtained a DFG-fellowship with further training in electrophysiology at the University College London, Department of Biophysics under R. Miledi. There, he studied nicotinic acetylcholine receptor ion channels. From 1984 he continued research in mechanisms of neural molecular signaling, focusing on calcium regulation and identification of the inositol(1,3,4,5)P4 receptor protein. From 1994 he is Professor of Neurochemistry in Magdeburg, Medical Faculty researching on various molecular mechanisms of neuroprotection in ischemia and stroke, covering functions of mitochondria, protease-activated receptors, P2Y nucleotide receptors, nuclear Peroxisome Proliferators Activated Receptors, and iPLA2isoforms.

The study in the authors’ laboratory was supported by grants from Bundesministerium für Bildung und Forschung (BMBF).

Conflict of interest statement

None to declare.

References

Aleshin, S., Grabeklis, S., Hanck, T., Sergeeva, M., and Reiser, G. (2009). Peroxisome proliferator-activated receptor (PPAR)-γ positively controls and PPARα negatively controls cyclooxygenase-2 expression in rat brain astrocytes through a convergence on PPARβ/δ via mutual control of PPAR expression levels. Mol. Pharmacol. 76, 414–424.10.1124/mol.109.056010Search in Google Scholar PubMed

Aleshin, S., Strokin, M., Sergeeva, M., and Reiser, G. (2013). Peroxisome proliferator-activated receptor (PPAR)β/δ, a possible nexus of PPARα- and PPARγ- dependent molecular pathways in neurodegenerative diseases; review and novel hypotheses. Neurochem. Int. 63, 322–330.10.1016/j.neuint.2013.06.012Search in Google Scholar PubMed

Ansari, M.A. and Scheff, S.W. (2011). NADPH-oxidase activation and cognition in Alzheimer disease progression. Free Radic. Biol. Med. 51, 171–178.10.1016/j.freeradbiomed.2011.03.025Search in Google Scholar PubMed PubMed Central

Antonenkov, V.D., Grunau, S., Ohlmeier, S., and Hiltunen, J.K. (2010). Peroxisomes are oxidative organelles. Antioxid. Redox Signal. 13, 525–537.10.1089/ars.2009.2996Search in Google Scholar PubMed

Armogida, M., Nistico, R., and Mercuri, N.B. (2012). Therapeutic potential of targeting hydrogen peroxide metabolism in the treatment of brain ischaemia. Br. J. Pharmacol. 166, 1211–1224.10.1111/j.1476-5381.2012.01912.xSearch in Google Scholar PubMed PubMed Central

Arsenijevic, D., de Bilbao, F., Plamondon, J., Paradis, E., Vallet, P., Richard, D., Langhans, W., and Giannakopoulos, P. (2006). Increased infarct size and lack of hyperphagic response after focal cerebral ischemia in peroxisome proliferator-activated receptor β-deficient mice. J. Cereb. Blood Flow Metab. 26, 433–445.10.1038/sj.jcbfm.9600200Search in Google Scholar PubMed

Aubourg, P. and Wanders, R. (2013). Peroxisomal disorders. Handb. Clin. Neurol. 113, 1593–1609.10.1016/B978-0-444-59565-2.00028-9Search in Google Scholar PubMed

Bastin, J., Aubey, F., Rotig, A., Munnich, A., and Djouadi, F. (2008). Activation of peroxisome proliferator-activated receptor pathway stimulates the mitochondrial respiratory chain and can correct deficiencies in patients’ cells lacking its components. J. Clin. Endocrinol. Metab. 93, 1433–1441.10.1210/jc.2007-1701Search in Google Scholar PubMed

Battistini, S., Ricci, C., Lotti, E.M., Benigni, M., Gagliardi, S., Zucco, R., Bondavalli, M., Marcello, N., Ceroni, M., and Cereda, C. (2010). Severe familial ALS with a novel exon 4 mutation (L106F) in the SOD1 gene. J. Neurol. Sci. 293, 112–115.10.1016/j.jns.2010.03.009Search in Google Scholar PubMed

Becker, J., Delayre-Orthez, C., Frossard, N., and Pons, F. (2008). Regulation of peroxisome proliferator-activated receptor-α expression during lung inflammation. Pulm. Pharmacol. Ther. 21, 324–330.10.1016/j.pupt.2007.08.001Search in Google Scholar PubMed

Bellinger, F.P., Bellinger, M.T., Seale, L.A., Takemoto, A.S., Raman, A.V., Miki, T., Manning-Boğ, A.B., Berry, M.J., White, L.R., and Ross, G.W. (2011). Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson’s brain. Mol. Neurodegener. 6, 8.10.1186/1750-1326-6-8Search in Google Scholar PubMed PubMed Central

Bernardo, A., Bianchi, D., Magnaghi, V., and Minghetti, L. (2009). Peroxisome proliferator-activated receptor-γ agonists promote differentiation and antioxidant defenses of oligodendrocyte progenitor cells. J. Neuropathol. Exp. Neurol. 68, 797–808.10.1097/NEN.0b013e3181aba2c1Search in Google Scholar PubMed

Bhateja, D.K., Dhull, D.K., Gill, A., Sidhu, A., Sharma, S., Reddy, B.V., and Padi, S.S. (2012). Peroxisome proliferator-activated receptor-α activation attenuates 3-nitropropionic acid-induced behavioral and biochemical alterations in rats: possible neuroprotective mechanisms. Eur. J. Pharmacol. 674, 33–43.10.1016/j.ejphar.2011.10.029Search in Google Scholar PubMed

Bordet, R., Ouk, T., Petrault, O., Gelé, P., Gautier, S., Laprais, M., Deplanque, D., Duriez, P., Staels, B., Fruchart, J.C., and Bastide, M. (2006). PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem. Soc. Trans. 34, 1341–1346.10.1042/BST0341341Search in Google Scholar PubMed

Chakravarthy, M.V., Zhu, Y., Lopez, M., Yin, L., Wozniak, D.F., Coleman, T., Hu, Z., Wolfgang, M., Vidal-Puig, A., Lane, M.D., et al. (2007). Brain fatty acid synthase activates PPARα to maintain energy homeostasis. J. Clin. Invest. 117, 2539–2552.10.1172/JCI31183Search in Google Scholar PubMed PubMed Central

Chen, X.R., Besson, V.C., Palmier, B., Garcia, Y., Plotkine, M., and Marchand-Leroux, C. (2007). Neurological recovery-promoting, anti-inflammatory, and anti-oxidative effects afforded by fenofibrate, a PPAR alpha agonist, in traumatic brain injury. J. Neurotrauma 24, 1119–1131.10.1089/neu.2006.0216Search in Google Scholar PubMed

Choi, D.H., Cristovao, A.C., Guhathakurta, S., Lee, J., Joh, T.H., Beal, M.F., and Kim, Y.S. (2012). NADPH oxidase 1-mediated oxidative stress leads to dopamine neuron death in Parkinson’s disease. Antioxid. Redox Signal. 16, 1033–1045.10.1089/ars.2011.3960Search in Google Scholar PubMed PubMed Central

Chuang, Y.C., Lin, T.K., Huang, H.Y., Chang, W.N., Liou, C.W., Chen, S.D., Chang, A.Y., and Chan, S.H. (2012). Peroxisome proliferator-activated receptors γ/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus. J. Neuroinflammation 9, 184.10.1186/1742-2094-9-184Search in Google Scholar PubMed PubMed Central

Cimini, A., Benedetti, E., Cristiano, L., Sebastiani, P., D’Amico, M.A., D’Angelo, B., and Di Loreto, S. (2005). Expression of peroxisome proliferator-activated receptors (PPARs) and retinoic acid receptors (RXRs) in rat cortical neurons. Neuroscience 130, 325–337.10.1016/j.neuroscience.2004.09.043Search in Google Scholar PubMed

Collino, M., Aragno, M., Mastrocola, R., Benetti, E., Gallicchio, M., Dianzani, C., Danni, O., Thiemermann, C., and Fantozzi, R. (2006a). Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: effects of the PPAR-α agonist WY14643. Free Radic. Biol. Med. 41, 579–589.10.1016/j.freeradbiomed.2006.04.030Search in Google Scholar PubMed

Collino, M., Aragno, M., Mastrocola, R., Gallicchio, M., Rosa, A.C., Dianzani, C., Danni, O., Thiemermann, C., and Fantozzi, R. (2006b). Modulation of the oxidative stress and inflammatory response by PPAR-γ agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. Eur. J. Pharmacol. 530, 70–80.10.1016/j.ejphar.2005.11.049Search in Google Scholar

Crosby, M.B., Svenson, J., Gilkeson, G.S., and Nowling, T.K. (2005). A novel PPAR response element in the murine iNOS promoter. Mol. Immunol. 42, 1303–1310.10.1016/j.molimm.2004.12.009Search in Google Scholar

Cullingford, T.E., Dolphin, C.T., and Sato, H. (2002). The peroxisome proliferator-activated receptor α-selective activator ciprofibrate upregulates expression of genes encoding fatty acid oxidation and ketogenesis enzymes in rat brain. Neuropharmacol. 42, 724–730.10.1016/S0028-3908(02)00014-XSearch in Google Scholar

Daff, S. (2010). NO synthase: structures and mechanisms. Nitric Oxide 23, 1–11.10.1016/j.niox.2010.03.001Search in Google Scholar

Damier, P., Hirsch, E.C., Zhang, P., Agid, Y., and Javoy-Agid, F. (1993). Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52, 1–6.10.1016/0306-4522(93)90175-FSearch in Google Scholar

Defaux, A., Zurich, M.G., Braissant, O., Honegger, P., and Monnet-Tschudi, F. (2009). Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination. J. Neuroinflammation 6, 15.10.1186/1742-2094-6-15Search in Google Scholar PubMed PubMed Central

Fan, Y., Wang, Y., Tang, Z., Zhang, H., Qin, X., Zhu, Y., Guan, Y., Wang, X., Staels, B., Chien, S., et al., (2008). Suppression of pro-inflammatory adhesion molecules by PPAR-δ in human vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 28, 315–321.10.1161/ATVBAHA.107.149815Search in Google Scholar PubMed

Fransen, M., Nordgren, M., Wang, B., and Apanasets, O. (2012). Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochim. Biophys. Acta 1822, 1363–1373.10.1016/j.bbadis.2011.12.001Search in Google Scholar PubMed

Garcia-Bueno, B., Madrigal, J.L., Lizasoain, I., Moro, M.A., Lorenzo, P., and Leza, J.C. (2005). Peroxisome proliferator-activated receptor gamma activation decreases neuroinflammation in brain after stress in rats. Biol. Psychiatry 57, 885–894.10.1016/j.biopsych.2005.01.007Search in Google Scholar PubMed

Girnun, G.D., Domann, F.E., Moore, S.A., and Robbins, M.E. (2002). Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter. Mol. Endocrinol. 16, 2793–2801.10.1210/me.2002-0020Search in Google Scholar PubMed

Glatz, T., Stock, I., Nguyen-Ngoc, M., Gohlke, P., Herdegen, T., Culman, J., and Zhao, Y. (2010). Peroxisome-proliferator-activated receptors γ and peroxisome-proliferator-activated receptors β/δ and the regulation of interleukin 1 receptor antagonist expression by pioglitazone in ischaemic brain. J. Hypertens. 28, 1488–1497.10.1097/HJH.0b013e3283396e4eSearch in Google Scholar

Gray, E., Ginty, M., Kemp, K., Scolding, N., and Wilkins, A. (2011). Peroxisome proliferator-activated receptor-α agonists protect cortical neurons from inflammatory mediators and improve peroxisomal function. Eur. J. Neurosci. 33, 1421–1432.10.1111/j.1460-9568.2011.07637.xSearch in Google Scholar

Gray, E., Ginty, M., Kemp, K., Scolding, N., and Wilkins, A. (2012). The PPAR-γ agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function. J. Neuroinflammation 9, 63.10.1186/1742-2094-9-63Search in Google Scholar

Heneka, M.T. and Landreth, G.E. (2007). PPARs in brain. Biochim. Biophys. Acta. 1771, 1031–1045.10.1016/j.bbalip.2007.04.016Search in Google Scholar

Inoue, I., Noji, S., Awata, T., Takahashi, K., Nakajima, T., Sonoda, M., Komoda, T., and Katayama, S. (1998). Bezafibrate has an antioxidant effect: peroxisome proliferator-activated receptor α is associated with Cu2+, Zn2+-superoxide dismutase in the liver. Life Sci. 63, 135–144.10.1016/S0024-3205(98)00249-5Search in Google Scholar

Jin, Y.N., Hwang, W.Y., Jo, C., and Johnson, G.V. (2012). Metabolic state determines sensitivity to cellular stress in Huntington disease: normalization by activation of PPARγ. PLoS One 7, e30406.10.1371/journal.pone.0030406Search in Google Scholar

Jung, T.W., Lee, J.Y., Shim, W.S., Kang, E.S., Kim, S.K., Ahn, C.W., Lee, H.C., and Cha, B.S. (2007). Rosiglitazone protects human neuroblastoma SH-SY5Y cells against MPP+ induced cytotoxicity via inhibition of mitochondrial dysfunction and ROS production. J. Neurol. Sci. 253, 53–60.10.1016/j.jns.2006.11.020Search in Google Scholar

Kalonia, H., Kumar, P., and Kumar, A. (2010). Pioglitazone ameliorates behavioral, biochemical and cellular alterations in quinolinic acid-induced neurotoxicity: possible role of peroxisome proliferator activated receptor-γ (PPARγ) in Huntington’s disease. Pharmacol. Biochem. Behav. 96, 115–124.10.1016/j.pbb.2010.04.018Search in Google Scholar

Kang, J., Yang, M., Jou, I., and Joe, E. (2001). Identification of protein kinase C isoforms involved in interferon-gamma-induced expression of inducible nitric oxide synthase in murine BV2 microglia. Neurosci. Lett. 299, 205–208.10.1016/S0304-3940(01)01515-4Search in Google Scholar

Kaur, B., Singh, N., and Jaggi, A.S. (2009). Exploring mechanism of pioglitazone-induced memory restorative effect in experimental dementia. Fundam. Clin. Pharmacol. 23, 557–566.10.1111/j.1472-8206.2009.00708.xSearch in Google Scholar PubMed

Kersten, S., Mandard, S., Escher, P., Gonzalez, F.J., Tafuri, S., Desvergne, B., and Wahli, W. (2001). The peroxisome proliferator-activated receptor α regulates amino acid metabolism. FASEB J. 15, 1971–1978.10.1096/fj.01-0147comSearch in Google Scholar PubMed

Kim, D.J., Murray, I.A., Burns, A.M., Gonzalez, F.J., Perdew, G.H., and Peters, J.M. (2005). Peroxisome proliferator-activated receptor-β/δ inhibits epidermal cell proliferation by down-regulation of kinase activity. J. Biol. Chem. 280, 9519–9527.10.1074/jbc.M413808200Search in Google Scholar PubMed

Kim, H.J., Ham, S.A., Paek, K.S., Hwang JS, Jung SY, Kim MY, Jin H, Kang ES, Woo IS, Kim HJ, et al., (2011). Transcriptional up-regulation of antioxidant genes by PPARδ inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 406, 564–569.10.1016/j.bbrc.2011.02.091Search in Google Scholar PubMed

Kim, Y.C., Park, T.Y., Baik, E., and Lee, S.H. (2012). Fructose-1,6-bisphosphate attenuates induction of nitric oxide synthase in microglia stimulated with lipopolysaccharide. Life Sci. 90, 365–372.10.1016/j.lfs.2011.12.011Search in Google Scholar PubMed

Kinouchi, H., Epstein, C.J., Mizui, T., Carlson, E., Chen, S.F., and Chan, P.H. (1991). Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc. Natl. Acad. Sci. USA 88, 11158–11162.10.1073/pnas.88.24.11158Search in Google Scholar PubMed PubMed Central

Knott, A.B. and Bossy-Wetzel, E. (2009). Nitric oxide in health and disease of the nervous system. Antioxid. Redox Signal. 11, 541–554.10.1089/ars.2008.2234Search in Google Scholar PubMed PubMed Central

Krey, G., Braissant, O., L’Horset, F., Kalkhoven, E., Perroud, M., Parker, M.G., and Wahli, W. (1997). Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol. Endocrinol. 11, 779–791.10.1210/mend.11.6.0007Search in Google Scholar PubMed

Lambeth, J.D. (2004). NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181–189.10.1038/nri1312Search in Google Scholar PubMed

Lee, T.I., Kao, Y.H., Chen, Y.C., and Chen, Y.J. (2009). Proinflammatory cytokine and ligands modulate cardiac peroxisome proliferator-activated receptors. Eur. J. Clin. Invest. 39, 23–30.10.1111/j.1365-2362.2008.02062.xSearch in Google Scholar PubMed

Leisewitz, A.V., Urrutia, C.R., Martinez, G.R., Loyola, G., and Bronfman, M. (2008). A PPARs cross-talk concertedly commits C6 glioma cells to oligodendrocytes and induces enzymes involved in myelin synthesis. J. Cell Physiol. 217, 367–376.10.1002/jcp.21509Search in Google Scholar PubMed

Lemay, D.G. and Hwang, D.H. (2006). Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics. J. Lipid Res. 47, 1583–1587.10.1194/jlr.M500504-JLR200Search in Google Scholar

Li, X., Du, J., Xu, S., Lin, X., and Ling, Z. (2013). Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces secondary damage in experimental spinal cord injury. J. Int. Med. Res. 41, 153–161.10.1177/0300060513476601Search in Google Scholar

Lin, M.T. and Beal, M.F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795.10.1038/nature05292Search in Google Scholar

Linscheid, P., Keller, U., Blau, N., Schaer, D.J., and Muller, B. (2003). Diminished production of nitric oxide synthase cofactor tetrahydrobiopterin by rosiglitazone in adipocytes. Biochem. Pharmacol. 65, 593–598.10.1016/S0006-2952(02)01562-9Search in Google Scholar

Liu, N., Qiang, W., Kuang, X., Thuillier, P., Lynn, W.S., and Wong, P.K. (2002). The peroxisome proliferator phenylbutyric acid (PBA) protects astrocytes from ts1 MoMuLV-induced oxidative cell death. J. Neurovirol. 8, 318–325.10.1080/13550280290100699Search in Google Scholar PubMed

Liu, X., Luo, D., Zheng, M., Hao, Y., Hou, L., and Zhang, S. (2010). Effect of pioglitazone on insulin resistance in fructose-drinking rats correlates with AGEs/RAGE inhibition and block of NADPH oxidase and NF kappa B activation. Eur. J. Pharmacol. 629, 153–158.10.1016/j.ejphar.2009.11.059Search in Google Scholar PubMed

Liu, J., Wang, P., Luo, J., Huang, Y., He, L., Yang, H., Li, Q., Wu, S., Zhelyabovska, O., and Yang, Q. (2011). Peroxisome proliferator-activated receptor β/δ activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition. Hypertension 57, 223–230.10.1161/HYPERTENSIONAHA.110.164590Search in Google Scholar PubMed PubMed Central

Loh, K.P., Huang, S.H., De Silva, R., Tan, B.K., and Zhu, Y.Z. (2006). Oxidative stress: apoptosis in neuronal injury. Curr. Alzheimer Res. 3, 327–337.10.2174/156720506778249515Search in Google Scholar PubMed

Luo, Y., Yin, W., Signore, A.P., Zhang, F., Hong, Z., Wang, S., Graham, S.H., and Chen, J. (2006). Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone. J. Neurochem. 97, 435–448.10.1111/j.1471-4159.2006.03758.xSearch in Google Scholar PubMed

Madrigal, J.L., Garcia-Bueno, B., Caso, J.R., Perez-Nievas, B.G., and Leza, J.C. (2006). Stress-induced oxidative changes in brain. CNS Neurol. Disord. Drug Targets 5, 561–568.10.2174/187152706778559327Search in Google Scholar PubMed

Madrigal, J.L., Kalinin, S., Richardson, J.C., and Feinstein, D.L. (2007). Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta. J. Neurochem. 103, 2092–2101.10.1111/j.1471-4159.2007.04888.xSearch in Google Scholar

Maier, C.M. and Chan, P.H. (2002). Role of superoxide dismutases in oxidative damage and neurodegenerative disorders. Neuroscientist 8, 323–334.10.1177/107385840200800408Search in Google Scholar

Marklund, S.L., Holme, E., and Hellner, L. (1982). Superoxide dismutase in extracellular fluids. Clin. Chim. Acta. 126, 41–51.10.1016/0009-8981(82)90360-6Search in Google Scholar

Mattson, M.P. (2007). Calcium and neurodegeneration. Aging Cell 6, 337–350.10.1111/j.1474-9726.2007.00275.xSearch in Google Scholar

Medhi, B., Aggarwal, R., and Chakrabarti, A. (2010). Neuroprotective effect of pioglitazone on acute phase changes induced by partial global cerebral ischemia in mice. Indian J. Exp. Biol. 48, 793–799.Search in Google Scholar

Miglio, G., Rosa, A.C., Rattazzi, L., Collino, M., Lombardi, G., and Fantozzi, R. (2009). PPARγ stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss. Neurochem. Int. 55, 496–504.10.1016/j.neuint.2009.05.001Search in Google Scholar

Mohagheghi, F., Khalaj, L., Ahmadiani, A., and Rahmani, B. (2013). 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. Neurotox. Res. 23, 225–237.10.1007/s12640-012-9338-3Search in Google Scholar

Murakami, K., Kondo, T., Kawase, M., Li, Y., Sato, S., Chen, S.F., and Chan, P.H. (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, 205–213.10.1523/JNEUROSCI.18-01-00205.1998Search in Google Scholar

Nagra, R.M., Becher, B., Tourtellotte, W.W., Antel, J.P., Gold, D., Paladino, T., Smith, R.A., Nelson, J.R., and Reynolds, W.F. (1997). Immunohistochemical and genetic evidence of myeloperoxidase involvement in multiple sclerosis. J. Neuroimmunol. 78, 97–107.10.1016/S0165-5728(97)00089-1Search in Google Scholar

Newaz, M., Blanton, A., Fidelis, P., and Oyekan, A. (2005). NAD(P)H oxidase/nitric oxide interactions in peroxisome proliferator activated receptor (PPAR)α-mediated cardiovascular effects. Mutat. Res. 579, 163–171.10.1016/j.mrfmmm.2005.02.024Search in Google Scholar PubMed

Oliver, C.N., Starke-Reed, P.E., Stadtman, E.R., Liu, G.J., Carney, J.M., and Floyd, R.A. (1990). Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion-induced injury to gerbil brain. Proc. Natl. Acad. Sci. USA 87, 5144–5147.10.1073/pnas.87.13.5144Search in Google Scholar PubMed PubMed Central

Ott, M., Gogvadze, V., Orrenius, S., and Zhivotovsky, B. (2007). Mitochondria, oxidative stress and cell death. Apoptosis 12, 913–922.10.1007/s10495-007-0756-2Search in Google Scholar PubMed

Paintlia, A.S., Paintlia, M.K., Singh, I., and Singh, A.K. (2006). IL-4-induced peroxisome proliferator-activated receptor gamma activation inhibits NF-κB trans activation in central nervous system (CNS) glial cells and protects oligodendrocyte progenitors under neuroinflammatory disease conditions: implication for CNS-demyelinating diseases. J. Immunol. 176, 4385–4398.10.4049/jimmunol.176.7.4385Search in Google Scholar PubMed

Patten, D.A., Germain, M., Kelly, M.A., and Slack, R.S. (2010). Reactive oxygen species: stuck in the middle of neurodegeneration. J. Alzheimers Dis. 20 (Suppl 2), S357–S367.10.3233/JAD-2010-100498Search in Google Scholar PubMed

Pesant, M., Sueur, S., Dutartre, P., Tallandier, M., Grimaldi, P.A., Rochette, L., and Connat, J.L. (2006). Peroxisome proliferator-activated receptor δ (PPARδ) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis. Cardiovasc. Res. 69, 440–449.10.1016/j.cardiores.2005.10.019Search in Google Scholar PubMed

Polak, P.E., Kalinin, S., Dello Russo, C., Gavrilyuk, V., Sharp, A., Peters, J.M., Richardson, J., Willson, T.M., Weinberg, G., and Feinstein, D.L. (2005). Protective effects of a peroxisome proliferator-activated receptor-β/δ agonist in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 168, 65–75.10.1016/j.jneuroim.2005.07.006Search in Google Scholar PubMed

Radermacher, K.A., Wingler, K., Langhauser, F., Altenhofer, S., Kleikers, P., Hermans, J.J., Hrabe de Angelis, M., Kleinschnitz, C., and Schmidt, H.H. (2013). Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress. Antioxid. Redox Signal. 18, 1418–1427.10.1089/ars.2012.4797Search in Google Scholar PubMed PubMed Central

Reiter, R.J., Tan, D.X., Osuna, C., and Gitto, E. (2000). Actions of melatonin in the reduction of oxidative stress. A review. J. Biomed. Sci. 7, 444–458.10.1007/BF02253360Search in Google Scholar PubMed

Ricote, M. and Glass, C.K. (2007). PPARs and molecular mechanisms of transrepression. Biochim. Biophys. Acta. 1771, 926–935.10.1016/j.bbalip.2007.02.013Search in Google Scholar PubMed PubMed Central

Ristow, M. and Schmeisser, S. (2011). Extending life span by increasing oxidative stress. Free Radic. Biol. Med. 51, 327–336.10.1016/j.freeradbiomed.2011.05.010Search in Google Scholar PubMed

Sain, H., Sharma, B., Jaggi, A.S., and Singh, N. (2011). Pharmacological investigations on potential of peroxisome proliferator-activated receptor-γ agonists in hyperhomocysteinemia-induced vascular dementia in rats. Neuroscience 192, 322–333.10.1016/j.neuroscience.2011.07.002Search in Google Scholar PubMed

Sanguino, E., Ramon, M., Roglans, N., Alegret, M., Sanchez, R.M., Vazquez-Carrera, M., and Laguna, J.C. (2003). Gemfibrozil increases the specific binding of rat-cortex nuclear extracts to a PPRE probe. Life Sci. 73, 2927–2937.10.1016/j.lfs.2003.04.001Search in Google Scholar

Santhanam, A.V., d’Uscio, L.V., He, T., and Katusic, Z.S. (2012). PPARδ agonist GW501516 prevents uncoupling of endothelial nitric oxide synthase in cerebral microvessels of hph-1 mice. Brain Res. 1483, 89–95.10.1016/j.brainres.2012.09.012Search in Google Scholar

Santos, M.J., Quintanilla, R.A., Toro, A., Grandy, R., Dinamarca, M.C., Godoy, J.A., and Inestrosa, N.C. (2005). Peroxisomal proliferation protects from β-amyloid neurodegeneration. J. Biol. Chem. 280, 41057–41068.10.1074/jbc.M505160200Search in Google Scholar

Schnegg, C.I., Greene-Schloesser, D., Kooshki, M., Payne, V.S., Hsu, F.C., and Robbins, M.E. (2013). The PPARdelta agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation. Free Radic. Biol. Med. 61C, 1–9.Search in Google Scholar

Schock, S.C., Xu, J., Duquette, P.M., Qin, Z., Lewandowski, A.J., Rai, P.S., Thompson, C.S., Seifert, E.L., Harper, M.E., and Chen, H.H. (2008). Rescue of neurons from ischemic injury by peroxisome proliferator-activated receptor-γ requires a novel essential cofactor LMO4. J. Neurosci. 28, 12433–12444.10.1523/JNEUROSCI.2897-08.2008Search in Google Scholar

Sergeeva, M.G., Aleshin, S.E., Grabeklis, S., and Reiser, G. (2010). PPAR activation has dichotomous control on the expression levels of cytosolic and secretory phospholipase A2 in astrocytes; inhibition in naive, untreated cells and enhancement in LPS-stimulated cells. J. Neurochem. 115, 399–410.10.1111/j.1471-4159.2010.06931.xSearch in Google Scholar

Shear, D.A., Dong, J., Gundy, C.D., Haik-Creguer, K.L., and Dunbar, G.L. (1998). Comparison of intrastriatal injections of quinolinic acid and 3-nitropropionic acid for use in animal models of Huntington’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry. 22, 1217–1240.Search in Google Scholar

Sheng, H., Brady, T.C., Pearlstein, R.D., Crapo, J.D., and Warner, D.S. (1999). Extracellular superoxide dismutase deficiency worsens outcome from focal cerebral ischemia in the mouse. Neurosci. Lett. 267, 13–16.10.1016/S0304-3940(99)00316-XSearch in Google Scholar

Shi, Y., Hon, M., and Evans, R.M. (2002). The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling. Proc. Natl. Acad. Sci. USA 99, 2613–2618.10.1073/pnas.052707099Search in Google Scholar PubMed PubMed Central

Shimazu, T., Inoue, I., Araki, N., Asano, Y., Sawada, M., Furuya, D., Nagoya, H., and Greenberg, J.H. (2005). A peroxisome proliferator-activated receptor-γ agonist reduces infarct size in transient but not in permanent ischemia. Stroke 36, 353–359.10.1161/01.STR.0000152271.21943.a2Search in Google Scholar PubMed

Singh, B., Sharma, B., Jaggi, A.S., and Singh, N. (2013). Attenuating effect of lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer’s disease type: possible involvement of PPAR-γ agonistic property. J. Renin Angiotensin Aldosterone Syst. 14, 124–135.10.1177/1470320312459977Search in Google Scholar PubMed

Smith, C.D., Carney, J.M., Starke-Reed, P.E., Oliver, C.N., Stadtman, E.R., Floyd, R.A., and Markesbery, W.R. (1991). Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc. Natl. Acad. Sci. USA 88, 10540–10543.10.1073/pnas.88.23.10540Search in Google Scholar PubMed PubMed Central

Stefanova, N., Georgievska, B., Eriksson, H., Poewe, W., and Wenning, G.K. (2012). Myeloperoxidase inhibition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Neurotox. Res. 21, 393–404.10.1007/s12640-011-9294-3Search in Google Scholar

Sterin-Borda, L., Ganzinelli, S., Berra, A., and Borda, E. (2003). Novel insight into the mechanisms involved in the regulation of the m1 muscarinic receptor, iNOS and nNOS mRNA levels. Neuropharmacol. 45, 260–269.10.1016/S0028-3908(03)00141-2Search in Google Scholar

Sun, X., Tang, Y., Tan, X., Li, Q., Zhong, W., Jia, W., McClain, C.J., and Zhou, Z. (2012). Activation of peroxisome proliferator-activated receptor-γ by rosiglitazone improves lipid homeostasis at the adipose tissue-liver axis in ethanol-fed mice. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G548–557.10.1152/ajpgi.00342.2011Search in Google Scholar

Takizawa, S., Matsushima, K., Shinohara, Y., Ogawa, S., Komatsu, N., Utsunomiya, H., and Watanabe, K. (1994). Immunohistochemical localization of glutathione peroxidase in infarcted human brain. J. Neurol. Sci. 122, 66–73.10.1016/0022-510X(94)90053-1Search in Google Scholar

Teissier, E., Nohara, A., Chinetti, G., Paumelle, R., Cariou, B., Fruchart, J.C., Brandes, R.P., Shah, A., and Staels, B. (2004). Peroxisome proliferator-activated receptor α induces NADPH oxidase activity in macrophages, leading to the generation of LDL with PPAR-α activation properties. Circ. Res. 95, 1174–1182.10.1161/01.RES.0000150594.95988.45Search in Google Scholar PubMed

Tureyen, K., Kapadia, R., Bowen, K.K., Satriotomo, I., Liang, J., Feinstein, D.L., and Vemuganti, R. (2007). Peroxisome proliferator-activated receptor-γ agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. J. Neurochem. 101, 41–56.10.1111/j.1471-4159.2006.04376.xSearch in Google Scholar PubMed

Van Veldhoven, P.P. (2010). Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J. Lipid Res. 51, 2863–2895.10.1194/jlr.R005959Search in Google Scholar PubMed PubMed Central

Walters, M.W. and Wallace, K.B. (2010). Urea cycle gene expression is suppressed by PFOA treatment in rats. Toxicol. Lett. 197, 46–50.10.1016/j.toxlet.2010.04.027Search in Google Scholar PubMed

Wan, B. and Moreadith, R.W. (1995). Structural characterization and regulatory element analysis of the heart isoform of cytochrome c oxidase VIa. J. Biol. Chem. 270, 26433–26440.10.1074/jbc.270.44.26433Search in Google Scholar PubMed

Wang, Y.X., Zhang, C.L., Yu, R.T., Cho, H.K., Nelson, M.C., Bayuga-Ocampo, C.R., Ham, J., Kang, H., and Evans, R.M. (2004). Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biol. 2, e294.10.1371/journal.pbio.0020294Search in Google Scholar PubMed PubMed Central

Wang, J.Y., Wen, L.L., Huang, Y.N., Chen, Y.T., and Ku, M.C. (2006a). Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation. Curr. Pharm. Des. 12, 3521–3533.10.2174/138161206778343109Search in Google Scholar PubMed

Wang, Z.J., Liang, C.L., Li, G.M., Yu, C.Y., and Yin, M. (2006b). Neuroprotective effects of arachidonic acid against oxidative stress on rat hippocampal slices. Chem. Biol. Interact. 163, 207–217.10.1016/j.cbi.2006.08.005Search in Google Scholar PubMed

Wang, Z.J., Liang, C.L., Li, G.M., Yu, C.Y., and Yin, M. (2007). Stearic acid protects primary cultured cortical neurons against oxidative stress. Acta. Pharmacol. Sin. 28, 315–326.10.1111/j.1745-7254.2007.00512.xSearch in Google Scholar PubMed

Wang, G., Liu, X., Guo, Q., and Namura, S. (2010). Chronic treatment with fibrates elevates superoxide dismutase in adult mouse brain microvessels. Brain Res. 1359, 247–255.10.1016/j.brainres.2010.08.075Search in Google Scholar PubMed PubMed Central

White, J.K., Auerbach, W., Duyao, M.P., Vonsattel, J.P., Gusella, J.F., Joyner, A.L., and MacDonald, M.E. (1997). Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat. Genet. 17, 404–410.10.1038/ng1297-404Search in Google Scholar PubMed

Yap, Y.W., Whiteman, M., and Cheung, N.S. (2007). Chlorinative stress: an under appreciated mediator of neurodegeneration? Cell Signal. 19, 219–228.Search in Google Scholar

Yi, J.H., Park, S.W., Brooks, N., Lang, B.T., and Vemuganti, R. (2008). PPARγ agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. Brain Res. 1244, 164–172.10.1016/j.brainres.2008.09.074Search in Google Scholar PubMed PubMed Central

Yoo, S.E., Chen, L., Na, R., Liu, Y., Rios, C., Van Remmen, H., Richardson, A., and Ran, Q. (2012). Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic. Biol. Med. 52, 1820–1827.10.1016/j.freeradbiomed.2012.02.043Search in Google Scholar PubMed PubMed Central

Yu, X., Shao, X.G., Sun, H., Li, Y.N., Yang, J., Deng, Y.C., and Huang, Y.G. (2008). Activation of cerebral peroxisome proliferator-activated receptors γ exerts neuroprotection by inhibiting oxidative stress following pilocarpine-induced status epilepticus. Brain Res. 1200, 146–158.10.1016/j.brainres.2008.01.047Search in Google Scholar PubMed

Zarzuelo, M.J., Jimenez, R., Galindo, P., Sánchez, M., Nieto, A., Romero, M., Quintela, A.M., López-Sepúlveda, R., Gómez-Guzmán, M., Bailón, E., et al. (2011). Antihypertensive effects of peroxisome proliferator-activated receptor-β activation in spontaneously hypertensive rats. Hypertension 58, 733–743.10.1161/HYPERTENSIONAHA.111.174490Search in Google Scholar PubMed

Zemolin, A.P., Meinerz, D.F., de Paula, M.T., Mariano, D.O., Rocha, J.B., Pereira, A.B., Posser, T., and Franco, J.L. (2012). Evidences for a role of glutathione peroxidase 4 (GPx4) in methylmercury induced neurotoxicity in vivo. Toxicology 302, 60–67.10.1016/j.tox.2012.07.013Search in Google Scholar PubMed

Zeng, Y., Xie, K., Dong, H., Zhang, H., Wang, F., Li, Y., and Xiong, L. (2012). Hyperbaric oxygen preconditioning protects cortical neurons against oxygen-glucose deprivation injury: role of peroxisome proliferator-activated receptor-γ. Brain Res. 1452, 140–150.10.1016/j.brainres.2012.02.063Search in Google Scholar PubMed

Zhao, X., Sun, G., Zhang, J., Strong, R., Song, W., Gonzales, N., Grotta, J.C., and Aronowski, J. (2007). Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor γ in microglia/macrophages. Ann. Neurol. 61, 352–362.10.1002/ana.21097Search in Google Scholar PubMed

Zhao, X., Strong, R., Zhang, J., Sun, G., Tsien, J.Z., Cui, Z., Grotta, J.C., and Aronowski, J. (2009). Neuronal PPARγ deficiency increases susceptibility to brain damage after cerebral ischemia. J. Neurosci. 29, 6186–6195.10.1523/JNEUROSCI.5857-08.2009Search in Google Scholar PubMed PubMed Central

Received: 2013-6-28
Accepted: 2013-9-4
Published Online: 2013-09-06
Published in Print: 2013-12-01

©2013 by Walter de Gruyter Berlin Boston

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