Skip to main content

Advertisement

SpringerLink
Log in

Peroxisome proliferator-activated receptors ligands and ischemia-reperfusion injury

  • Review
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Peroxisome proliferator-activated receptors (PPARs) belong to a subfamily of transcription nuclear factors. Three isoforms of PPARs have been identified: α, β/δ and γ, encoded by different genes and distributed in various tissues. They play important roles in metabolic processes like regulation of glucose and lipid redistribution. They also have anti-atherogenic, anti-inflammatory as well as antihypertensive functions. There is good evidence that ligands of PPARs reduce tissue injury associated with ischemia and reperfusion. The potential utility of PPAR ligands in ischemia and reperfusion will be discussed in this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abdelrahman M, Sivarajah A, Thiemermann C (2005) Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock. Cardiovasc Res 65:772–781

    PubMed  CAS  Google Scholar 

  • Abraham D, Taghavi S, Riml P, Paulus P, Hofmann M, Baumann C, Kocher A, Klepetko W, Aharinejad S (2002) VEGF-A and -C but not -B mediate increased vascular permeability in preserved lung grafts. Transplantation 73:1703–1706

    PubMed  CAS  Google Scholar 

  • Al Mehdi AB, Shuman H, Fisher AB (1997) Intracellular generation of reactive oxygen species during nonhypoxic lung ischemia. Am J Physiol 272:L294–L300

    Google Scholar 

  • Al Mehdi AB, Zhao G, Fisher AB (1998a) ATP-independent membrane depolarization with ischemia in the oxygen-ventilated isolated rat lung. Am J Respir Cell Mol Biol 18:653–661

    Google Scholar 

  • Al Mehdi AB, Zhao G, Dodia C, Tozawa K, Costa K, Muzykantov V, Ross C, Blecha F, Dinauer M, Fisher AB (1998b) Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+Circ Res 83:730–737

    Google Scholar 

  • Ames A III (1968) Cerebral ischemia II. The no-reflow phenomenon. Amer J Pathol 52:437–453

    Google Scholar 

  • Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S (1990) Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348:730–732

    PubMed  CAS  Google Scholar 

  • Arany I, Safirstein RL (2003) Cisplatin nephrotoxicity. Semin Nephrol 23:460–464

    PubMed  CAS  Google Scholar 

  • Argmann CA, Cock TA, Auwerx J (2005) Peroxisome proliferator-activated receptor gamma: the more the merrier? Eur J Clin Invest 35:82–92

    PubMed  CAS  Google Scholar 

  • Attuwaybi BO, Kozar RA, Moore-Olufemi SD, Sato N, Hassoun HT, Weisbrodt NW, Moore FA (2004) Heme oxygenase-1 induction by hemin protects against gut ischemia/reperfusion injury. J Surg Res 118:53–57

    PubMed  CAS  Google Scholar 

  • Barger PM, Kelly DP (2000) PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 10:238–245

    PubMed  CAS  Google Scholar 

  • Berger JP, Akiyama TE, Meinke PT (2005) PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci 26:244–251

    PubMed  CAS  Google Scholar 

  • Bloomfield Rubins H (2001) Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation 103:2828–2833

    PubMed  CAS  Google Scholar 

  • Bonegio R, Lieberthal W (2002) Role of apoptosis in the pathogenesis of acute renal failure. Curr Opin Nephrol Hypertens 11:301–308

    PubMed  Google Scholar 

  • Boscoe MJ, Goodwin AT, Amrani M, Yacoub MH (2000) Endothelins and the lung. Int J Biochem Cell Biol 32:41–62

    PubMed  CAS  Google Scholar 

  • Boulanger C, Lüscher TF (1990) Endothelin is released from the porcine aorta: inhibition by endothelium-derived nitric oxide. J Clin Invest 85:587–590

    PubMed  CAS  Google Scholar 

  • Bulhak AA, Sjoquist PO, Xu CB, Edvinsson L, Pernow J (2006) Protection against myocardial ischaemia/reperfusion injury by PPAR-alpha activation is related to production of nitric oxide and endothelin-1. Basic Res Cardiol 101:244–252

    PubMed  CAS  Google Scholar 

  • Burdick AD, Kim DJ, Peraza MA, Gonzalez FJ, Peters JM (2006) The role of peroxisome proliferator-activated receptor-beta/delta in epithelial cell growth and differentiation. Cell Signal 18(1):9–20

    PubMed  CAS  Google Scholar 

  • Burne-Taney MJ, Rabb H (2003) The role of adhesion molecules and T cells in ischemic renal injury. Curr Opin Nephrol Hypertens 12:85–90

    PubMed  CAS  Google Scholar 

  • Calnek DS, Mazzella L, Roser S, Roman J, Hart CM (2003) Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 23:52–57

    PubMed  CAS  Google Scholar 

  • Chan KL, Zhang XH, Fung PCW, Guo WH, Tam PKH (1999) Role of nitric oxide in intestinal ischaemia-reperfusion injury studied using electron paramagnetic resonance. Br J Surg 86:1427–1432

    PubMed  CAS  Google Scholar 

  • Chatterjee PK (2004) The cyclopentenone prostaglandin 15-deoxy-delta(12,14)-prostaglandin J2 ameliorates ischemic acute renal failure. Cardiovasc Res 61:630–643

    PubMed  CAS  Google Scholar 

  • Chung BH (2005) Protective effect of peroxisome proliferator activated receptor gamma agonists on diabetic and non-diabetic renal diseases. Nephrology (Carlton) 10(Suppl 2):S40–S43

    CAS  Google Scholar 

  • Collino M, Aragno M, Mastrocola R, Benetti E, Gallicchio M, Dianzani C, Danni O, Thiemermann C, Fantozzi R (2006a) Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: effects of the PPAR-alpha agonist WY14643. Free Radic Biol Med 41:579–589

    PubMed  CAS  Google Scholar 

  • Collino M, Aragno M, Mastrocola R, Gallicchio M, Rosa AC, Dianzani C, Danni O, Thiemermann C, Fantozzi R (2006b) Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. Eur J Pharmacol 530:70–80

    PubMed  CAS  Google Scholar 

  • Cook SA, Matsui T, Li L, Rosenzweig A (2002) Transcriptional effects of chronic Akt activation in the heart. J Biol Chem 277:22528–22533

    PubMed  CAS  Google Scholar 

  • Cuzzocrea S (2003) Rosiglitazone and 15-deoxy-delta12,14-prostaglandin J2, ligands of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), reduce ischaemia/reperfusion injury of the gut. Br J Pharmacol 140:366–376

    PubMed  CAS  Google Scholar 

  • Cuzzocrea S (2004a) Peroxisome proliferator-activated receptors gamma ligands and ischemia and reperfusion injury. Vascul Pharmacol 41:187–195

    PubMed  CAS  Google Scholar 

  • Cuzzocrea S (2004b) WY 14643, a potent exogenous PPAR-alpha ligand, reduces intestinal injury associated with splanchnic artery occlusion shock. Shock 22:340–346

    PubMed  CAS  Google Scholar 

  • Cuzzocrea S, Zingarelli B, Caputi AP (1998) Role of constitutive nitric oxide synthase and peroxynitrite production in a rat model of splanchnic artery occlusion shock. Life Sci 63:789–799

    PubMed  CAS  Google Scholar 

  • Cuzzocrea S, Chatterjee P, Mazzon E, Dugo L, De Sarro A, Van de Loo FAJ, Caputi AP, Thiemermann C (2002) Role of induced nitric oxide in the initiation of the inflammatory response after postischemic injury. Shock 18:169–176

    PubMed  Google Scholar 

  • Cuzzocrea S, Rossi A, Serraino I, Di Paola R, Dugo L, Genovese T, Caputi AP, Sautebin L (2003) 5-Lipoxygenase knockout mice exhibit a resistance to splanchnic artery occlusion shock. Shock 20:230–236

    PubMed  CAS  Google Scholar 

  • Date H, Matsumura A, Manchester JK, Obo H, Lima O, Cooper JM, Sundaresan S, Lowry OH, Cooper JD (1993) Evaluation of lung metabolism during successful twenty-four-hour canine lung preservation. J Thorac Cardiovasc Surg 105:480–491

    PubMed  CAS  Google Scholar 

  • Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS (2003) Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 26:2983–2989

    PubMed  CAS  Google Scholar 

  • Delerive P, Martin-Nizard F, Chinetti G, Trottein F, Fruchart JC, Najib J, Duriez P, Staels B (1999) Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res 85:394–402

    PubMed  CAS  Google Scholar 

  • Demertzis S, Langer F, Graeter T, Dwenger A, Georg T, Schafers HJ (1999) Amelioration of lung reperfusion injury. Eur J Cardiothorac Surg 16:174–180

    PubMed  CAS  Google Scholar 

  • Denecker G, Vercammen D, Declercq W, Vandenabeele P (2001) Apoptotic and necrotic cell death induced by death domain receptors. Cell Mol Life Sci 58:356–370

    PubMed  CAS  Google Scholar 

  • Deplanque D (2003) Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. J Neurosci 23:6264–6271

    PubMed  CAS  Google Scholar 

  • Despres JP, Lemieux I, Robins SJ (2004) Role of fibric acid derivatives in the management of risk factors for coronary heart disease. Drugs 64:2177–2198

    PubMed  CAS  Google Scholar 

  • Desvergne B, Michalik L, Wahli W (2004) Be fit or be sick: peroxisome proliferator-activated receptors are down the road. Mol Endocrinol 18:1321–1332

    PubMed  CAS  Google Scholar 

  • Dewald O, Sharma S, Adrogue J, Salazar R, Duerr GD, Crapo JD, Entman ML, Taegtmeyer H (2005) Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity. Circulation 112:407–415

    PubMed  CAS  Google Scholar 

  • Diemer NH, Johansen FF, Benveniste H (1993) Ischemia as an excitotoxic lesion: protection against hippocampal neuron loss by denervation. Acta Neurochir Suppl 57:94–101

    CAS  Google Scholar 

  • Ding G, Cheng L, Qin Q, Frontin S, Yang Q (2006) PPARdelta modulates lipopolysaccharide-induced TNFalpha inflammation signaling in cultured cardiomyocytes. J Mol Cell Cardiol 40:821–828

    PubMed  CAS  Google Scholar 

  • Donnahoo KK, Meldrum DR, Shenkar R, Chung CS, Abraham E, Harken AH (2000) Early renal ischemia, with or without reperfusion, activates NF-κB and increases TNF-α bioactivity in the kidney. J Urol 163:1328–1332

    PubMed  CAS  Google Scholar 

  • Dormandy JA (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366:1279–1289

    PubMed  CAS  Google Scholar 

  • Elsharkawy AM, Oakley F, Mann DA (2005) The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 10:927–939

    PubMed  CAS  Google Scholar 

  • Engler R (1987) Consequences of activation and adenosine mediated inhibition of granulocytes during myocardial ischemia. Federation Proc 46:2407–412

    Google Scholar 

  • Fiorucci S (2005) Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. J Pharmacol Exp Ther 315:58–68

    PubMed  CAS  Google Scholar 

  • Fischer S, Cassivi SD, Xavier AM, Cardella JA, Cutz E, Edwards V, Liu M, Keshavjee S (2000) Cell death in human lung transplantation: apoptosis induction in human lungs during ischemia and after transplantation. Ann Surg 231:424–431

    PubMed  CAS  Google Scholar 

  • Fisher AB, Dodia C, Tan ZT, Ayene I, Eckenhoff RG (1991) Oxygen-dependent lipid peroxidation during lung ischemia. J Clin Invest 88:674–679

    PubMed  CAS  Google Scholar 

  • Fragasso G (2003) Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am Heart J 146:E18

    PubMed  CAS  Google Scholar 

  • Frangogiannis NG, Smith CW, Entman ML (2002) The inflammatory response in myocardial infarction. Cardiovasc Res 53:31–47

    PubMed  CAS  Google Scholar 

  • Frank MM (1987) Complement in the pathophysiology of human disease. N Engl J Med 316:1525–1530

    Article  PubMed  CAS  Google Scholar 

  • Fredenrich A, Grimaldi PA (2005) PPAR delta: an uncompletely known nuclear receptor. Diabetes Metab 31:23–27

    PubMed  CAS  Google Scholar 

  • Fruchart JC, Staels B, Duriez P (2001) The role of fibric acids in atherosclerosis. Curr Atheroscler Rep 3:83–92

    PubMed  CAS  Google Scholar 

  • Galli A (2002) Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122:1924–1940

    PubMed  CAS  Google Scholar 

  • Gerlach J, Jorres A, Nohr R, Zeilinger K, Spatkowski G, Neuhaus P (1999) Local liberation of cytokines during liver preservation. Transpl Int 12:261–265

    PubMed  CAS  Google Scholar 

  • Giannini S, Serio M, Galli A (2004) Pleiotropic effects of thiazolidinediones: taking a look beyond antidiabetic activity. J Endocrinol Invest 27:982–991

    PubMed  CAS  Google Scholar 

  • Gobe G, Zhang XJ, Willgoss DA, Schoch E, Hogg NA, Endre ZH (2000) Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat. J Am Soc Nephrol 11:454–467

    PubMed  CAS  Google Scholar 

  • Gonon AT, Gourine AV, Pernow J (2000) Cardioprotection from ischemia and reperfusion injury by an endothelin A receptor antagonist in relation to nitric oxide production. J Cardiovasc Pharmacol 36:405–412

    PubMed  CAS  Google Scholar 

  • Gonon AT, Gourine AV, Middelveld RJ, Alving K, Pernow J (2001) Limitation of infarct size and attenuation of myeloperoxidase activity by an endothelin A receptor antagonist following ischemia and reperfusion. Basic Res Cardiol 96:454–462

    PubMed  CAS  Google Scholar 

  • Gonon AT, Bulhak A, Labruto F, Sjoquist PO, Pernow J (2007) Cardioprotection mediated by rosiglitazone, a peroxisome proliferatoractivated receptor gamma ligand, in relation to nitric oxide. Basic Res Cardiol 102:80–89

    PubMed  CAS  Google Scholar 

  • Goto M, Takei Y, Kawano S, Nagano K, Tsuji S, Masuda E, Nishimura Y, Okumura S, Kashiwagi T, Fusamoto H, Kamada T (1994) Endothelin-1 involved in the pathogenesis of ischemia/reperfusion liver injury by hepatic microcirculatory disturbances. Hepatology 19:675–681

    PubMed  CAS  Google Scholar 

  • Grace PA (1994) Ischaemia-reperfusion injury. Br J Surg 81:637–647

    PubMed  CAS  Google Scholar 

  • Granger DN (1988) Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol 255:H1269–H1275

    PubMed  CAS  Google Scholar 

  • Granger DN, Kubes P (1994) The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J Leukoc Biol 55:662–675

    PubMed  CAS  Google Scholar 

  • Granger DN, Hollwarth ME, Parks DA (1986) Ischemia-reperfusion injury: role of oxygen-derived free radicals. Acta Physiol Scand Suppl 548:47–63

    PubMed  CAS  Google Scholar 

  • Grattagliano I, Vendemiale G, Lauterburg BH (1999) Reperfusion injury of the liver: role of mitochondria and protection by glutathione ester. J Surg Res 86:2–8

    PubMed  CAS  Google Scholar 

  • Guan Y (2004) Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. J Am Soc Nephrol 15:2801–2815

    PubMed  CAS  Google Scholar 

  • Guder WG, Ross BD (1984) Enzyme distribution along the nephron. Kidney Int 26:101–111

    PubMed  CAS  Google Scholar 

  • Hellemans K (2003) Peroxisome proliferator-activated receptor-beta signaling contributes to enhanced proliferation of hepatic stellate cells. Gastroenterology 124:184–201

    PubMed  CAS  Google Scholar 

  • Hertz L (1981) Features of astrocyte function apparently involved in the response of central nervous tissue to ischemia-hypoxia. J Cereb Blood Flow Metab 1:143–153

    PubMed  CAS  Google Scholar 

  • Heuser D, Guggenberger H (1985) Ionic changes in brain ischemia and alterations produced by drugs. Br J Anesth 57:23

    CAS  Google Scholar 

  • Hisama N, Yamaguchi Y, Ishiko T, Miyanari N, Ichiguchi O, Goto M, Mori K, Watanabe K, Kawamura K, Tsurufuji S, Ogawa M (1996) Kupffer cell production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion injury in rats. Hepatology 24:1193–1198

    PubMed  CAS  Google Scholar 

  • Homeister JW, Lucchesi BR (1994) Complement activation and inhibition in myocardial ischemia and reperfusion injury. Annu Rev Pharmacol Toxicol 34:17–40

    PubMed  CAS  Google Scholar 

  • Ichikawa H (2002) A specific peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, pioglitazone, ameliorates gastric mucosal damage induced by ischemia and reperfusion in rats. Redox Rep 7:343–346

    PubMed  CAS  Google Scholar 

  • Inoue H (2003) Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor alpha in mice. Neurosci Lett 352:203–206

    PubMed  CAS  Google Scholar 

  • Iredale JP (2003) Cirrhosis: new research provides a basis for rational and targeted treatments. BMJ 327:143–147

    PubMed  Google Scholar 

  • Ishibashi N, Weisbrot-Lefkowitz M, Reuhl K, Inouye M, Morichnitchenko O (1999) Modulation of chemokine expression during ischemia/reperfusion in transgenic mice overproducing human glutathione peroxidases. J Immunol 163:5666–5677

    PubMed  CAS  Google Scholar 

  • Israelian-Konaraki Z, Reaven PD (2005) Peroxisome proliferator-activated receptor-alpha and atherosclerosis: from basic mechanisms to clinical implications. Cardiology 103:1–9

    PubMed  Google Scholar 

  • Ito K (2004) Protective effects of preischemic treatment with pioglitazone, a peroxisome proliferator-activated receptor-gamma ligand, on lung ischemia-reperfusion injury in rats. Eur J Cardiothorac Surg 25:530–536

    PubMed  Google Scholar 

  • Jaeschke H (1998) Mechanism of reperfusion injury after warm ischemia of the liver. J Hepatol 21:402–408

    Google Scholar 

  • Jaeschke H, Farhood A (1991) Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver in vivo. Am J Physiol Gastrointest Liver Physiol 260:G355–G362

    CAS  Google Scholar 

  • Jaeschke H, Farhood A, Smith CW (1990) Neutrophils contribute to ischemia-reperfusion injury in rat liver in vivo. FASEB J 4:3355–3359

    PubMed  CAS  Google Scholar 

  • Jaeschke H, Bautista AP, Spolarics Z, Spitzer JJ (1992) Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats. J Leukoc Biol 52:377–382

    PubMed  CAS  Google Scholar 

  • Jaeschke H, Farhood A, Bautista AP, Spolarics Z, Spitzer JJ (1993) Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Physiol Gastrointest Liver Physiol 264:G801–G809

    CAS  Google Scholar 

  • James EJ, Zhao ZQ, Vinten-Johansen J (1999) The role of neutrophils in myocardial ischemia-reperfusion injury. Cardiovasc Res 43:860–878

    Google Scholar 

  • Jonas S (1995) Prophylactic pharmacologic neuroprotection against focal cerebral ischemia. Ann NY Acad Sci 765:21–25

    PubMed  CAS  Google Scholar 

  • Kalimo H, Garcia JH, Kamijyo Y (1977) The ultrastructure of brain death II. Electron microscopy of feline cortex after complete ischemia. Virchow’s Arch B Cell Path 25:207–220

    CAS  Google Scholar 

  • Kantor PF, Lucien A, Kozak R, Lopaschuk GD (2000) The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 86:580–588

    PubMed  CAS  Google Scholar 

  • Kaplan J, Dimlich RVW, Biros MH, Hesges J (1987) Mechanisms of ischemic cerebral injury. Resuscitation 15:149–169

    PubMed  CAS  Google Scholar 

  • Karlsson U, Schultz RL (1966) Fixation of the central nervous system for electron microscopy by aldehyde perfusion. III. Structural changes after exsanguination and delayed perfusion. J Ultrastruc Res 14:57–63

    Google Scholar 

  • Karol AK, Bonda TA, Korecki J, Wlodzimierz JM (2002) Oxidative stress and neutrophil activation-the two keystones of ischemia-reperfusion injury. Int J Cardiol 86:41–59

    Google Scholar 

  • Kelly RF (2000) Current strategies in lung preservation. J Lab Clin Med 136:427–440

    PubMed  CAS  Google Scholar 

  • Kelly KJ, Tolkoff-Rubin NE, Rubin RH, Williams WW Jr, Meehan SM, Meschter CL, Christenson JG, Bonventre JV (1996a) An oral platelet-activating factor antagonist, Ro-24-4736, protects the rat kidney from ischemic injury. Am J Physiol Renal Fluid Electrolyte Physiol 271:F1061–F1067

    CAS  Google Scholar 

  • Kelly KJ, Williams WW Jr, Colvin RB, Meehan SM, Springer TA, Gutiérrez-Ramos JC, Bonventre JV (1996b) Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 97:1056–1063

    PubMed  CAS  Google Scholar 

  • Khandoudi N, Delerive P, Berrebi-Bertrand I, Buckingham RE, Staels B, Bril A (2002) Rosiglitazone, a peroxisome proliferator-activated receptor-gamma, inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury. Diabetes 51:1507–1514

    PubMed  CAS  Google Scholar 

  • King RC (2000) Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. Ann Thorac Surg 69:1681–1685

    PubMed  CAS  Google Scholar 

  • Kips JC (2001) Cytokines in asthma. Eur Respir J Suppl 34:24s–33s

    PubMed  CAS  Google Scholar 

  • Kosonen O, Kankaanranta H, Malo-Ranta U, Moilanen E (1999) Nitric oxide-releasing compounds inhibit neutrophil adhesion to endothelial cells. Eur J Pharmacol 382:111–117

    PubMed  CAS  Google Scholar 

  • Kourembanas S, Marsden PA, McQuillan LP, Faller DV (1991) Hypoxia induces endothelin expression and secretion in cultured human endothelium. J Clin Invest 88:1054–1057

    PubMed  CAS  Google Scholar 

  • Kumamoto Y, Suematsu M, Shimazu M, Kato Y, Sano T, Makino N, Hirano KI, Naito M, Wakabayashi G, Ishimura Y, Kitajima M (1999) Kupffer cell-independent acute hepatocellular oxidative stress and decreased bile formation in post-cold-ischemic rat liver. Hepatology 30:1454–1463

    PubMed  CAS  Google Scholar 

  • Kuwano K, Hara N (2000) Signal transduction pathways of apoptosis and inflammation induced by the tumor necrosis factor receptor family. Am J Respir Cell Mol Biol 22:147–149

    PubMed  CAS  Google Scholar 

  • Lansman JB (1988) Endothelial mechanosensors: going with the flow. Nature 331:481–482

    PubMed  CAS  Google Scholar 

  • Lee TM, Chou TF (2003) Troglitazone administration limits infarct size by reduced phosphorylation of canine myocardial connexin43 proteins. Am J Physiol Heart Circ Physiol 285:H1650–H1659

    PubMed  CAS  Google Scholar 

  • Lemay S, Rabb H, Postler G, Singh AK (2000) Prominent and sustained up-regulation of gp130-signaling cytokines and the chemokine MIP-2 in murine renal ischemia-reperfusion injury. Transplantation 69:959–963

    PubMed  CAS  Google Scholar 

  • Lentsch AB, Yoshidome H, Cheadle WG, Miller FN, Edwards MJ (1998) Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and KC. Hepatology 27:507–512

    PubMed  CAS  Google Scholar 

  • Letavernier E, Perez J, Joye E, Bellocq A, Fouqueray B, Haymann JP, Heudes D, Wahli W, Desvergne B, Baud L (2005) Peroxisome proliferator-activated receptor beta/delta exerts a strong protection from ischemic acute renal failure. J Am Soc Nephrol 16:2395–2402

    PubMed  CAS  Google Scholar 

  • Li S (2004) PPAR-alpha ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of renal endonuclease G. Am J Physiol Renal Physiol 287:F990–F998

    PubMed  CAS  Google Scholar 

  • Li JM, Shah AM (2001) Differential NADPH- versus NADH-dependent superoxide production by phagocyte-type endothelial cell NADPH oxidase. Cardiovasc Res 52:477–486

    PubMed  CAS  Google Scholar 

  • Li S, Gokden N, Okusa MD, Bhatt R, Portilla D (2005) Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF. Am J Physiol Renal Physiol 289:F469–F480

    PubMed  CAS  Google Scholar 

  • Liu HR (2004) Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion. Cardiovasc Res 62:135–144

    PubMed  CAS  Google Scholar 

  • Liu P, Fisher MA, Farhood A, Smith CW, Jaeschke H (1994) Beneficial effects of extracellular glutathione against endotoxin-induced liver injury during ischemia and reperfusion. Circ Shock 43:64–70

    PubMed  CAS  Google Scholar 

  • Luquet S, Gaudel C, Holst D, Lopez-Soriano J, Jehl-Pietri C, Fredenrich A, Grimaldi PA (2005) Roles of PPAR delta in lipid absorption and metabolism: a new target for the treatment of type 2 diabetes. Biochim Biophys Acta 1740:313–317

    PubMed  CAS  Google Scholar 

  • Luster AD (1998) Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med 338:436–445

    PubMed  CAS  Google Scholar 

  • Marra F (2005) Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis. World J Gastroenterol 11:4931–4938

    PubMed  CAS  Google Scholar 

  • McCord JM (1985) Oxygen derived free radicals in postischemic tissue injury. N Eng J Med 312:159–163

    Article  CAS  Google Scholar 

  • McCuskey RS (2000) Morphological mechanisms for regulating blood flow through hepatic sinusoids. Liver 20:3–7

    PubMed  CAS  Google Scholar 

  • Meldrum DR (1998) Tumor necrosis factor in the heart. Am J Physiol Regul Integr Comp Physiol 274 (3Pt2):R577–R595

    CAS  Google Scholar 

  • Minamiya Y, Tozawa K, Kitamura M, Saito S, Ogawa J (1998) Platelet-activating factor mediates intercellular adhesion molecule-1-dependent radical production in the nonhypoxic ischemia rat lung. Am J Respir Cell Mol Biol 19:150–157

    PubMed  CAS  Google Scholar 

  • Molavi B, Chen J, Mehta JL (2006) Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK. Am J Physiol Heart Circ Physiol 291:H687–H693

    PubMed  CAS  Google Scholar 

  • Molitoris BA, Sutton TA (2004) Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 66:496–499

    PubMed  Google Scholar 

  • Monaghan DT, Holets RV, Toy DW, Cotman CW (1983) Anatomical distributions of four pharmacologically distinct 3H-glutamate binding sites. Nature 306:176–179

    PubMed  CAS  Google Scholar 

  • Montalto MC, Hart ML, Jordan JE, Wada K, Stahl GL (2003) Role for complement in mediating intestinal nitric oxide synthase-2 and superoxide dismutase expression. Am J Physiol 285:G197–G206

    CAS  Google Scholar 

  • Muia C, Mazzon E, Crisafulli C, Di Paola R, Genovese T, Caputi AP, Cuzzocrea S (2006) Role of endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands in the development of gut ischemia and reperfusion in mice. Shock 25:17–12

    Google Scholar 

  • Mullane KM, Salmon JA, Kraemer R (1987) Leukocyte derived metabolites of arachidonic acid in ischemia-induced myocardial injury. Federation Proc 46:2422–2433

    CAS  Google Scholar 

  • Naito Y, Takagi T, Uchiyama K, Handa O, Tomatsuri N, Imamoto E, Kokura S, Ichikawa H, Yoshida N, Yoshikawa T (2002) Suppression of intestinal ischemia-reperfusion injury by a specific peroxisome proliferator-activated receptor-gamma ligand pioglitazone in rats. Redox Rep 7:294–299

    PubMed  CAS  Google Scholar 

  • Naka Y, Marsh HC, Scesney SM, Oz MC, Pinsky DJ (1997) Complement activation as a cause for primary graft failure in an isogeneic rat model of hypothermic lung preservation and transplantation. Transplantation 64:1248–1255

    PubMed  CAS  Google Scholar 

  • Nakajima A (2001) Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury. Gastroenterology 120:460–469

    PubMed  CAS  Google Scholar 

  • Nakamura S, Nishiyama R, Serizawa A, Yokoi Y, Suzuki S, Konno H, Baba S, Muro H (1995) Hepatic release of endothelin-1 after warm ischemia. Transplantation 59:679–684

    PubMed  CAS  Google Scholar 

  • Oberbauer R, Rohrmoser M, Regele H, Muhlbacher F, Mayer G (1999) Apoptosis of tubular epithelial cells in donor kidney biopsies predicts early renal allograft function. J Am Soc Nephrol 10:2006–2013

    PubMed  CAS  Google Scholar 

  • Okada M, Yan SF, Pinsky DJ (2002) Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets. FASEB J 16:1861–1868

    PubMed  CAS  Google Scholar 

  • Okaya T, Lentsch AB (2004) Peroxisome proliferator-activated receptor-alpha regulates postischemic liver injury. Am J Physiol Gastrointest Liver Physiol 286:G606–G612

    PubMed  CAS  Google Scholar 

  • Okuaki Y, Miyazaki H, Zeniya M, Ishikawa T, Ohkawa Y, Tsuno S, Sakaguchi M, Hara M, Takahashi H, Toda G (1996) Splenectomy-reduced hepatic injury induced by ischemia/reperfusion in the rat. Liver 16:188–194

    PubMed  CAS  Google Scholar 

  • Onody A, Zvara A, Hackler L Jr, Vigh L, Ferdinandy P, Puskas LG (2003) Effect of classic preconditioning on the gene expression pattern of rat hearts:a DNA microarray study. FEBS Lett 536:35–40

    PubMed  CAS  Google Scholar 

  • Oz MC, Liao H, Naka Y, Seldomridge A, Becker DN, Michler RE, Smith CR, Rose EA, Stern DM, Pinsky DJ (1995) Ischemia-induced interleukin-8 release after human heart transplantation: a potential role for endothelial cells. Circulation 92:II428–II432

    PubMed  CAS  Google Scholar 

  • Ozaki M, Deshpande SS, Angkeow P, Bellan J, Lowenstein CJ, Dinauer MC, Goldschmidt-Clermont PJ, Irani K (2000) Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo. FASEB J 14:418–429

    PubMed  CAS  Google Scholar 

  • Panchapakesan U, Sumual S, Pollock CA, Chen X (2005) PPARgamma agonists exert antifibrotic effects in renal tubular cells exposed to high glucose. Am J Physiol Renal Physiol 289:F1153–F1158

    PubMed  CAS  Google Scholar 

  • Parks DA, Granger DN (1986) Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 250:G749–G753

    PubMed  CAS  Google Scholar 

  • Planaguma A (2005) The selective cyclooxygenase-2 inhibitor SC-236 reduces liver fibrosis by mechanisms involving non-parenchymal cell apoptosis and PPARgamma activation. FASEB J 19:1120–1122

    PubMed  CAS  Google Scholar 

  • Portilla D (2000) Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure. Am J Physiol Renal Physiol 278:F667–F675

    PubMed  CAS  Google Scholar 

  • Reichelt KL (1978) The chemical basis for the intolerance of the brain to anoxia. Acta Anesthesiol Scand Suppl 29:35–46

    Google Scholar 

  • Rhenchrona S (1985) Brain acidosis. Ann Emerg Med 14:770–776

    Google Scholar 

  • Roberto A, Prado EA (2002) Ischemia/reperfusion injury. J Surg Res 105:248–258

    Google Scholar 

  • Safar P (1986) Cerebral resuscitation after cardiac arrest. A review. Circulation 74(Suppl IV):138

    Google Scholar 

  • Safirstein R, DiMari J, Megyesi J, Price P (1998) Mechanisms of renal repair and survival following acute injury. Semin Nephrol 18:519–522

    PubMed  CAS  Google Scholar 

  • Sambandam N (2006) Chronic activation of PPARalpha is detrimental to cardiac recovery following ischemia. Am J Physiol Heart Circ Physiol 290:H87–H95

    PubMed  CAS  Google Scholar 

  • Santos MJ (2005) Peroxisomal proliferation protects from beta-amyloid neurodegeneration. J Biol Chem 280:41057–41068

    PubMed  CAS  Google Scholar 

  • Sanz MJ, Johnston B, Issekutz A, Kubes P (1999) Endothelin causes P-selectin-dependent leukocyte rolling and adhesion within rat mesenteric microvessels. Am J Physiol 277:H1823–H1830

    PubMed  CAS  Google Scholar 

  • Sato N (2005) Differential induction of PPAR{gamma} by luminal glutamine and iNOS by luminal arginine in the rodent post ischemic small bowel. Am J Physiol Gastrointest Liver Physiol. DOI 10.1152/ajpgi.00248.2005

  • Sato Y, Hogg JC, English D, van Eeden SF (2000) Endothelin-1 changes polymorphonuclear leukocytes’ deformability and CD11b expression and promotes their retention in the lung. Am J Respir Cell Mol Biol 23:404–410

    PubMed  CAS  Google Scholar 

  • Sekhon B, Sekhon C, Khan M, Patel SJ, Singh I, Singh AK (2003) N-Acetyl cysteine protects against injury in a rat model of focal cerebral ischemia. Brain Res 971:1–8

    PubMed  CAS  Google Scholar 

  • Serrick C, Adoumie R, Giaid A, Shennib H (1994) The early release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma after ischemia reperfusion injury in the lung allograft. Transplantation 58:1158–1162

    PubMed  CAS  Google Scholar 

  • Shaw MJ, Shennib H, Bousette N, Ohlstein EH, Giaid A (2001) Effect of endothelin receptor antagonist on lung allograft apoptosis and NOSII expression. Ann Thorac Surg 72:386–390

    PubMed  CAS  Google Scholar 

  • She H, Xiong S, Hazra S, Tsukamoto H (2005) Adipogenic transcriptional regulation of hepatic stellate cells. J Biol Chem 280:4959–4967

    PubMed  CAS  Google Scholar 

  • Shennib H, Lee AG, Kuang JQ, Yanagisawa M, Ohlstein EH, Giaid A (1998) Efficacy of administering an endothelin-receptor antagonist (SB209670) in ameliorating ischemia-reperfusion injury in lung allografts. Am J Respir Crit Care Med 157:1975–1981

    PubMed  CAS  Google Scholar 

  • Shimazu T (2005) A peroxisome proliferator-activated receptor-gamma agonist reduces infarct size in transient but not in permanent ischemia. Stroke 36:353–359

    PubMed  CAS  Google Scholar 

  • Siesjo BK (1981) Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab 1:155–185

    PubMed  CAS  Google Scholar 

  • Sivarajah A, McDonald MC, Thiemermann C (2005) The cardioprotective effects of preconditioning with endotoxin, but not ischemia, are abolished by a peroxisome proliferator-activated receptor-gamma antagonist. J Pharmacol Exp Ther 313:896–901

    PubMed  CAS  Google Scholar 

  • Staels B (2005) PPARgamma and atherosclerosis. Curr Med Res Opin 21:S13–S20

    PubMed  CAS  Google Scholar 

  • Staels B, Fruchart JC (2005) Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 54:2460–2470

    PubMed  CAS  Google Scholar 

  • Sundararajan S (2005) Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia. Neuroscience 130:685–696

    PubMed  CAS  Google Scholar 

  • Suwa T, Hogg JC, Hards J, van Eeden SF (2001) Interleukin-6 changes deformability of neutrophils and induces their sequestration in the lung. Am J Resp Crit Care Med 970–976

  • Suzuki S, Toledo-Pereyra LH (1994) Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury. J Surg Res 57:253–258

    PubMed  CAS  Google Scholar 

  • Taghavi S, Abraham D, Riml P, Paulus P, Schafer R, Klepetko W, Aharinejad S (2002) Co-expression of endothelin-1 and vascular endothelial growth factor mediates increased vascular permeability in lung grafts before reperfusion. J Heart Lung Transplant 21:600–603

    PubMed  Google Scholar 

  • Thadhani R, Pascual M, Bonventre JV (1996) Medical progress—acute renal failure. N Engl J Med 334:1448–1460

    PubMed  CAS  Google Scholar 

  • Thiemermann C, Ruetten H, Wu CC, Vane JR (1995) The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 116:2845–2851

    PubMed  CAS  Google Scholar 

  • Tien M, Aust SD (1982) Comparative aspects of several models of lipid peroxidation systems. In: Yagi K (ed) Lipid peroxides in biology and medicine. Academic Press, New York, p 23–39

    Google Scholar 

  • Toyama T (2004) PPARalpha ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats. Biochem Biophys Res Commun 324:697–704

    PubMed  CAS  Google Scholar 

  • Turnage RH, Guice KS, Oldham KT (1994) Endotoxemia and remote organ injury following intestinal reperfusion. J Surg Res 56:571–578

    PubMed  CAS  Google Scholar 

  • Van Nimwegen D, Sheldon H (1966) Early postmortem changes in cerebellar neurons of the rat. J Ultrastruc Res 14:36–46

    Google Scholar 

  • Vollmar B, Glasz J, Leiderer R, Post S, Menger MD (1994) Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia-reperfusion. Am J Pathol 145:1421–1431

    PubMed  CAS  Google Scholar 

  • Wada K (2004) Protective effect of endogenous PPARgamma against acute gastric mucosal lesions associated with ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 287:G452–G458

    PubMed  CAS  Google Scholar 

  • Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C (2002) Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J 16:1027–1040

    PubMed  CAS  Google Scholar 

  • Wheeler MD (2003) Impaired Ras membrane association and activation in PPARalpha knockout mice after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 284:G302–G312

    PubMed  CAS  Google Scholar 

  • Witthaut R, Farhood A, Smith CW, Jaeschke H (1994) Complement and tumor necrosis factor contribute to Mac-1 (CD11b/CD18) upregulation and systemic neutrophil activation during endotoxemia in vivo. J Leukoc Biol 55:105–111

    PubMed  CAS  Google Scholar 

  • Wolf G, Ziyadeh FN, Thaiss F, Tomaszewski J, Caron RJ, Wenzel U, Zahner G, Helmchen U, Stahl RA (1997) Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells: role of the antiotensin type 2 receptor. J Clin Invest 100:1047–1058

    PubMed  CAS  Google Scholar 

  • Xia G, Martin AE, Besner GE (2003) Heparin-binding EGF-like growth factor downregulates expression of adhesion molecules and infiltration of inflammatory cells after intestinal ischemia/reperfusion injury. J Pediatr Surg 38:434–439

    PubMed  Google Scholar 

  • Xu J, Fu Y, Chen A (2003) Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am J Physiol Gastrointest Liver Physiol 285:G20–G30

    PubMed  CAS  Google Scholar 

  • Xu Y, Lu L, Greyson C, Rizeq M, Nunley K, Wyatt B, Bristow MR, Long CS, Schwartz GG (2006) The PPAR-alpha activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol 290(5):H1798–H1807

    PubMed  CAS  Google Scholar 

  • Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) Endothelin: a novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 322:411–415

    Google Scholar 

  • Yavrom S (2005) Peroxisome proliferator-activated receptor gamma suppresses proximal alpha 1(I) collagen promoter via inhibition of p300-facilitated NF-I binding to DNA in hepatic stellate cells. J Biol Chem 280:40650–40659

    PubMed  CAS  Google Scholar 

  • Yokoyama Y, Baveja R, Sonin N, Nakanishi K, Zhang JX, Clemens MG (2000) Altered endothelin receptor subtype expression in hepatic injury after ischemia/reperfusion. Shock 13:72–78

    Article  PubMed  CAS  Google Scholar 

  • Yue TL (2003) Activation of peroxisome proliferator-activated receptor-alpha protects the heart from ischemia/reperfusion injury. Circulation 108:2393–2399

    PubMed  CAS  Google Scholar 

  • Zhang B, Borderie D, Sogni P, Soubrane O, Houssin D, Calmus Y (1997) NO-mediated vasodilation in the rat liver. Role of hepatocytes and liver endothelial cells. J Hepatol 26:1348–1355

    PubMed  CAS  Google Scholar 

  • Zhao G, Al Mehdi AB, Fisher AB (1997) Anoxia-reoxygenation versus ischemia in isolated rat lungs. Am J Physiol 273:L1112–L1117

    PubMed  CAS  Google Scholar 

  • Zhao Y, Patzer A, Gohlke P, Herdegen T, Culman J (2005) The intracerebral application of the PPARgamma-ligand pioglitazone confers neuroprotection against focal ischaemia in the rat brain. Eur J Neurosci 22:278–282

    PubMed  Google Scholar 

  • Zhao Y, Patzer A, Herdegen T, Gohlke P, Culman J (2006) Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats. FASEB J 20(8):1162–1175

    PubMed  CAS  Google Scholar 

  • Zimmermann KC, Bonzon C, Green DR (2001) The machinery of programmed cell death. Pharmacol Ther 92:57–70

    PubMed  CAS  Google Scholar 

  • Zou L, Attuwaybi B, Kone BC (2003) Effects of NF-kappa B inhibition on mesenteric ischemia-reperfusion injury. Am J Physiol 284:G713–G721

    CAS  Google Scholar 

  • Zwacka RM, Zhang Y, Halldorson J, Schlossberg H, Dudus L, Engelhardt JF (1997) CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J Clin Invest 100:279–289

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi, 98100, Messina, Italy

    Rosanna Di Paola & Salvatore Cuzzocrea

  2. IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy

    Rosanna Di Paola & Salvatore Cuzzocrea

Authors
  1. Rosanna Di Paola
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salvatore Cuzzocrea
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Salvatore Cuzzocrea.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Di Paola, R., Cuzzocrea, S. Peroxisome proliferator-activated receptors ligands and ischemia-reperfusion injury. Naunyn-Schmied Arch Pharmacol 375, 157–175 (2007). https://doi.org/10.1007/s00210-007-0141-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-007-0141-2

Keywords

Search

Navigation