Effects of Luteolin on Liver, Kidney and Brain in Pentylentetrazol-Induced Seizures: Involvement of Metalloproteinases and NOS Activities

Abstract

Objective: Flavonoids are an important group of recognized antioxidants in plants. Luteolin (LUT) is a natural flavonoid in the plant kingdom. This study was aimed to investigate the effects of the LUT in the liver, kidney and brain of pentylentetrazol (PTZ)-induced seizure and the relationship between nitric oxide synthases (iNOS, eNOS) and matrix metalloproteinases (MMP2, MMP9). Materials and Methods: LUT (10 mg/kg) was given intraperitoneally during two weeks prior to seizure induction. A single dose PTZ 80 mg/kg i.p. was administered and seizures were observed and evaluated with regard to latency, frequency and stage for one hour. Results: Seizure frequen cy after PTZ administration was significantly decreased in LUT pretreated rats (p<0.05). An increase of immunhistochemical reactions of iNOS and MMP2, but a decrease of eNOS activity, were observed in rat hippocampus and peripheral tissues during the PTZ induced seizures. LUT pretreatment reversed the iNOS and MMP2 activity to the control levels and significantly increased the eNOS activity (p<0.001). Conclusion: LUT seems to have an effective role in reducing the seizure frequency and a protective role on peripheral organ injury in animal models of seizure. The protective effect of LUT in seizures and the seizure induced peripheral tissue damage warrant further investigations.

Keywords

• Luteolin, pentylentetrazol, seizure, metalloproteinases, NOS

Effects of Luteolin on Liver, Kidney and Brain in Pentylentetrazol-Induced Seizures: Involvement of Metalloproteinases and NOS Activities

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References

1. Benavente-Garcia O, Castillo J. Update on uses and properties of citrus flavonoids: new finding in anticancer, cardiovascular and antiinflammatory activity. J Agric Food Chem 2008;56:6185-205. [CrossRef]
2. Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, et al. Effect of luteolin and quercetin, inhibitors of tyrosine kinase on cell growth and metastasis. Associated properties in A431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol 1999;128:999-1010. [CrossRef]
3. Lin CW, Hou WC, Shen SC, Juan SH, Ko CH, Wang LM, et al. Quercetin inhibition of tumor invasion via suppressing PKC /ERK/ AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 2008;29:1807-15. [CrossRef]
4. Dajas F, Rivera F, Blasina F, Arredondo F, Echeverry C, Lafon L, et al. Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox Res 2003;5:425-32. [CrossRef]
5. Duarte J, Perez-Palencia R, Vargas F, Ocete MA, Perez-Vizcaino F, Zarzuelo A, et al. Antihypertensive effect of the flavonoid quercetin in spontaneously hypertensive rats. Br J Pharmacol 2001;133:117-24. [CrossRef]
6. Kotanidou A, Xagorari A, Bagli E, Kitsanta P, Fotsis T, Papapet- ropoulos A, et al. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice. Am J Respir Crit Care Med 2002;165:818-23.
7. Lacerda G, Krummel T, Sabourdy C, Ryvlin P, Hirsch E. Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Neurology 2006;67:S28-33. [CrossRef]
8. Uzüm G, Sarper Diler A, Bahçekapili N, Ziylan YZ. Erythropoietin prevents the increase in blood brain barrier permeability during pentylenetetrazole induced seizures. Life Sci 2006;78:2571-6. [CrossRef]

9. Patsoukis N, Zervoudakis G, Panagopoulos NT, Georgiou CD, Angelatou F, Matsokis NA. Thiol redox state (TRS) and oxida- tive stress in the Mouse hippocampus after pentylenetetrazol-in- duced epileptic seizure. Neurosci Lett 2004;357:83-6. [CrossRef]
10. Banati RB, Gehrman J, Schubert P, Kreutzbeg GW. Cytotoxicity of microglia. Glia 1993;7:111-8. [CrossRef]
11. Giulian D, Corpuz M. Microglial secretion products and their im- pact the nervous system. Adv Neurol 1993;59:315-20.
12. Takacs E, Nyilas R, Szepesi Z, Baracskay P, Karlsen B, Rosvold T, et al. Matrix metalloproteinase 9 activity increased by two different types of epileptic seizures that do not induce neuronal death: A possible role in homeostatic synaptic plasticity. Neurochem Int 2010;56:799-809. [CrossRef]
13. Jourquin J, Tremblay E, Decanis N, Charton G, Hanessian S, Chol- let AM, et al. Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxic- ity after kainate. Eur J Neurosci 2003;18:1507-17. [CrossRef]
14. Hendriks JJA, Alblas J, van der Pol SMA, van Tol EAF, Dijkstra CD, de Vries HE. Flavonoids Influence Monocytic GTPase Activity and Are Protective in Experimental Allergic Encephalitis. J Exp Med 2004;200:1667-72. [CrossRef]
15. Domitrovic R, Jakovac H, Milin C, Radosevic-Stasic B. Dose-and time dependent effects of luteolin on carbon tetrachloride-in- duced hepatotoxicity in mice. Exp Toxicol Pathol 2009;61:581-9. [CrossRef]
16. Malemud CJ. Matrix metalloproteinases (MMP’s) in healty and disease: an overview. Front Biosci 2006;11:696-701. [CrossRef]
17. Sivaramakrishnan V, Niranjali Devaraj S. Morin regulates the ex- pression of NF-Kb-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma. Chem Biol İnteract 2009;180:353-9. [CrossRef]
18. van Hoorn DE, Nijveldt RJ, Boelens PG, Hofman Z, van Leeuwen PA, van Norren K. Effects of Preoperative Flavonoid Supplemen- tation on Different Organ Functions in Rats. JPEN J Parenter En- teral Nutr 2006;30:302-8. [CrossRef]
19. Kolankaya D, Korkmaz A. Luteolin prevents ischemia/reperfusion- induced damage in the rat kidney. Toxicol Lett 2008;180:S50. [CrossRef]
20. Cho JY, Kim IS, Jang YH, Kim AR, Lee SR. Protective effect of Quercetin, A natural flavonoid Against Neuronal damage after transient Global Cerebral Ischemia. Neurosci Lett 2006;404:330-5. [CrossRef]
21. Duarte J, Jimenez R, O’Valle F, Galisteo M, Perez-Palencia R, Vargas F, et al. Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats. J Hypertens 2002;20:1843-54. [CrossRef]
22. Yamazaki KG, Romero-Perez D, Barraza-Hidalgo M, Cruz M, Cortez-Gomez B, Rivas M, et al. Short and long term effects of (-)-epicatechin on myocardial ischemia reperfusion injury. Am J Physiol Heart Circ Physiol 2008;295:H761-7. [CrossRef]
23. Dunnick JK, Hailey JR. Toxicity and carcinogenicity studies of quercetin, a natural component of foods. Fundam Appl Toxicol 1992;19:423-31. [CrossRef]
24. Rundfeldt C, Koch R, Richter A, Mevissen M, Gerecke U, Loschen W. Dose-dependent anticonvulsant and proconvulsant effects of nitric oxide synthase inhibitors on seizure thereshold in corti- cal stimulation model in rats. Eur J Pharmacol 1995;274:73-81. [CrossRef]
25. Homayoun H, Khavandgar S, Dehpour AR. Anticonvulsant effects of cyclosporin on pentylentetrazol-induced seizure and kindling: modulation by nitricoxidergic system. Brain Res 2002;939:1-10. [CrossRef]
26. Jayakumar AR, Sujatha R, Paul V, Asokan C, Govindasamy S, Jayakumar R. Role of nitric oxide on GABA, glutamic acid, activi- ties of GABA-T and GAD in rat brain cerebral cortex. Brain Res 1999;837:229-35. [CrossRef]
27. Senturk LM, Seli E, Gutıerrez LS, Mor G, Zeyneloglu HB, Arıcı A. Monocyte chemotactic protein-1 expression in human corpus luteum. Mol Hum Reprod 1999;5:697-702. [CrossRef]
28. Taşkin EI, Akgun Dar K, Kapucu A, Yagci A, Caner M, Dogruman H. Effects of concentrated grape juice (enoant®) on eac and its relation with NO. Revue de Médecine Vétérinaire 2008;159:123-9.
29. Kang SS, Lee JY, Choi YK, Kim GS, Han BH. Neuroprotec- tive efects of flavones on hydrogen peroxide-induced apop- tosis in SH-SY5Y neuroblostoma cells. Bioorg Med Chem Lett 2004;14:2261-4. [CrossRef]
30. Fernandez SP, Wasowski C, Loscalzo LM, Granger RE, Johnston GA, Paladini AC, et al. Central nervous system depressant ac- tion of flavonoid glycosides. Eur J Pharmacol 2006;539:168-76. [CrossRef]
31. Coleta M, Campos MG, Cotrim MD, Lima TC, Cunha AP. Assess- ment of luteolin (3’, 4’, 5, 7-tetrahydroxyflavone) neuropharma- cological activity. Behav Brain Res 2008;189:75-82. [CrossRef]
32. Suzuki J, Ogawa M, Maejima Y, Isobe K, Tanaka H, Sagesaka YM, et al. Tea catechins attenuate chronic ventricular-remodelling after myocardial ischemia in rats. J Mol Cell Cardiol 2007;42:432-40. [CrossRef]
33. Sun J, Druhan LJ, Zweier JL. Reactive oxygen and nitrogen spe- cies regulate inducible nitric oxide synthase function shifting the balance of nitric oxide and superoxide production. Arch Biochem Biophys 2010;494:130-7. [CrossRef]
34. Park KI, Chu K, Jung KH, Kim JH, Kang KM, Lee ST, et al. Role of cortical dysplasia in epileptogenesis following prolonged febrile seizure. Epilepsia 2010;51:1809-19. [CrossRef]
35. Gill SS, Pulido OM. Glutamate receptors in peripheral tissues: current knowledge, future research and implication for toxicol- ogy. Toxicol Pathol 2001;29:208-23. [CrossRef]
36. Olszanecki R, Gebska A, Kozlovski VI, Gryglewski RJ. Flavonoids and nitric oxide synthase. J Physiol Pharmacol 2002;53:571-84.
37. Michaluk P, Kaczmarek L. Matrix metalloproteinase-9 in glu- tamate-dependent adult brain function and dysfunction. Cell Death Differ 2007;14:1255-8. [CrossRef]
38. Wilczynski GM, Konopacki FA, Wilczek E, Lasiecka Z, Gorlewicz A, Michaluk P, et al. İmportant role of matrix metalloproteinase 9 in epileptogenesis. J Cell Biol 2008;180:1021-35. [CrossRef]
39. Kim GW, Kim HJ, Cho KJ, Kim HW, Cho YJ, Lee BI. The role of MMP- 9 in integrin-mediated hippocampal cell death after pilocarpine-in- duced status epilepticus. Neurobiol Dis 2009;36:169-80. [CrossRef]
40. Ende C, Gebhardt R. İnhibition of matrix metalloproteinase 2 and 9 activities by selected flavonoids. Planta Med 2004;70:1006-8. [CrossRef]