Benfluorex, Friends or Foe? The Effects of Benfluorex on Oxidative Status in the Brain During Experimental Diabetes

Yıl 2021, , 357 - 363, 28.09.2021

Emine Gülçeri Güleç Peker , Doç. Dr. Barbaros Balabanlı , Çiğdem Özer , Şule Coşkun Cevher

https://doi.org/10.35229/jaes.929547

Öz

Benfluorex is a pharmacological agent with antidiabetic and antihyperlipidemic properties. In this study, the brain's oxidative and non-enzymatic antioxidant status in diabetic and benfluorex administrated diabetic rats have been investigated. For the experimental procedures, three groups of 18 Wistar albino rats were used as the control, diabetes (induced by streptozotocin), and benfluorex treated diabetic rats (benfluorex administration intragastric 50 mg/kg daily for 21 days). Brain NOx, TBARS, GSH, AA levels, and MPO activity were determined spectrophotometrically. Benfluorex administration was caused that decreased lipid peroxidation and MPO activity while increased non-enzymatic antioxidant and NOx levels. These results showed that benfluorex treatment positively affects lipid peroxidation and non-enzymatic antioxidant status of the brain during diabetes.

Anahtar Kelimeler

Benfluorex, brain, diabetes, lipid peroxidation, non-enzymatic antioxidants, nitric oxide.

Benfloreks: Dost mu, Düşman mı? Deneysel Diyabette, Benfloreksin Beyindeki Oksidatif Olaylara Etkileri

Öz

Benfloreks, antidiyabetik ve antihiperlipidemik özelliklere sahip farmakolojik bir ajandır. Bu çalışmada, uygulanan diyabetik sıçanlarda benfloreks tedavisinin beynin oksidatif ve enzimatik olmayan antioksidan durumu üzerindeki etkileri araştırılmıştır. Deneysel prosedürler için, kontrol, diyabet (streptozotosin ile indüklenen) ve benfloreks ile tedavi edilmiş diyabetik sıçanlar (benfloreks 21 gün boyunca intragastrik 50 mg/kg dozda uygulanmıştır) olarak 18 Wistar albino sıçanından oluşan üç grup kullanıldı. Beyin NOx, TBARS, GSH, AA seviyeleri ve MPO aktivitesi spektrofotometrik olarak belirlendi. Benfloreks uygulaması, lipid peroksidasyonunu ve MPO aktivitesini azaltırken; enzimatik olmayan antioksidan seviyelerini ve NOx düzeylerini arttırmıştır. Bu sonuçlar, benfloreks tedavisinin, diyabet sırasında beynin lipid peroksidasyonunu ve enzimatik olmayan antioksidan durumu olumlu etkilediğini göstermiştir.

Anahtar Kelimeler

Benfloreks, beyin, diyabet, lipid peroksidasyonu, enzimatik olmayan antioksidanlar, nitrik oksit.

Kaynakça

• Aragno, M., Parola, S., Tamagno, E., Brignardello, E., Manti, R., Danni, O. & Boccuzzi, G. (2000). Oxidative derangement in rat synaptosomes induced by hyperglycemia: restorative effect of dehydroepiandrosterone treatment. Biochemistry & Pharmacology, 60(3):389-395. doi: 10.1016/s0006-2952(00)00327-0.
• Ates, O., Caylı, S.R., Altınoz, E., Altinoz, E., Kocak, A., Durak, M.A., Turkoz, Y. & Yologlu, S. (2007). Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats. Journal of Clinical Neuroscience, 14(3):256-260. doi: 10.1016/j.jocn.2005.12.010.
• Ates, O., Yucel, N., Cayli, S.R., Altinoz, E., Yologlu, S., Kocak, A., Cakir, C.O. & Turkoz, Y. (2006). Neuroprotective effect of etomidate in the central nervous system of streptozotocin-induced diabetic rats. Neurochemical Research, 31(6):777-783. doi: 10.1007/s11064-006-9076-0.
• Avogaro, A., Fadini, G.P. & Gallo, A. (2006). Endothelial dysfunction in type 2 diabetes mellitus. Nutrition, Metabolism and Cardiovascular Diseases, 16(1):39‐45. doi: 10.1016/j.numecd.2005.10.015.
• Aykac, A.G., Uysal, M., Yalcın, A.S., Koçak-Toker, N., Sivas, A. & Oz, H. (1985). The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology, 36(1):71-76. doi: 10.1016/0300-483x(85)90008-3.
• Berger, J., Shepart, D., Morrow, F. & Taylor, A. (1989). Relationship between dietary intake and tissue levels reduced and total vitamin C in nonscorbutic guinea pig. The Journal of Nutrition, 119(5):734-740. doi: 10.1093/jn/119.5.734.
• Bianchi, R., Bongers, V., Bravenboer, B. & Erkelens, D.W. (1993). Effects of benfluorex on insulin resistance and lipid metabolism in obese type II diabetic patients. Diabetes Care, 16(4):557-559. doi: 10.2337/diacare.16.4.557.
• Boutet, K., Frachon, I., Jobic, Y., Gut-Gobert, C., Leroyer, C., Carlhant-Kowalski, D., Sitbon, O., Simonneau, G. & Humbert, M. (2009). Fenfluramine-like cardiovascular side-effects of benfluorex. European Respiratory Journal, 33(3): 684-688. doi: 10.1183/09031936.00086308.
• Brindley, D.N., Akester, H., Derick, G.P., Irvine, C.D., Patmore, R.D., Spencer, H., Yule-Smith, A., Finnerty, C., Saxton, J., Macdonald, I.A. & et al. (1988). Effects of chronic administration of benfluorex to rats on the metabolism of corticosterone, glucose, triacylglycerol, glycerol and fatty acid. Biochemistry & Pharmacology, 37(4):695-705. doi: 10.1016/0006-2952(88)90144-x.
• Casini, A., Ferrali, M. & Pompella, A. (1986). Lipid peroxidation and cellular damage in extrahepatic tissue of bromobenzene-intoxicated mice. American Journal of Pathology, 123(3):520-531. PMID: 3717304
• Darvesh, A.S. & Gudelsky, G.A. (2003). Activation of 5-HT2 receptors induces glycogenolysis in the rat brain. European Journal of Pharmacology, 464(2-3):135-140. doi: 10.1016/s0014-2999(03)01432-8.
• De Feo, P., Lavielle, R., De Gregoris, P. & Bolli, G.B. (1993). Anti-hyperglycemic mechanisms of benfluorex in type II diabetes mellitus. Diabetes Metabolic Reviews, 9(1):35-41.doi: 10.1002/dmr.5610090507.
• El‐Akabawy, G. & El‐Kholy, W. (2014). Neuroprotective effect of ginger in the brain of streptozotocin‐induced diabetic rats. Annals of Anatomy, 196(2-3):119‐128. doi: 10.1016/j.aanat.2014.01.003.
• Faheem, N.M. & El Askary, A. (2017). Neuroprotective role of curcumin on the hippocampus against the structural and serological alterations of streptozotocin-induced diabetes in Sprague Dawley rats. Iranian Journal of Basic Medical Sciences, 20(6):690-699. doi: 10.22038/IJBMS.2017.8839.
• Frachon, I., Etienne, Y., Jobic, Y., Le Gal, G., Humbert, M. & Leroyer, C. (2010). Benfluorex and unexplained valvular heart disease: a case-control study. PLoS ONE, 5(1):e10128. doi: 10.1371/journal.pone.0010128.
• Galvan-Arzate, S. & Santamaria, A. (2002). Neurotoxicity of diethylpropion: neurochemical and behavioral findings in rats. Annual New York Academy of Sciences, 965(1):214-224. PMID: 12105097.
• Glowick, S.P. & Kaplan, S.D. (1955). Methods in enzymology. Academic Press, New York, pp 769-782.
• Green, L.C., Wagner, D.A., Glogowski, J., Skipper, P.L., Wishnok, J.S. & Tannenbaum, S.R. (1982). Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Analitic Biochemistry, 126(1):131-138. doi: 10.1016/0003-2697(82)90118-x.
• Gurel-Gokmen, B., Ipekci, H., Oktay, S., Alev, B., Ustundag, U.V., Ak, E., Akakın, D., Sener, G., Emekli-Alturfan, E., Yarat, A. & Tunali-Akbay, T. (2018). Melatonin improves hyperglycemia induced damages in rat brain. Diabetes Metabolism Research and Reviews, 34(8): e3060.doi: 10.1002/dmrr.3060.
• Halliwell, B. (1994). Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet, 344(8924):721-724. doi: 10.1016/s0140-6736(94)92211-x.
• Ibrahim, D.S. (2016). Neuroprotective effect of Cucumis melo var. flexuosus leaf extract on the brains of rats with streptozotocin‐induced diabetes. Metabolic Brain Disease, 32(1):69‐75. doi: 10.1007/s11011-016-9886-y.
• Kino, M., Yamato, T. & Aomine, M. (2004). Simultaneous measurement of nitric oxide, blood glucose, and monoamines in the hippocampus of diabetic rat: an in vivo microdialysis study. Neurochemistry International, 44(2):65-73. doi: 10.1016/s0197-0186(03)00125-6.
• Kohl, C., Ravel, D., Girard, J. & Pégorier, J.P. (2002). Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression. Diabetes, 51(8):2363-2368. doi: 10.2337/diabetes.51.8.2363.
• Kurutas, E.B. (2016). The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutrition Journal, 15(1):71-99. doi: 10.1186/s12937-016-0186-5. doi: 10.1186/s12937-016-0186-5.
• Lazarević-Pasti, T., Leskovac, A. & Vasić, V. (2015). Myeloperoxidase Inhibitors as Potential Drugs. Current Drug Metabolism, 16(3):168-190. doi: 10.2174/138920021603150812120640.
• Le Ven, F., Tribouilloy, C., Habib, G., Gueffet, J.P., Maréchaux, S., Eicher, J.C., Blanchard-Lemoine, B., Rousseau, J., Hénon, P., Jobic, Y. & Etienne, Y. (2011). Valvular heart disease associated with benfluorex therapy: results from the French multicentre registry. European Journal of Echocardiography, 12(4):265-271. doi: 10.1093/ejechocard/jeq172.
• Miranda, K.M., Espey, M.G. & Wink, D.A. (2001). A rapid simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide, 5(1):62-71. doi: 10.1006/niox.2000.0319.
• Montilla, P., Barcos, M., Munoz, M.C., Bujalance, I., Munoz-Castaneda, J.R. & Tunez, I. (2005). Red wine prevents brain oxidative stress and nephropathy in stretozotocin-induced diabetic rats. Journal of Biochemistry and Molecular Biology, 38(5):538-544. doi: 10.5483/bmbrep.2005.38.5.539.
• Moulin, P., Andre, M., Alawi, H., Dos Santos, L.C., Khalid, A.K., Koev, D., Moore, R., Serban, V., Picandet, B. & Francillard, M. (2009). Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18 to 34-week, open-label, extension period. Diabetes & Metabolism, 35(1):64-70. doi: 10.1016/j.diabet.2008.10.002.
• Muriach, M., Flores‐Bellver, M., Romero, F.J. & Bracia, J.M. (2014). Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxidative Medicine and Cellular Longevity, 2014(1):1‐9. doi: 10.1155/2014/102158.
• Noctor, G., Gomez, L., Vanacker, H. & Foyer, C.H. (2002). Interactions between biosynthesis, compartmentation, and transport in the control of glutathione homeostasis and signalling. Journal of Experimental Botany, 53(372):1283-1304. doi: 10.1093/jexbot/53.372.1283.
• Noize, P., Sauer, M., Bruneval, P., Moreau, M., Pathak, A., Bagheri, H. & Montastruc, J.L. (2006). Valvular heart disease in a patient taking benfluorex. Fundamental & Clinical Pharmacology, 20(6):577-578. doi: 10.1111/j.1472-8206.2006.00441.x.
• Ogunyinka, B.I., Oyinloye, B.E., Osunsanmi F.O., Opoku, A.R. & Kappo, A.P. (2016). Modulatory influence of Parkia biglobosa protein isolate on testosterone and biomarkers of oxidative stress in brain and testes of streptozotocin‐induced diabetic male rats. International Journal of Physiology, Pathophysiology and Pharmacology, 8(3):78‐86. PMID: 27785334
• Ong, S.E., Koh, J.J.K., Toh, S.E.S., Chia, K.S., Balabanova, D., McKee, M., Perel, P. & Legido-Quigley, H. (2018). Assessing the influence of health systems on Type 2 Diabetes Mellitus awareness, treatment, adherence, and control: A systematic review. PLoS One, 29;13(3): e0195086. doi: 10.1371/journal.pone.0195086.
• Pandey, K.B., Mishra, N. & Rizvi, S.I. (2010). Protein oxidation biomarkers in plasma of type 2 diabetic patients. Clinical Biochemistry, 43(4-5):508-511. doi: 10.1016/j.clinbiochem.2009.11.011.
• Piero, M.N., Nzaro, G.M. & Njagi, J.M. (2014). Diabetes mellitus – a devastating metabolic disorder. Asian Journal of Biomedical and Pharmaceutical Sciences, 04 (40):1-7. doi: 10.15272/ajbps.v4i40.645
• Rafel Ribera, J., Casanas Munoz, R., Anguera Ferrando, N., Batalla Sahún, N., Castro Cels, A. & Pujadas Capmany, R. (2003). Valvular heart disease associated with benfluorex. Revista Espanola de Cardiologia, 56(2):215-216. doi: 10.1016/s0300-8932(03)76849-3.
• Ravel, D. & Laudignon, N. (1996). Research prospects with benfluorex. Journal of Diabetes Complications, 10(5):246-254. doi: 10.1016/1056-8727(96)00045-1.
• Riccio, A., Vigili de Kreutzenberg, S., Dorella, M., Da Tos, V., De Biasi, L., Marescotti, M.C., Tiengo, A. & Del Prato, S. (1993). Mechanism(s) of the blood glucose lowering action of benfluorex. Diabetes Metabolic Reviews, 9(1): 19-27. doi: 10.1002/dmr.5610090505. PMID: 8299485.
• Roth, B.L. (2007). Drugs and valvular heart disease. New England Journal of Medicine, 356(1):6 -9. doi: 10.1056/NEJMp068265.
• Rothman, R.B., Baumann, M.H., Savage, J.E., Rauser, L., McBride, A., Hufeisen, S.J. & Roth, B.L. (2000). Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation, 102(23):2836-2841. doi: 10.1161/01.cir.102.23.2836.
• Serradas, P., Blondel, O., Bailbe, D. & Portha, B. (1993). Benfluorex normalizes hyperglycemia and reverses hepatic insulin resistance in STZ-induced diabetic rats. Diabetes, 42(4):564-570. doi: 10.2337/diab.42.4.564.
• Szkudelski, T. (2001). The mechanism of alloxan and streptozotocin action in β cells of rat pancreas. Physiological Research, 50(1):536-546. PMID: 11829314.
• Tribouilloy, C., Rusinaru, D., Henon, P., Tribouilloy, L., Leleu, F., Andréjak, M., Sevestre, H., Peltier, M. & Caus, T. (2010). Restrictive organic mitral regurgitation associated with benfluorex therapy. European Journal of Echocardiography, 11(7):614-621. doi: 10.1093/ejechocard/jeq027.
• Tribouilloy, C., Rusinaru, D., Maréchaux, S., Jeu, A., Ederhy, S., Donal, E., Réant, P., Arnalsteen, E., Boulanger, J., Ennezat, PV., Garban, T. & Jobic, Y. (2012). Increased risk of left heart valve regurgitation associated with benfluorex use in patients with diabetes mellitus: a multicenter study. Circulation, 126(24) :2852-2858. doi: 10.1093/ejechocard/jeq027.
• Uzar, E., Alp, H., Cevik, M.U., Fırat, U., Evliyaoglu, O., Tufek, A. & Altun, Y. (2012). Ellagic acid attenuates oxidative stress on brain and sciatic nerve and improves histopathology of brain in streptozotocin-induced diabetic rats. Neurological Sciences, 33(3):567-574. doi: 10.1007/s10072-011-0775-1.
• Xu., L., Zhu, J., Yin, W. & Ding, X. (2015). Astaxanthin improves cognitive deficits from oxidative stress, nitric oxide synthase and inflammation through upregulation of PI3K/Akt in diabetes rat. International Journal of Clinival & Experimental Pathology, 8(6):6083-6094. PMID: 26261486
• Zhang, W.J., Tan, Y.F., Yue, J.T., Vranic, M. & Wojtowicz, J.M. (2008). Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurologica Scandinavica, 117(3):205-210. PMID: 17854417.