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Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas

Year 2017, Volume: 21 Issue: 3, 570 - 577, 20.06.2017
https://doi.org/10.12991/marupj.319312

Abstract

Valproic acid (VPA), an effective antiepileptic and
anticonvulsant drug, has some toxic side effects due to
causing elevated oxidant production. The aim of this study
is to investigate the effects of edaravone, a potent free radical
scavenger on VPA induced toxicity and tissue damage by
biochemical and histological examinations on pancreas. Female
Sprague Dawley rats were divided into four groups as follows;
control, edaravone, VPA, VPA+edaravon. VPA and edaravone
were injected intraperitonally for seven days. Total protein,
lipid peroxidation (LPO), sialic acid (SA) and glutathione
(GSH) levels and alkaline phosphatase (ALP), tissue factor
(TF), superoxide dismutase (SOD), glutathione-S-transferase
(GST), catalase (CAT), glutathione peroxidase (GPx) and
myeloperoxidase (MPO) activities were determined in pancreas
homogenates. In VPA given group, LPO and SA levels, and ALP,
TF, MPO activities significantly increased and GST, CAT, GPx
activities significantly decreased compared to control group. A
marked morphological damage was detected in the VPA group.
Ameliorative effects of edaravone were observed in SA, TF,
CAT, GPx parameters and histological examination in the VPA
group. Therefore, edaravone may be effective in moderation
and/or reduction of toxic effects of VPA on pancreas.

References

  • 1. Iasemidis LD. Seizure prediction and its application. Neurosurg Clin N Am 2011; 22: 489-506. 2. Brodie MJ, Barry SJE, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012; 78: 1548-54. 3. Gerstner T, Büsing D, Bell N, Longin E, Kasper JM, Klostermann W, Hebing B, Hanefeld F, Eckel U, Hoffman R, Bettendorf U, Weidner B, Wiemer-Kruel A, Brockmann K, Neumann FW, Sandriese T, Wolff M, König S. Valproic acid-induced pancreatitis: 16 new cases and a review of the literature. J Gastroenterol 2007; 42: 39-48. 4. Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neur 2012; 11: 792-802. 5. Belcastro V, D’Egidio C, Striano P, Verrotti A. Metabolic and endocrine effects of valproic acid chronic treatment. Epilepsy Res 2013; 107: 1-8. 6. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Anthony F, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott P, Wijdicks EFM. Guidelines for the early management of adults with ischemic stroke. Stroke 2007; 38: 1655-711. 7. Xi H, Akishita M, Nagai K, Yu W, Hasegawa H, Eto M, Kozaki K, Toba K. Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis. Atherosclerosis 2007; 191: 281-9. 8. Kikuchi K, Tancharoen S, Takeshiga N, Yoshitomi M, Morioka M, Murai Y, Tanaka E. The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease. Int J Mol Sci 2013; 14: 13909-30. 9. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193; 265-75. 10. Yagi K. Assay for blood plasma or serum. Methods Enzymol 1981; 105: 328-37. 11. Warren L. The thiobarbituric acid assay of sialic acids. J Biol Chem 1959; 234: 1971-5. 12. Beutler E. Gluthatione: red cell metabolism. A manual biochemical methods. New York: Grune and Stratton, 1975, pp:112-14. 13. Walter K, Schült C. Acid and alkaline phosphatase in serum (two point method) In Methods of enzymatic Analysis Ed: Bergmeyer HU, 2nd ed. FL, 1974, pp:856-86. 14. Ingram GIC, Hills M. Reference method for the one stage prothrombin time test on human blood. Thromb Haemostas 1976; 36: 237-8. 15. Mylorie AA, Collins H, Umbles C, Kyle J. Erythrocyte SOD activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol 1986; 82: 512-20. 16. Habig WH, Jacoby WB. Assays for differentation of glutathione-S-transferases. Methods in Enzymol 1981; 77: 398-405. 17. Aebi H. Catalase in vitro. Methods Enzymol 1984; 105: 121-6. 18. Paglia DE, Valentine WN. Studies on the quantitative and quantitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967; 70: 158-68. 19. Wei H, Frenkel K. In vivo formation of oxidized DNA bases in tumor promoter- treated mouse skin. Cancer Res 1991; 51: 4443-9. 20. Hamed SA, Abdellah MM, El-Melegy N. Blood levels of trace elements, electrolytes, and oxidative stress/antioxidant systems in epileptic patients. J Pharmacol Sci 2004; 96: 465-73. 21. Tung EY, Winn LM. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: A role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol 2011; 80: 979-87. 22. Chaudhary S, Ganjoo P, Raiusddin S, Parvez, S. Nephroprotective activities of quercetin with potential relevance to oxidative stress induced by valproic acid. Protoplasma 2015; 252: 209-17. 23. Mittal K, Mehta P, Mittal A, Aggarwal HK. Valproate induced thrombocytopenia and renal dysfunction: Case report. IJPRR 2016; 5: 39-41. 24. Yamamoto Y, Kuwahara T, Watanabe K. Antioxidation activity of 3-methyl-1-phenyl-pyrazolin-5-one. Redox Rep 1996; 2: 333-8. 25. Varki A. Sialic acids in human health and disease. Trends Mol Med 2008; 14: 351-60. 26. Funk CD. Lipoxygenase pathways as mediators of early inflammatory events in atherosclerosis. Arterioscl Throm Vas 2006; 26: 1204-6. 27. Svalheim S, Røste LS, Nakken KO, Taubøll E. Bone health in adults with epilepsy. Acta Neurol Scand 2011; 124: 89-95 28. Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, Maeda H, Satoh K. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001; 14: 445-9. 29. Voudris K, Moustaki M, Zeis PM, Dimou S, Vagiakou E, Tsagris B, Skardoutsou A. Alkaline phosphatase and its isoenzyme activity for the evaluation of bone metabolism in children receiving anticonvulsant monotherapy. Seizure 2001; 11: 377-80. 30. Giray T, Vitrinel A, Comert S, Deniz NC, Erdag GC, Kesler E, Sadıkoglu S, Akın Y. The evaluation of the effects of antiepileptic drugs on bone metabolism. Turk Arch Ped 2005; 40: 221-6. 31. Yarat A, Tunali T, Piririciler R, Akyuz S, Ipbuker A, Emekli N. Salivary thromboplastic activity in diabetic and healthy controls. Clin Oral Invest 2004; 8: 36-9. 32. Cannizzaro E, Albisetti M, Wohlrab G, Schmugge M. Severe bleeding complications during antiepileptic treatment with valproic acid in children. Neuropediatrics 2007; 38: 42-5. 33. Gidal B, Spencer N, Maly M, Pitterle M, Williams E, Collins M, Jones J. Valproate mediated disturbances of hemostasis. Relationship to dose and plasma concentration. Neurology 1994; 44: 1418-22. 34. Graf WD, Oleinik OE, Glauser TA, Maertens P, Eder DN, Pippenger CE. Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy. Neuropediatrics 1998; 29: 195-201. 35. Płonka-Półtorak E, Zagrodzki P, Chłopicka J, Bartoń H, Westermarck T, Kaipainen P, Kaski M, Atroshi F. Valproic acid modulates superoxide dismutase, uric acid-independent FRAP and zinc in blood of adult epileptic patients. Biol Trace Elem Res 2011; 143: 1424-34. 36. Vidya M, Subramanian P. Effects of α-ketoglutarate on antioxidants and lipid peroxidation products in rats treated with sodium valproate. J Appl Biomed 2006; 4: 141-6. 37. Espandiari P, Laura JZ, Schnackenberg K, Miller TJ, Knapton A, Herman EH, Beger RD, Hanig JP. Age-related differences in susceptibility to toxic effects of valproic acid in rats. J Appl Toxicol 2008; 28: 628-37. 38. Moreiras M, Reguez E, Guina I. On the toxicity of valproic acid. Clin Nephrol 1990; 51: 187-9. 39. El-Deeb T. The effect of valproic acid on the pancreatic acini of the adult rats and the possible protective role of L-carnitine. Light, electron microscopy and DNA electrophoresis. Egyptian J Histol 2006; 29: 1-8.

Valproik Asit İle Oluşturulan Pankreas Hasarında Edaravanun Etkisinin İncelenmesi

Year 2017, Volume: 21 Issue: 3, 570 - 577, 20.06.2017
https://doi.org/10.12991/marupj.319312

Abstract

Antiepileptik ve antikonvülzan etkili bir ilaç olan valproik asit
(VPA) oksidan üreminde artışa neden olduğundan toksik yan
etkilere sahiptir. Bu çalışmanın amacı güçlü bir serbest radikal
yakalayıcısı olan edaravonun VPA’nın yol açtığı toksisite ve
doku hasarı üzerine etkilerini biyokimyasal ve histolojik
olarak araştırmaktır. Dişi Spraque Dawley türü sıçanlar
kontrol, edaravon (30 mg kg-1 gün-1), VPA (0.5 mg kg-1 gün-
1), VPA+edaravon (aynı dozlarda) olmak üzere dört gruba
ayrıldı. VPA ve edaravon intraperitonal olarak 7 gün boyunca
verildi. Total protein, lipit peroksidasyon (LPO), siyalik asit
(SA) ve glutatyon (GSH) düzeyleri ve alkalen fosfataz (ALP),
doku faktörü (DF), süperoksit dismutaz (SOD), glutatyon-
S-transferaz (GST), katalaz (KAT), glutatyon peroksidaz
(GPx) ve miyeloperoksidaz (MPO) aktiviteleri pankreas
homojenatlarında ölçüldü. LPO ve SA düzeyleri ve ALP, DF ve
MPO aktiviteleri kontrol grubuna göre kıyaslandığında VPA
grubunda anlamlı olarak arttı. GST, KAT ve GPx aktiviteleri
kontrol grubuna göre kıyaslandığında VPA grubunda anlamlı
olarak azaldı. VPA grubunda morfolojik olarak belirgin bir
hasar tespit edildi. Edaravonun olumlu etkisi SA, DF, KAT ve
GPx parametrelerinde ve histolojik incelemede gözlemlendi.
Bu nedenle, edaravon VPA’nın pankreastaki zararlı etkilerinin
giderilmesinde ve/veya azaltılmasında yararlı olabilir.

References

  • 1. Iasemidis LD. Seizure prediction and its application. Neurosurg Clin N Am 2011; 22: 489-506. 2. Brodie MJ, Barry SJE, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012; 78: 1548-54. 3. Gerstner T, Büsing D, Bell N, Longin E, Kasper JM, Klostermann W, Hebing B, Hanefeld F, Eckel U, Hoffman R, Bettendorf U, Weidner B, Wiemer-Kruel A, Brockmann K, Neumann FW, Sandriese T, Wolff M, König S. Valproic acid-induced pancreatitis: 16 new cases and a review of the literature. J Gastroenterol 2007; 42: 39-48. 4. Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neur 2012; 11: 792-802. 5. Belcastro V, D’Egidio C, Striano P, Verrotti A. Metabolic and endocrine effects of valproic acid chronic treatment. Epilepsy Res 2013; 107: 1-8. 6. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Anthony F, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott P, Wijdicks EFM. Guidelines for the early management of adults with ischemic stroke. Stroke 2007; 38: 1655-711. 7. Xi H, Akishita M, Nagai K, Yu W, Hasegawa H, Eto M, Kozaki K, Toba K. Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis. Atherosclerosis 2007; 191: 281-9. 8. Kikuchi K, Tancharoen S, Takeshiga N, Yoshitomi M, Morioka M, Murai Y, Tanaka E. The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease. Int J Mol Sci 2013; 14: 13909-30. 9. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193; 265-75. 10. Yagi K. Assay for blood plasma or serum. Methods Enzymol 1981; 105: 328-37. 11. Warren L. The thiobarbituric acid assay of sialic acids. J Biol Chem 1959; 234: 1971-5. 12. Beutler E. Gluthatione: red cell metabolism. A manual biochemical methods. New York: Grune and Stratton, 1975, pp:112-14. 13. Walter K, Schült C. Acid and alkaline phosphatase in serum (two point method) In Methods of enzymatic Analysis Ed: Bergmeyer HU, 2nd ed. FL, 1974, pp:856-86. 14. Ingram GIC, Hills M. Reference method for the one stage prothrombin time test on human blood. Thromb Haemostas 1976; 36: 237-8. 15. Mylorie AA, Collins H, Umbles C, Kyle J. Erythrocyte SOD activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol 1986; 82: 512-20. 16. Habig WH, Jacoby WB. Assays for differentation of glutathione-S-transferases. Methods in Enzymol 1981; 77: 398-405. 17. Aebi H. Catalase in vitro. Methods Enzymol 1984; 105: 121-6. 18. Paglia DE, Valentine WN. Studies on the quantitative and quantitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967; 70: 158-68. 19. Wei H, Frenkel K. In vivo formation of oxidized DNA bases in tumor promoter- treated mouse skin. Cancer Res 1991; 51: 4443-9. 20. Hamed SA, Abdellah MM, El-Melegy N. Blood levels of trace elements, electrolytes, and oxidative stress/antioxidant systems in epileptic patients. J Pharmacol Sci 2004; 96: 465-73. 21. Tung EY, Winn LM. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: A role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol 2011; 80: 979-87. 22. Chaudhary S, Ganjoo P, Raiusddin S, Parvez, S. Nephroprotective activities of quercetin with potential relevance to oxidative stress induced by valproic acid. Protoplasma 2015; 252: 209-17. 23. Mittal K, Mehta P, Mittal A, Aggarwal HK. Valproate induced thrombocytopenia and renal dysfunction: Case report. IJPRR 2016; 5: 39-41. 24. Yamamoto Y, Kuwahara T, Watanabe K. Antioxidation activity of 3-methyl-1-phenyl-pyrazolin-5-one. Redox Rep 1996; 2: 333-8. 25. Varki A. Sialic acids in human health and disease. Trends Mol Med 2008; 14: 351-60. 26. Funk CD. Lipoxygenase pathways as mediators of early inflammatory events in atherosclerosis. Arterioscl Throm Vas 2006; 26: 1204-6. 27. Svalheim S, Røste LS, Nakken KO, Taubøll E. Bone health in adults with epilepsy. Acta Neurol Scand 2011; 124: 89-95 28. Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, Maeda H, Satoh K. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001; 14: 445-9. 29. Voudris K, Moustaki M, Zeis PM, Dimou S, Vagiakou E, Tsagris B, Skardoutsou A. Alkaline phosphatase and its isoenzyme activity for the evaluation of bone metabolism in children receiving anticonvulsant monotherapy. Seizure 2001; 11: 377-80. 30. Giray T, Vitrinel A, Comert S, Deniz NC, Erdag GC, Kesler E, Sadıkoglu S, Akın Y. The evaluation of the effects of antiepileptic drugs on bone metabolism. Turk Arch Ped 2005; 40: 221-6. 31. Yarat A, Tunali T, Piririciler R, Akyuz S, Ipbuker A, Emekli N. Salivary thromboplastic activity in diabetic and healthy controls. Clin Oral Invest 2004; 8: 36-9. 32. Cannizzaro E, Albisetti M, Wohlrab G, Schmugge M. Severe bleeding complications during antiepileptic treatment with valproic acid in children. Neuropediatrics 2007; 38: 42-5. 33. Gidal B, Spencer N, Maly M, Pitterle M, Williams E, Collins M, Jones J. Valproate mediated disturbances of hemostasis. Relationship to dose and plasma concentration. Neurology 1994; 44: 1418-22. 34. Graf WD, Oleinik OE, Glauser TA, Maertens P, Eder DN, Pippenger CE. Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy. Neuropediatrics 1998; 29: 195-201. 35. Płonka-Półtorak E, Zagrodzki P, Chłopicka J, Bartoń H, Westermarck T, Kaipainen P, Kaski M, Atroshi F. Valproic acid modulates superoxide dismutase, uric acid-independent FRAP and zinc in blood of adult epileptic patients. Biol Trace Elem Res 2011; 143: 1424-34. 36. Vidya M, Subramanian P. Effects of α-ketoglutarate on antioxidants and lipid peroxidation products in rats treated with sodium valproate. J Appl Biomed 2006; 4: 141-6. 37. Espandiari P, Laura JZ, Schnackenberg K, Miller TJ, Knapton A, Herman EH, Beger RD, Hanig JP. Age-related differences in susceptibility to toxic effects of valproic acid in rats. J Appl Toxicol 2008; 28: 628-37. 38. Moreiras M, Reguez E, Guina I. On the toxicity of valproic acid. Clin Nephrol 1990; 51: 187-9. 39. El-Deeb T. The effect of valproic acid on the pancreatic acini of the adult rats and the possible protective role of L-carnitine. Light, electron microscopy and DNA electrophoresis. Egyptian J Histol 2006; 29: 1-8.
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Details

Subjects Health Care Administration
Journal Section Articles
Authors

Sehkar Oktay This is me

Burçin Alev-tüzüner This is me

Sevim Tunalı This is me

Esin Ak This is me

Ebru Emekli-alturfan This is me

Tuğba Tunalı-akbay This is me

Leyla Koç-öztürk This is me

Şule Çetinel This is me

Refiye Yanardağ This is me

Ayşen Yarat This is me

Publication Date June 20, 2017
Published in Issue Year 2017 Volume: 21 Issue: 3

Cite

APA Oktay, S., Alev-tüzüner, B., Tunalı, S., Ak, E., et al. (2017). Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas. Marmara Pharmaceutical Journal, 21(3), 570-577. https://doi.org/10.12991/marupj.319312
AMA Oktay S, Alev-tüzüner B, Tunalı S, Ak E, Emekli-alturfan E, Tunalı-akbay T, Koç-öztürk L, Çetinel Ş, Yanardağ R, Yarat A. Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas. Marmara Pharm J. June 2017;21(3):570-577. doi:10.12991/marupj.319312
Chicago Oktay, Sehkar, Burçin Alev-tüzüner, Sevim Tunalı, Esin Ak, Ebru Emekli-alturfan, Tuğba Tunalı-akbay, Leyla Koç-öztürk, Şule Çetinel, Refiye Yanardağ, and Ayşen Yarat. “Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas”. Marmara Pharmaceutical Journal 21, no. 3 (June 2017): 570-77. https://doi.org/10.12991/marupj.319312.
EndNote Oktay S, Alev-tüzüner B, Tunalı S, Ak E, Emekli-alturfan E, Tunalı-akbay T, Koç-öztürk L, Çetinel Ş, Yanardağ R, Yarat A (June 1, 2017) Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas. Marmara Pharmaceutical Journal 21 3 570–577.
IEEE S. Oktay, “Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas”, Marmara Pharm J, vol. 21, no. 3, pp. 570–577, 2017, doi: 10.12991/marupj.319312.
ISNAD Oktay, Sehkar et al. “Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas”. Marmara Pharmaceutical Journal 21/3 (June 2017), 570-577. https://doi.org/10.12991/marupj.319312.
JAMA Oktay S, Alev-tüzüner B, Tunalı S, Ak E, Emekli-alturfan E, Tunalı-akbay T, Koç-öztürk L, Çetinel Ş, Yanardağ R, Yarat A. Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas. Marmara Pharm J. 2017;21:570–577.
MLA Oktay, Sehkar et al. “Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas”. Marmara Pharmaceutical Journal, vol. 21, no. 3, 2017, pp. 570-7, doi:10.12991/marupj.319312.
Vancouver Oktay S, Alev-tüzüner B, Tunalı S, Ak E, Emekli-alturfan E, Tunalı-akbay T, Koç-öztürk L, Çetinel Ş, Yanardağ R, Yarat A. Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas. Marmara Pharm J. 2017;21(3):570-7.