Edaravone’s Hepatoprotective Effects Against Oxidative Stress in Valproic acid –induced rat model

Year 2024, Volume: 11 Issue: 4, 1629 - 1640, 03.12.2024

Neziha Hacıhasanoğlu Çakmak , Refiye Yanardağ

https://doi.org/10.18596/jotcsa.1548185

Abstract

In this experimental study, the effect of edaravone (EDA) on liver damage caused by valproic acid (VPA) was investigated. The antioxidant, oxidative stress, and inflammation indicators such as glutathione (GSH), total lipid (TL), sialic acid (SA), aspartate (AST) and alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) were examined. Male Sprague Dawley rats were used in the experiment and randomly divided into 4 groups. The experiment lasted for 7 days. Group I: control group rats; Group II: rats receiving 0.5 g/kg VPA intraperitoneally daily. Group III: rats receiving 30 mg/kg EDA intraperitoneally daily. Group IV: rats receiving 0.5 g/kg VPA and 30 mg/kg EDA intraperitoneally daily (at the same time). On day 8, all animals were sacrificed under anesthesia, and liver tissues were removed. VPA caused the decreases in GSH, CAT, SOD, GPx, GR, and GST values and the increases in AST, ALT, ALP, GGT, sialic acid, and total lipid values. EDA reversed the in all values. These results suggest that EDA administration potentially reduces liver injury in VPA-induced hepatotoxicity.

Keywords

Liver, Edaravone, Valproic acid, Oxidative stress, Antioxidant

References

• 1. Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia [Internet]. 1994 Apr 5;35(s2):S1–6. Available from: <URL>.
• 2. Johannessen Landmark C. Antiepileptic drugs in non-epilepsy disorders. CNS Drugs [Internet]. 2008 Aug 29;22(1):27–47. Available from: <URL>.
• 3. Johannessen Landmark C, Larsson PG, Rytter E, Johannessen SI. Antiepileptic drugs in epilepsy and other disorders—A population-based study of prescriptions. Epilepsy Res [Internet]. 2009 Nov 1;87(1):31–9. Available from: <URL>.
• 4. García-Morales I, Sancho Rieger J, Gil-Nagel A, Herranz Fernández JL. Antiepileptic drugs. Neurologist [Internet]. 2007 Nov;13(6):S20–8. Available from: <URL>.
• 5. Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK, et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med [Internet]. 2010 Jun 10;362(23):2185–93. Available from: <URL>.
• 6. Rahman M, Awosika A, Nguyen H. Valproic acid [Internet]. 2024. Available from: <URL>.
• 7. Mishra MK, Kukal S, Paul PR, Bora S, Singh A, Kukreti S, et al. Insights into structural modifications of valproic acid and their pharmacological profile. Molecules [Internet]. 2021 Dec 24;27(1):104. Available from: <URL>.
• 8. Zhang XZ, Li XJ, Zhang HY. Valproic acid as a promising agent to combat Alzheimer’s disease. Brain Res Bull [Internet]. 2010 Jan 15;81(1):3–6. Available from: <URL>.
• 9. Brown BL, Craycraft LK, Justice SB. Valproic acid in the treatment of migraines. Adv Emerg Nurs J [Internet]. 2020 Oct 1;42(4):243–53. Available from: <URL>.
• 10. Shnayder NA, Grechkina V V., Khasanova AK, Bochanova EN, Dontceva EA, Petrova MM, et al. Therapeutic and toxic effects of valproic acid metabolites. Metabolites [Internet]. 2023 Jan 16;13(1):134. Available from: <URL>.
• 11. Yee CS, Vázquez GH, Hawken ER, Biorac A, Tondo L, Baldessarini RJ. Long-term treatment of bipolar disorder with valproate: Updated systematic review and meta-analyses. Harv Rev Psychiatry [Internet]. 2021 May 1;29(3):188–95. Available from: <URL>.
• 12. Meseguer ES, Elizalde MU, Borobia AM, Ramírez E. Valproic acid-induced liver injury: A case-control study from a prospective pharmacovigilance program in a tertiary hospital. J Clin Med [Internet]. 2021 Mar 10;10(6):1153. Available from: <URL>.
• 13. Nørgaard M, Jacobsen J, Ratanajamit C, Jepsen P, Mclaughlin JK, Pedersen L, et al. Valproic acid and risk of acute pancreatitis: A population-based case-control study. 2006;13(2):113–7. Available from: <URL>.
• 14. Salimi A, Alyan N, Akbari N, Jamali Z, Pourahmad J. Selenium and L-carnitine protects from valproic acid-Induced oxidative stress and mitochondrial damages in rat cortical neurons. Drug Chem Toxicol [Internet]. 2022 May 4;45(3):1150–7. Available from: <URL>.
• 15. Gayam V, Mandal AK, Khalid M, Shrestha B, Garlapati P, Khalid M. Valproic acid induced acute liver injury resulting in hepatic encephalopathy- a case report and literature review. J Community Hosp Intern Med Perspect [Internet]. 2018 Sep 3;8(5):311–4. Available from: <URL>.
• 16. Rodriguez C, Mayo JC, Sainz RM, Antolín I, Herrera F, Martín V, et al. Regulation of antioxidant enzymes: A significant role for melatonin. J Pineal Res [Internet]. 2004 Jan 11;36(1):1–9. Available from: <URL>.
• 17. Gunata M, Parlakpinar H, Acet HA. Melatonin: A review of its potential functions and effects on neurological diseases. Rev Neurol (Paris) [Internet]. 2020 Mar 1;176(3):148–65. Available from: <URL>.
• 18. Kabuto H, Hasuike S, Minagawa N, Shishibori T. Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues. Environ Res [Internet]. 2003 Sep 1;93(1):31–5. Available from: <URL>.
• 19. Green A, Ashwood T. Free radical trapping as a therapeutic approach to neuroprotection in stroke: Experimental and clinical studies with NXY-059 and free radical scavengers. Curr Drug Target -CNS Neurol Disord [Internet]. 2005 Apr 1;4(2):109–18. Available from: <URL>.
• 20. Saini AK, Patel RJ, Sharma SS, H. S. AK. Edaravone attenuates hydroxyl radical stress and augmented angiotensin II response in diabetic rats. Pharmacol Res [Internet]. 2006 Jul 1;54(1):6–10. Available from: <URL>.
• 21. Abe K, Yuki S, Kogure K. Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger. Stroke [Internet]. 1988 Apr;19(4):480–5. Available from: <URL>.
• 22. Nishi H, Watanabe T, Sakurai H, Yuki S, Ishibashi A. Effect of MCI-186 on brain edema in rats. Stroke [Internet]. 1989 Sep;20(9):1236–40. Available from: <URL>.
• 23. Watanabe K, Tanaka M, Yuki S, Hirai M, Yamamoto Y. How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Clin Biochem Nutr [Internet]. 2018 Jan 1;62(1):20–38. Available from: <URL>.
• 24. Kikuchi K, Tancharoen S, Takeshige N, Yoshitomi M, Morioka M, Murai Y, et al. The efficacy of edaravone (Radicut), a free radical scavenger, for cardiovascular disease. Int J Mol Sci [Internet]. 2013 Jul 4;14(7):13909–30. Available from: <URL>.
• 25. Beutler E. Glutathione in red blood cell metabolism. A manuel biochem methods. Ann Intern Med [Internet]. 1975;83(6):919. Available from: <URL>.
• 26. Frings CS, Fendley TW, Dunn RT, Queen CA. Improved Determination of Total Serum Lipids by the Sulfo-Phospho-Vanillin Reaction. Clin Chem [Internet]. 1972 Jul 1;18(7):673–4. Available from: <URL>.
• 27. Warren L. The thiobarbituric acid assay of sialic acids. J Biol Chem [Internet]. 1959;234(8):1971–5. Available from: <URL>.
• 28. Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol [Internet]. 1957 Jul 1;28(1):56–63. Available from: <URL>.
• 29. Walter K, Schütt C. Acid and alkaline phosphatase in serum. In: Urlich Bergmeyer H, editor. Methods Enzym Anal [Internet]. 1974. p. 856–60. Available from: <URL>.
• 30. Szasz G. A kinetic photometric method for serum γ-Glutamyl transpeptidase. Clin Chem [Internet]. 1969 Feb 1;15(2):124–36. Available from: <URL>.
• 31. Aebi H. Catalase in vitro. In: Methods in Enzymology [Internet]. Methods Enzymol; 1984. p. 121–6. Available from: <URL>.
• 32. Mylroie AA, Collins H, Umbles C, Kyle J. Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol [Internet]. 1986 Mar 15;82(3):512–20. Available from: <URL>.
• 33. Wendel A. Glutathione peroxidase. In: Methods in Enzymology [Internet]. Methods Enzymol; 1981. p. 325–33. Available from: <URL>.
• 34. Habig WH, Jakoby WB. Assays for differentiation of glutathione S-Transferases. In: Methods in Enzymology [Internet]. Academic Press; 1981. p. 398–405. Available from: <URL>.
• 35. Lowry O, Rosebrough N, Farr A, Randall R. Protein measurement with the folin phenol reagent. J Biol Chem [Internet]. 1951;193(1):265–75. Available from: <URL>.
• 36. Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, et al. Drug-induced liver injury. Nat Rev Dis Prim [Internet]. 2019 Aug 22;5(1):58. Available from: <URL>.
• 37. Shah J, Lingiah V, Pyrsopoulos N, Galan M. Acute liver injury in a patient treated with rosuvastatin: A rare adverse effect. Gastroenterol Res [Internet]. 2019;12(5):263–6. Available from: <URL>.
• 38. Zhou L, Chen L, Zeng X, Liao J, Ouyang D. Ginsenoside compound K alleviates sodium valproate-induced hepatotoxicity in rats via antioxidant effect, regulation of peroxisome pathway and iron homeostasis. Toxicol Appl Pharmacol [Internet]. 2020 Jan 1;386:114829. Available from: <URL>.
• 39. Chang TKH, Abbott FS. Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity. Drug Metab Rev [Internet]. 2006 Jan 9;38(4):627–39. Available from: <URL>.
• 40. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J [Internet]. 2009 Jan 1;417(1):1–13. Available from: <URL>.
• 41. Cagin YF, Parlakpinar H, Polat A, Vardi N, Atayan Y, Erdogan MA, et al. The protective effects of apocynin on ionizing radiation-induced intestinal damage in rats. Drug Dev Ind Pharm [Internet]. 2016 Feb 1;42(2):317–24. Available from: <URL>.
• 42. Graf W, Oleinik O, Glauser T, Maertens P, Eder D, Pippenger C. Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy. Neuropediatrics [Internet]. 1998 Aug 12;29(04):195–201. Available from: <URL>.
• 43. Reed DJ. Glutathione: Toxicological implications. Annu Rev Pharmacol Toxicol [Internet]. 1990 Apr 1;30(1):603–31. Available from: <URL>.
• 44. Meister A. Selective modification of glutathione metabolism. Science (80- ) [Internet]. 1983 Apr 29;220(4596):472–7. Available from: <URL>.
• 45. Bindhumol V, Chitra KC, Mathur PP. Bisphenol A induces reactive oxygen species generation in the liver of male rats. Toxicology [Internet]. 2003 Jun 30;188(2–3):117–24. Available from: <URL>.
• 46. Kabuto H, Amakawa M, Shishibori T. Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sci [Internet]. 2004 Apr 30;74(24):2931–40. Available from: <URL>.
• 47. Bailly C, Hecquet PE, Kouach M, Thuru X, Goossens JF. Chemical reactivity and uses of 1-phenyl-3-methyl-5-pyrazolone (PMP), also known as edaravone. Bioorg Med Chem [Internet]. 2020 May 15;28(10):115463. Available from: <URL>.
• 48. Yamamoto Y, Kuwahara T, Watanabe K, Watanabe K. Antioxidant activity of 3-methyl-1-phenyl-2-pyrazolin-5-one. Redox Rep [Internet]. 1996 Oct 13;2(5):333–8. Available from: <URL>.
• 49. Ohara K, Fujii A, Ichimura Y, Sato K, Mukai K. Kinetic study of radical-scavenging and vitamin E-regenerating actions of edaravone (3-Methyl-1-phenyl-2-pyrazolin-5-one). Bull Chem Soc Jpn [Internet]. 2006 Mar 1;79(3):421–6. Available from: <URL>.
• 50. Hu C, Nydes M, Shanley KL, Morales Pantoja IE, Howard TA, Bizzozero OA. Reduced expression of the ferroptosis inhibitor glutathione peroxidase‐4 in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurochem [Internet]. 2019 Feb 3;148(3):426–39. Available from: <URL>.
• 51. Ferretti G, Bacchetti T. Peroxidation of lipoproteins in multiple sclerosis. J Neurol Sci [Internet]. 2011 Dec 15;311(1–2):92–7. Available from: <URL>.
• 52. Hussein AM, Awadalla A, Abbas KM, Sakr HF, Elghaba R, Othman G, et al. Chronic valproic acid administration enhances oxidative stress, upregulates IL6 and downregulates Nrf2, Glut1 and Glut4 in rat’s liver and brain. Neuroreport [Internet]. 2021 Jul 7;32(10):840–50. Available from: <URL>.
• 53. Abdelkader NF, Elyamany M, Gad AM, Assaf N, Fawzy HM, Elesawy WH. Ellagic acid attenuates liver toxicity induced by valproic acid in rats. J Pharmacol Sci [Internet]. 2020 May 1;143(1):23–9. Available from: <URL>.
• 54. Khodayar MJ, Kalantari H, Khorsandi L, Ahangar N, Samimi A, Alidadi H. Taurine attenuates valproic acid-induced hepatotoxicity via modulation of RIPK1/RIPK3/MLKL-mediated necroptosis signaling in mice. Mol Biol Rep [Internet]. 2021 May 25;48(5):4153–62. Available from: <URL>.
• 55. Turkyilmaz IB, Altas N, Arisan I, Yanardag R. Effect of vitamin B6 on brain damage in valproic acid induced toxicity. J Biochem Mol Toxicol [Internet]. 2021 Sep 26;35(9):e22855. Available from: <URL>.
• 56. Oktay S, Alev B, Tunali S, Emekli-Alturfan E, Tunali-Akbay T, Koc-Ozturk L, et al. Edaravone ameliorates the adverse effects of valproic acid toxicity in small intestine. Hum Exp Toxicol [Internet]. 2015 Jun 10;34(6):654–61. Available from: <URL>.
• 57. Alzoubi KH, Aburashed ZO, Mayyas F. Edaravone protects from memory impairment induced by chronic L-methionine administration. Naunyn Schmiedebergs Arch Pharmacol [Internet]. 2020 Jul 27;393(7):1221–8. Available from: <URL>.
• 58. Singh S, Kumar A. Protective effect of edaravone on cyclophosphamide induced oxidative stress and neurotoxicity in Rats. Curr Drug Saf [Internet]. 2019 Sep 17;14(3):209–16. Available from: <URL>.
• 59. Zhu G, Zeng Y, Peng W, Lu C, Cai H, Abuduxukuer Z, et al. Edaravone alleviated allergic airway inflammation by inhibiting oxidative stress and endoplasmic reticulum stress. Eur J Pharmacol [Internet]. 2024 Jan 5;966:176317. Available from: <URL>.
• 60. Yamamoto Y, Terada K, Takahashi Y, Imai K, Kagawa Y, Inoue Y. Influence of antiepileptic drugs on serum lipid levels in adult epilepsy patients. Epilepsy Res [Internet]. 2016 Nov 1;127:101–6. Available from: <URL>.
• 61. Nikolaos T, Stylianos G, Chryssoula N, Irini P, Christos M, Dimitrios T, et al. The effect of long-term antiepileptic treatment on serum cholesterol (TC, HDL, LDL) and triglyceride levels in adult epileptic patients on monotherapy. Med Sci Monit [Internet]. 2004;10(4):MT50–2. Available from: <URL>.
• 62. Erminio C, Ferini-Strambi L, Calori G, Zamboni M, Iannaccone S, Smirne S. Effect of chronic antiepileptic treatment on biochemical parameters. Clin Neuropharmacol [Internet]. 1994;17(2):199–203. Available from: <URL>.
• 63. Guo H, Dong N, Chen F, Zeng Y, Hu Y, Xia Y, et al. Effect of long‐term valproic acid therapy on lipid profiles in paediatric patients with epilepsy: A meta‐analysis. Epileptic Disord [Internet]. 2022 Oct 3;24(5):822–30. Available from: <URL>.
• 64. Keaney JF, Gaziano JM, Xu A, Frei B, Curran-Celentano J, Shwaery GT, et al. Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits. Proc Natl Acad Sci [Internet]. 1993 Dec 15;90(24):11880–4. Available from: <URL>.
• 65. Keaney JF, Xu A, Cunningham D, Jackson T, Frei B, Vita JA. Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. J Clin Invest [Internet]. 1995 Jun 1;95(6):2520–9. Available from: <URL>.
• 66. Lamb DJ, Reeves GL, Taylor A, Ferns GA. Dietary copper supplementation reduces atherosclerosis in the cholesterol-fed rabbit. Atherosclerosis [Internet]. 1999 Sep 1;146(1):33–43. Available from: <URL>.
• 67. Xi H, Akishita M, Nagai K, Yu W, Hasegawa H, Eto M, et al. Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis. Atherosclerosis [Internet]. 2007 Apr 1;191(2):281–9. Available from: <URL>.
• 68. Varki A. Sialic acids in human health and disease. Trends Mol Med [Internet]. 2008 Aug 1;14(8):351–60. Available from: <URL>.
• 69. Succari M, Foglietti MJ, Percheron F. Perchlorosoluble glycoproteins and myocardial infarct: modifications of the carbohydrate moiety (author’s transl. Pathol Biol [Internet]. 1982 Mar 1;30(3):151–4. Available from: <URL>.
• 70. Crook M, Tutt P. Serum sialic acid concentration in patients with hypertriglyceridaemia showing the Frederickson’s IIB phenotype. Clin Sci [Internet]. 1992 Nov 1;83(5):593–5. Available from: <URL>.
• 71. Rastam L, Lindberg G, Folsom AR, Burke GL, Nilsson-Ehle P, Lundblad A. Association between serum sialic acid concentration and carotid atherosclerosis measured by B-mode ultrasound. Int J Epidemiol [Internet]. 1996;25(5):953–8. Available from: <URL>.
• 72. Crook M, Haq M, Haq S, Tutt P. Plasma sialic acid and acute-phase proteins in patients with myocardial infarction. Angiology [Internet]. 1994 Aug 1;45(8):709–15. Available from: <URL>.
• 73. Oktay S, Alev-Tüzüner B, Tunalı S, Ak E, Emekli-Alturfan E, Tunalı-Akbay T, et al. Investigation of the effects of edaravone on valproic acid induced tissue damage in pancreas. Marmara Pharm J [Internet]. 2017 Jun 20;21(3):570–7. Available from: <URL>.
• 74. Kandemir FM, Ileriturk M, Gur C. Rutin protects rat liver and kidney from sodium valproate-induce damage by attenuating oxidative stress, ER stress, inflammation, apoptosis and autophagy. Mol Biol Rep [Internet]. 2022 Jul 29;49(7):6063–74. Available from: <URL>.
• 75. Koroglu OF, Gunata M, Vardi N, Yildiz A, Ates B, Colak C, et al. Protective effects of naringin on valproic acid-induced hepatotoxicity in rats. Tissue Cell [Internet]. 2021 Oct 1;72:101526. Available from: <URL>.
• 76. Hassanein EHM, Mohamed WR, Hussein RM, Arafa ESA. Edaravone alleviates methotrexate-induced testicular injury in rats: Implications on inflammation, steroidogenesis, and Akt/p53 signaling. Int Immunopharmacol [Internet]. 2023 Apr 1;117:109969. Available from: <URL>.
• 77. Seyedinia SA, Tarahomi P, Abbarin D, Sedaghat K, Rashidy-Pour A, Yaribeygi H, et al. Saffron and crocin ameliorate prenatal valproic acid-induced autistic-like behaviors and brain oxidative stress in the male offspring rats. Metab Brain Dis [Internet]. 2023 Oct 11;38(7):2231–41. Available from: <URL>.
• 78. Fan SR, Ren TT, Yun MY, Lan R, Qin XY. Edaravone attenuates cadmium-induced toxicity by inhibiting oxidative stress and inflammation in ICR mice. Neurotoxicology [Internet]. 2021 Sep 1;86:1–9. Available from: <URL>.
• 79. Emekli Alturfan E, Alev B, Tunali S, Oktay S, Tunali AT, Ozturk L, et al. Effects of Edaravone on Cardiac Damage in Valproic Acid Induced Toxicity. Ann Clin Lab Sci [Internet]. 2015;45(2):166–72. Available from: <URL>.
• 80. Pippenger CE. Valproate therapy depresses GSH-Px and superoxide dismutase enzyme activity. A possible mechanism for VPA induced idiosyncratic drug toxicity. Clin Chem [Internet]. 1989;35:1173-. Available from: <URL>.
• 81. Cotariu D, Evans S, Zaidman JL, Marcus O. Early changes in hepatic redox homeostasis following treatment with a single dose of valproic acid. Biochem Pharmacol [Internet]. 1990 Aug 1;40(3):589–93. Available from: <URL>.
• 82. Hamed SA, Abdellah MM, El-Melegy N. Blood levels of trace elements, electrolytes, and oxidative stress/antioxidant systems in epileptic patients. J Pharmacol Sci [Internet]. 2004;96(4):465–73. Available from: <URL>.
• 83. Cengiz M, Yüksel A, Seven M. The effects of carbamazepine and valproic acid on the erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children. Pharmacol Res [Internet]. 2000 Apr 1;41(4):423–5. Available from: <URL>.
• 84. Kürekçi AE, Alpay F, Tanindi Ş, Gokçay E, Ozcan O, Akin R, et al. Plasma trace element, plasma glutathione peroxidase, and superoxide dismutase levels in epileptic children receiving antiepileptic drug therapy. Epilepsia [Internet]. 1995 Jun 28;36(6):600–4. Available from: <URL>.
• 85. Bayrak BB, Yilmaz S, Hacihasanoglu Cakmak N, Yanardag R. The effects of edaravone, a free‐radical scavenger in lung injury induced by valproic acid demonstrated via different biochemical parameters. J Biochem Mol Toxicol [Internet]. 2021 Sep 26;35(9):e22847. Available from: <URL>.
• 86. Tabassum H, Parvez S, Rehman H, Dev Banerjee B, Siemen D, Raisuddin S. Nephrotoxicity and its prevention by taurine in tamoxifen induced oxidative stress in mice. Hum Exp Toxicol [Internet]. 2007 Jun 1;26(6):509–18. Available from: <URL>.
• 87. Öztaylan Y, Türkyılmaz İ, Yanardağ R. The effects of alpha lipoic acid on lens injury in rats administered with valproic acid. J Istanbul Fac Med [Internet]. 2022 Aug 17;85(4):557–63. Available from: <URL>.
• 88. Chaudhary S, Parvez S. An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats. Neuroscience [Internet]. 2012 Dec 6;225:258–68. Available from: <URL>.
• 89. Hassan MQ, Akhtar MS, Akhtar M, Ali J, Haque SE, Najmi AK. Edaravone protects rats against oxidative stress and apoptosis in experimentally induced myocardial infarction: Biochemical and ultrastructural evidence. Redox Rep [Internet]. 2015 Nov 2;20(6):275–81. Available from: <URL>.
• 90. Tong V, Teng XW, Chang TKH, Abbott FS. Valproic acid I: Time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicol Sci [Internet]. 2005 Aug 1;86(2):427–35. Available from: <URL>.
• 91. Chaudhary S, Ganjoo P, Raiusddin S, Parvez S. Nephroprotective activities of quercetin with potential relevance to oxidative stress induced by valproic acid. Protoplasma [Internet]. 2015 Jan 8;252(1):209–17. Available from: <URL>.
• 92. Lu XY, Li MQ, Li YT, Yao JY, Zhang LX, Zeng ZH, et al. Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder. Neuropharmacology [Internet]. 2024 Nov 1;258:110089. Available from: <URL>.