Valproic acid induced oxidative brain injury in rats: Protective effect of edaravone

Neziha Hacıhasanoğlu Çakmak; Refiye Yanardağ

doi:10.33988/auvfd.1738110

Valproic acid induced oxidative brain injury in rats: Protective effect of edaravone

Abstract

Valproic acid (2-propyl valeric acid, VPA) is the drug of choice for the treatment of migraine, bipolar disorder, and epileptic disorders in both children and adults. Although VPA has beneficial effects, long-term administration is reported to damage many tissues and organs. VPA administration increases free-radical production. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDA) is a potent antioxidant that protects against oxidative stress. The aim of our study was to investigate the protective effects of EDA against brain damage in VPA-treated rats. Male Sprague Dawley rats were used in our study. The rats were randomly divided into four groups: control, EDA, VPA, and VPA+EDA. EDA and VPA were administered intraperitoneally at doses of 30 mg/kg and 0.5 g/kg, respectively daily for 7 days. On day 8, all animals were sacrificed under anesthesia, and brain tissues were removed. VPA caused decreases in the levels of reduced glutathione (GSH, P<0.05), glutathione peroxidase (GPx, P<0.001), glutathione reductase (GR, P<0.001), and paraoxonase (PON, P<0.0001). On the other hand, VPA increased values of lipid peroxidation (LPO, P<0.05), catalase (CAT, P<0.05), superoxide dismutase (SOD, P<0.0001), glutathione-S-transferase (GST, P<0.01), xanthine oxidase (XO, P<0.01), adenosine deaminase (ADA, P<0.001), protein carbonyl (PC, P<0.0001), myeloperoxidase (MPO, P<0.0001), sialic acid (SA, P<0.0001), and acetylcholinesterase (AChE, P<0.0001) compared with the control group. EDA reversed all values. These results suggest that EDA administration potentially reduces VPA-induced brain injury.

Keywords

References

Aaberg KM, Gunnes N, Bakken IJ, et al (2017): Incidence and prevalence of childhood epilepsy: a nationwide cohort study. Pediatrics, 139, e20163908.
Abe K, Yuki S, Kogure K (1988): Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger. Stroke, 19, 480–5.
Aebi H (1984): Catalase in vitro. Methods Enzymol, 105, 121–126.
Agresti C, Mechelli R, Olla S, et al (2020): Oxidative status in multiple sclerosis and off-targets of antioxidants: the case of edaravone. Curr Med Chem, 27, 2095–2105.
Alshogran OY, Aseel YAT, Shreen DN (2022): Exploring the effects of edaravone in rats with contrast-induced acute kidney injury. Life Sci, 309, 121006.
Aviram M, Hardak E, Vaya J, et al (2000): Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON 1 esterase and peroxidase-like activities. Circulation, 101, 2510–2517.
Baldissera MD, Souza CF, Santos RCV, et al (2018): Blood–brain barrier breakdown and myeloperoxidase activity in silver catfish experimentally infected with Pseudomonas aeruginosa. J Fish Dis, 41, 209-213.
Bayrak BB, Sancar S, Hacihasanoglu Cakmak N, et al (2025): Ameliorative effects of edaravone against valproic acid-induced kidney damage. J Mol Histol, 56, 4.

Beghi E (2020): The epidemiology of epilepsy. Neuroepidemiology, 54, 185–191.
Berlett BS, Stadtman ER (1997): Protein oxidation in aging, disease, and oxidative stress. J Biol Chem, 272, 20313-20316.
Beutler E (1975): Reduced Gutathione (GSH). 112–114. In: Bergmeyer HV (ed) Red Blood Cell Metabolism. A Manual Of Biochemical Methods, 2nd edn. Grune and Stratton, New York.
Brown BL, Craycraft LK, Justice SB (2020): Valproic acid in the treatment of migraines. Adv Emerg Nurs J, 42, 243–253.
Chaudhary S, Ganjoo P, Raiusddin S, et al (2015): Nephroprotec¬tive activities of quercetin with potential relevance to oxidative stress induced by valproic acid. Protoplasma, 252, 209–217.
Chaudhary S, Parvez S (2012): An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats, Neuroscience, 225, 258-268.
Chen YCB, Liang CS, Wang LJ, et al (2022): Comparative effectiveness of valproic acid in different serum concentrations for maintenance treatment of bipolar disorder: A retrospective cohort study using target trial emulation framework. EClinMed, 54, 101678.
Corte ED, Stirpe F (1968): Regulation of xanthine oxidase in rat liver: modifications of the enzyme activity of rat liver supernatant on storage at 20 degrees. Biochem J, 108, 349–351.
Crook M, Tutt P (1992): Serum sialic acid concentration in patients with hypertriglyceridaemia showing the Frederickson’s IIB phenotype. Clin Sci, 83, 593–595.
Crook M, Haq M, Haq S, et al (1994): Plasma sialic acid and acute-phase proteins in patients with myocardial infarction. Angiology, 45, 709–715.
Ellman GL, Courtney KD, Andres V, et al (1961): A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol, 7, 88-95.
Feng S, Yang Q, Liu M, et al (2011): Edaravone for acute ischaemic stroke. Cochrane Database of Systematic Reviews, 12, CD007230.
Furlong CE, Richter RJ, Seidel SJ (1988): Role of genetic polymor¬phism of human plasma paraoxonase/arylesterase in hydrolysis of the insecticide metabolites chlorpyrifos oxon and paraoxon. Am J Hum Gen, 43, 230–238.
Gomes CV, Kaser MP, Tomé AR, et al (2011): Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta, 1808, 1380-1399.
Graf W, Oleinik O, Glauser T, et al (1998): Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy. Neuropediatrics, 29, 195–201.
Gunata M, Parlakpinar H, Acet HA (2020): Melatonin: A review of its potential functions and effects on neurological diseases. Rev Neurol, 176, 148–65.
Habig WH, Jakoby WB (1981): Assays for differentation of glutathione-S-transferases. Methods Enzymol, 77, 398-405.
Hacihasanoglu Cakmak N, Yanardag R (2015): Edaravone, a free radi¬cal scavenger, protects liver against valproic acid induced toxic¬ity. J Serb Chem Soc, 80, 627–637.
Hassan MQ, Akhtar MS, Akhtar M, et al (2015): Edaravone protects rats against oxidative stress and apoptosis in experimentally induced myocardial infarction: Biochemical and ultrastructural evidence. Redox Rep, 20, 275–81.
Hassan MQ, Akhtar MS, Afzal O, et al (2020): Edaravone and benidipine protect myocardial damage by regulating mitochondrial stress, apoptosis signalling and cardiac biomarkers against doxorubicin-induced cardiotoxicity. Clin Exp Hypertens, 42, 381-392.
Heidari R, Jafari F, Khodaei F, et al (2018): Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrol, 23, 351–361.
Işık M, Demir Y, Kırıcı M, et al (2015): Changes in the anti-oxidant system in adult epilepsy patients receiving anti-epileptic drugs. Arch Physiol Biochem, 121, 97-102.
Jafarian I, Eskandari MR, Mashayekhi V, et al (2013): Toxicity of valproic acid in isolated rat liver mitochondria. Toxicol Mech Methods, 23, 617-623.
Jiao SS, Yao XQ, Liu YH, et al (2015): Edaravone alleviates Alzheimer’s diseasetype pathologies and cognitive deficits. Proc Natl Acad Sci U S A, 112, 5225–5230.
Jin DQ, Li G, Kim JS, et al (2004): Preventive effects of laminaria japonica aqueous extract on the oxidative stress and xanthine oxidase activity in streptozotocin-induced diabetic rat liver. Biol Pharm Bull, 27,1037–1040.
Johnson EL (2019): Seizures and epilepsy. Med Clin North Am, 103, 309–324.
Karker H (1964): Method for estimation of serum adenosine deaminase. Scand J Clin Lab Invest, 16, 570-574.
Katyayan A, Diaz-Medina G (2021): Epilepsy: Epileptic syndromes and treatment. Neurol Clin, 39, 779–795.
Kawasaki T, Kitao T, Nakagawa K, et al (2007): Nitric oxide-induced apoptosis incultured rat astrocytes: protection by edaravone, a radical scavenger. Glia, 55, 1325-1333.
Kettle AJ, Winterbourn CC (1997): Myeloperoxidase: a key regulator of neutrophil oxidant production. Redox Rep, 3, 3-15.
Kikuchi K, Tancharoen S, Takeshige N, et al (2013): The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease. Int J Mol Sci, 14,13909–13930.
Kikuchi K, Uchikado H, Miyagi N, et al (2011): Beyond neurological disease: new targets for edaravone. Int J Mol Med, 28, 899–906.
Kikuchi K, Takeshige N, Miura N, et al (2012): Beyond free radical scavenging: beneficial effects of edaravone (Radicut) in various diseases (review). Exp Ther Med, 3, 3–8.
Kumar H, Sharma B (2016): Memantine ameliorates autistic behavior, biochemistry & blood brain barrier impairments in rats. Brain Res Bull, 124, 27-39.
Ledwozyw A, Michalak J, Stephien A, et al (1986): The rela¬tionship plasma triglycerides, cholesterol, total lipids and lipid peroxidation products during human atherosclerosis. Clin Chim Acta, 155, 275–284.
Lehmann M, Regland B, Blennow K, et al (2003): Vitamin B12-B6-folate treatment improves blood-brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment. Dement Geriatr Cogn Disord, 16, 145-150.
Levine RL, Garland D, Oliver CN, et al (1990): Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol, 186, 464-478.
Lowry OH, Rosebrough NJ, Farr AL, et al (1951): Protein mea¬surement with the Folin phenol reagent. J Biol Chem, 193, 265– 275.
Lu XY, Meng-Qing L, Yong-Tao L, et al (2024): Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder. Neuropharmacology, 258, 110089.
Meister A (1983): Selective modification of glutathione metabolism. Science, 220, 472–477.
Mylroie AA, Collins H, Umbles C, et al (1986): Erythrocyte super¬oxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol, 82, 512–520.
Natori T, Kodaira F, Hirasawa T, et al (2008): Augmentation of polysialic acid by valproic acid in early postnatal mouse hippocampus and primary cultured hippocampal neurons. J Biosci Bioeng, 105, 164-167.
Navab M, Hama-Levy S, Van Lenten BJ, et al (1997): Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest, 99, 2005–2019.
Nematollah A, Maloos N, Abdolali N, et al (2017): Zinc deficiency and oxidative stress involved in valproic acid induced hepatotoxicity: Protection by zinc and selenium supplementation. Biol Trace Elem Res, 179, 102–109.
Nermin E, Sheikh A, Petrilla J, et al (2020): The dual-active histamine h3 receptor antagonist and acetylcholine esterase ınhibitor e100 alleviates autistic-like behaviors and oxidative stress in valproic acid induced autism in mice. Int J Mol Sci, 21, 3996.
Nishi H, Watanabe T, Sakurai H, et al (1989): Effect of MCI-186 on brain edema in rats. Stroke, 20, 1236–40.
Okatani Y, Wakatsuki A, Enzan H, et al (2003): Edaravone protects against ischemia/reperfusion-induced oxidative damage to mitochondria in rat liver. Eur J Pharmacol, 465, 163-170.
Oktay NŞ, Alev Tüzüner B, Tunalı S, et al (2024): Potential protective role of radicut in valproic acid-induced oxidative stress in rat spleen. Igusabder, 22, 308-319.
Oktay S, Alev-Tüzüner B, Tunalı S, et al (2017): Investigation of the effects of edaravone on valproic acid induced tissue damage in pancreas. Marmara Pharm J, 21, 570–577.
Phyu MP, Tangpong J (2014): Neuroprotective effects of xanthone derivative of Garcinia mangostana against lead-induced acetylcholinesterase dysfunction and cognitive impairment. Food Chem Toxicol, 70, 151-156.
Reed DJ (1990): Glutathione: Toxicological implications. Annu Rev Pharmacol Toxicol, 30, 603–31.
Rodriguez C, Mayo JC, Sainz RM, et al (2004): Regulation of antioxidant enzymes: A significant role for melatonin. J Pineal Res, 36,1–9.
Romoli M, Mazzocchetti P, D’Alonzo R, et al (2019): Valproic acid and epilepsy: from molecular mechanisms to clinical evidences. Curr Neuropharmacol, 17, 926–946.
Safdar A, Ismail F (2023): A comprehensive review on pharmacological applications and drug-induced toxicity of valproic acid. Saudi Pharm J, 31, 265–278.
Sanjiv S, Abhishek K (2019): Protective effect of edaravone on cyclophosphamide ınduced oxidative stress and neurotoxicity in rats. Curr Drug Saf, 14, 209-216.
Sari RA, Tays S, Yilmaz O, et al (2003): Correlation of serum levels of adenosine deaminase activity and its isoenzymes with disease activity in rheumatoid arthritis. Clin Exp Rheumatol, 21, 87-90.
Seyedinia SA, Tarahomi P, Abbarin D, et al (2023): Saffron and crocin ameliorate prenatal valproic acid-induced autistic-like behaviors and brain oxidative stress in the male offspring rats. Metab Brain Dis, 38, 2231–2241.
Shen Y, Zhang J, Xu Y, et al (2023): Ultrasound-enhanced brain delivery of edaravone provides additive amelioration on disease progression in an ALS mouse model. Brain Stimul, 16, 628–641.
Sokmen BB, Tunali S, Yanardag R (2012): Effects of vitamin U (S-methyl methionine sulphonium chloride) on valproic acid induced liver injury in rats. Food Chem Toxicol, 50, 3562-3566.
Stadtman ER, Levine RL (2000): Protein oxidation. Ann N Y Acad Sci, 899, 191-208.
Tarazi FI, Sahli ZT, Wolny M, et al (2014): Emerging therapies for Parkinson’s disease: from bench to bedside. Pharmacol Ther, 144, 123–133.
Taş S, Sarandöl E, Dirican M (2014): Vitamin B6 supplementation ımproves oxidative stress and enhances serum paraoxonase/arylesterase activities in streptozotocin-ınduced diabetic rats. Sci World J, 351598.
Thimmulappa RK, Chattopadhyay I, Rajasekaran S (2019): Oxidative Stress Mechanism In The Pathogenesis Of Environmental Lung Diseases. 103-137. Oxidative Stress in Lung Diseases. Springer Nature. Singapore.
Tunali S, Cimen ES, Yanardag R (2020): The effects of chard on brain damage in valproic acid-induced toxicity. J Food Biochem, 44, e13382.
Tunali S, Kahraman S, Yanardag R (2015): Vitamin U, a novel free radical scavenger, prevents lens injury in rats administered with valproic acid. Hum Exp Toxicol, 34, 904-910.
Turkyilmaz B, Altas N, Arisan I, et al (2021): Effect of vitamin B6 on brain damage in valproic acid induced toxicity. J Biochem Mol Toxicol, 35, e22855.
Turkyilmaz IB, Sokmen BB, Yanardag R (2020): Alpha‐lipoic acid prevents brain injury in rats administered with valproic acid. J Biochem Mol Toxicol, 34, e22580.
Türkyılmaz IB, Karatuğ Kaçar A, Bolkent Ş, et al (2023): Damage to liver tissue caused by valproic acid used for treating epilepsy: Protective effects of vitamin B6. Arch Epilepsy, 29, 9-15.
Warren L (1959): The thiobarbituric acid assay of sialic acids. J Biol Chem, 234, 1971-1975.
Wei H, Frenkel K (1991): In vivo formation of oxidized DNA bases in tumor promoter-treated mouse skin. Cancer Res, 51, 4443-4449.
Wendel A (1981): Glutathione peroxidase. Methods Enzymol, 77, 325.

Details

Primary Language

English

Subjects

Veterinary Biochemistry

Journal Section

Research Article

Authors

Neziha Hacıhasanoğlu Çakmak ^*
0000-0002-6183-5015
Türkiye

Refiye Yanardağ
0000-0003-4185-4363
Türkiye

Early Pub Date

January 25, 2026

Publication Date

January 25, 2026

Submission Date

July 8, 2025

Acceptance Date

December 4, 2025

Published in Issue

Year 2026 Volume: 73 Number: 2

DOI

https://doi.org/10.33988/auvfd.1738110

IZ

https://izlik.org/JA78PE89AN

Cite

RIS / Bibtex

APA

Hacıhasanoğlu Çakmak, N., & Yanardağ, R. (2026). Valproic acid induced oxidative brain injury in rats: Protective effect of edaravone. Ankara Üniversitesi Veteriner Fakültesi Dergisi, 73(2), 185-193. https://doi.org/10.33988/auvfd.1738110

AMA

1.Hacıhasanoğlu Çakmak N, Yanardağ R. Valproic acid induced oxidative brain injury in rats: Protective effect of edaravone. Ankara Univ Vet Fak Derg. 2026;73(2):185-193. doi:10.33988/auvfd.1738110

Chicago

Hacıhasanoğlu Çakmak, Neziha, and Refiye Yanardağ. 2026. “Valproic Acid Induced Oxidative Brain Injury in Rats: Protective Effect of Edaravone”. Ankara Üniversitesi Veteriner Fakültesi Dergisi 73 (2): 185-93. https://doi.org/10.33988/auvfd.1738110.

EndNote

Hacıhasanoğlu Çakmak N, Yanardağ R (April 1, 2026) Valproic acid induced oxidative brain injury in rats: Protective effect of edaravone. Ankara Üniversitesi Veteriner Fakültesi Dergisi 73 2 185–193.

IEEE

[1]N. Hacıhasanoğlu Çakmak and R. Yanardağ, “Valproic acid induced oxidative brain injury in rats: Protective effect of edaravone”, Ankara Univ Vet Fak Derg, vol. 73, no. 2, pp. 185–193, Apr. 2026, doi: 10.33988/auvfd.1738110.

ISNAD

Hacıhasanoğlu Çakmak, Neziha - Yanardağ, Refiye. “Valproic Acid Induced Oxidative Brain Injury in Rats: Protective Effect of Edaravone”. Ankara Üniversitesi Veteriner Fakültesi Dergisi 73/2 (April 1, 2026): 185-193. https://doi.org/10.33988/auvfd.1738110.

JAMA

1.Hacıhasanoğlu Çakmak N, Yanardağ R. Valproic acid induced oxidative brain injury in rats: Protective effect of edaravone. Ankara Univ Vet Fak Derg. 2026;73:185–193.

MLA

Hacıhasanoğlu Çakmak, Neziha, and Refiye Yanardağ. “Valproic Acid Induced Oxidative Brain Injury in Rats: Protective Effect of Edaravone”. Ankara Üniversitesi Veteriner Fakültesi Dergisi, vol. 73, no. 2, Apr. 2026, pp. 185-93, doi:10.33988/auvfd.1738110.

Vancouver

1.Neziha Hacıhasanoğlu Çakmak, Refiye Yanardağ. Valproic acid induced oxidative brain injury in rats: Protective effect of edaravone. Ankara Univ Vet Fak Derg. 2026 Apr. 1;73(2):185-93. doi:10.33988/auvfd.1738110