Protective effects of vitamin U on valproic acid-induced renal damage in rats_Journal of Epilepsy

Authors：

JIANG Jiaomei , LU Xiaomei , ZHANG Ming ,  ZHAO Jing , LENG Yu , WU Pengcheng , WANG Fen

Department of Neurology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China;

Corresponding author：

ZHAO Jing, Email: 8734590@qq.com

Keywords：

Valproic Acid; Vitamin U; Renal Function; Rat

DOI：

10.7507/2096-0247.20180078

Video：

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Objective The aim of present study was to investigate the protective effect of vitamin U on renal toxicity induced by sodium valproate (VPA) and provide laboratory data for clinical application of VPA. Methods In this study, 48 female rats were used. These animals were randomly divided into 4 groups: control group (group A), vitamin U group (group B), VPA group (group C), vitamin U+ VPA group (group D). Group A was given the same amount of normal saline, group B was given Vit U 50 mg/(kg·d), group C was given VPA 300 mg/(kg·d) and group D was given Vit U 50 mg/(kg·d) firstly, then VPA 300 mg/(kg·d) after 1 hours by gavage. After 2 or 4 weeks of continuous administration, the kidneys were collected from these rats after blood collection. Total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), serum creatinine (Cr), urea (BUN) and uric acid (UA) were detected by automatic biochemical analyzer. Result ① Blood lipid. There were significant differences in TC and LDL between the group A and group C (P<0.05), and the level of TC and LDL in group C were significantly higher. ② Serum biochemical indexes of renal function. There was no significant difference in Cr, UA and BUN four groups at 2w (P>0.05). At 4w, compared with the other three groups, the Cr, BUN and UA level of VPA group were significantly higher (P<0.05). But there was no significant difference between the group A and the group D. ③ Pathological morphology of renal tissue. At 2w, there was no obvious abnormality in renal structures among the four groups. At 4w, inflammatory lesions were only seen in VPA group, and mild inflammatory cell infiltration were seen in other three groups. Conclusion VPA can lead to a higher level of blood lipid. The renal toxicity induced by VPA may have a certain relationship with the time of drug exposure, and vitamin U has a protective effect on the renal toxicity induced by VPA.

Citation： JIANG Jiaomei, LU Xiaomei, ZHANG Ming, ZHAO Jing, LENG Yu, WU Pengcheng, WANG Fen. Protective effects of vitamin U on valproic acid-induced renal damage in rats. Journal of Epilepsy, 2018, 4(6): 486-491. doi: 10.7507/2096-0247.20180078 Copy

1.	Song P, Liu Y, Yu X, et al. Prevalence of epilepsy in China between 1990 and 2015: a sys-tematic review and meta-analysis. J Glob Health, 2017, 7(2): 020706.
2.	Havali C, Gucuyener K, Buyan N, et al. Does nephrotoxicity exist in pediatric epileptic patients on valproate or carbamazepine therapy? J Child Neurol, 2015, 30(3): 301-306.
3.	Heidari R, Jafari F, Khodaei F, et al. Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology (Carlton), 2018, 23(4): 351-361.
4.	Martin G, Durozard D, Besson J, et al. Effect of the antiepileptic drug sodium valproate on gluta-mine and glutamate metabolism in isolated human kidney tubules. Biochim Biophys Acta, 1990, 1033(3): 261-266.
5.	Heidari R, Jafari F, Khodaei F, et al. The mechanism of valproic acid-induced Fanconi syn-drome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology (Carlton), 2018, 23(4): 351-361.
6.	Birben E, Sahiner UM, Sackesen C, et al. Oxidative stress and antioxidant defense. World Allergy Organ J, 2012, 5(1): 9-19.
7.	Pourahmad J, Eskandari MR, Kaghazi A, et al. A new approach on valproic acid induced hepatotoxicity: involvement of lysosomal membrane leakiness and cellular proteolysis. Toxicol In Vitro, 2012, 26(4): 545-551.
8.	Auinger K, Muller V, Rudiger A, et al. Valproic acid intoxication imitating brain death. Am J Emerg Med, 2009, 27(9): 1177.e5-6.
9.	Tung EW, 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(6): 979-987.
10.	Chaudhary S, Ganjoo P, Raiusddin S, et al. Nephroprotective activities of quercetin with potential relevance to oxidative stress induced by valproic acid. Protoplasma, 2015, 252(1): 209-217.
11.	Son YR, Choi EH, Kim GT, et al. Bioefficacy of Graviola leaf extracts in scavenging free radicals and upregulating antioxidant genes. Food Funct, 2016, 7(2): 861-871.
12.	Liu HH, Lu P, Guo Y, et al. An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity. Genome Res, 2010, 20(1): 28-35.
13.	Tunali S, Kahraman S, Yanardag R. Vitamin U, a novel free radical scavenger, prevents lens injury in rats administered with valproic acid. Hum Exp Toxicol, 2015, 34(9): 904-910.
14.	Sokmen BB, Tunali S, Yanardag R. Effects of vitamin U (S-methyl methionine sulphonium chloride) on valproic acid induced liver injury in rats. Food Chem Toxicol, 2012, 50(10): 3562-3566.
15.	Vyas MV, Davidson BA, Escalaya L, et al. Antiepileptic drug use for treatment of epilepsy and dyslipidemia: systematic review. Epilepsy Res, 2015, 113: 44-67.
16.	赵晶, 冯伟, 罗新民, 等. 丙戊酸钠对成人癫痫患者脂质代谢的影响. 中国新药与临床杂志, 2010, 29(3): 203-206.
17.	Seri K, Matsuo T, Taniguchi T, et al. Hypolipidemic effects of S-methylmethionine (vitamin U) using various experimental procedures. Arzneimittelforschung, 1980, 30(10): 1694-1703.
18.	Seri K, Amemiya K, Sugimoto H, et al. Effects of S-methylmethionine (vitamin U) on experi-mental nephrotic hyperlipidemia. Arzneimittelforschung, 1979, 29(10): 1517-1520.
19.	Gezginci-Oktayoglu S, Turkyilmaz IB, Ercin M, et al. Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. Protoplasma, 2016, 253(1): 127-135.
20.	Raza M, Al-Shabanah OA, Al-Bekairi AM, et al. Pathomorphological changes in mouse liver and kidney during prolonged valproate administration. Int J Tissue React, 2000, 22(1): 15-21.
21.	Raza M, Al-Bekairi AM, Ageel AM, et al. Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder: time dependence of peroxidative injury. Pharmacol Res, 1997, 35(2): 153-157.
22.	Ben-Cherif W, Dridi I, Aouam K, et al. Chronotolerance study of the antiepileptic drug valproic acid in mice. J Circadian Rhythms, 2012, 10(1): 1-7.
23.	Ranocha P, Mcneil S D, Ziemak M J, et al. The S-methylmethionine cycle in angiosperms: ubiq-uity, antiquity and activity. Plant J, 2001, 25(5): 575-84.
24.	Oktay S, Bayrak G, Alev B, et al. The effect of vitamin U on the lung tissue of pentyleneterazole-induced seizures in rats. Naunyn Schmiedebergs Arch Pharmacol, 2018, 391(2): 177-184.
25.	El-Shenawy NS, Hamza RZ. Nephrotoxicity of sodium valproate and protective role of L-cysteine in rats at biochemical and histological levels. J Basic Clin Physiol Pharmacol, 2016, 27(5): 497-504.

1. Song P, Liu Y, Yu X, et al. Prevalence of epilepsy in China between 1990 and 2015: a sys-tematic review and meta-analysis. J Glob Health, 2017, 7(2): 020706.
2. Havali C, Gucuyener K, Buyan N, et al. Does nephrotoxicity exist in pediatric epileptic patients on valproate or carbamazepine therapy? J Child Neurol, 2015, 30(3): 301-306.
3. Heidari R, Jafari F, Khodaei F, et al. Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology (Carlton), 2018, 23(4): 351-361.
4. Martin G, Durozard D, Besson J, et al. Effect of the antiepileptic drug sodium valproate on gluta-mine and glutamate metabolism in isolated human kidney tubules. Biochim Biophys Acta, 1990, 1033(3): 261-266.
5. Heidari R, Jafari F, Khodaei F, et al. The mechanism of valproic acid-induced Fanconi syn-drome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology (Carlton), 2018, 23(4): 351-361.
6. Birben E, Sahiner UM, Sackesen C, et al. Oxidative stress and antioxidant defense. World Allergy Organ J, 2012, 5(1): 9-19.
7. Pourahmad J, Eskandari MR, Kaghazi A, et al. A new approach on valproic acid induced hepatotoxicity: involvement of lysosomal membrane leakiness and cellular proteolysis. Toxicol In Vitro, 2012, 26(4): 545-551.
8. Auinger K, Muller V, Rudiger A, et al. Valproic acid intoxication imitating brain death. Am J Emerg Med, 2009, 27(9): 1177.e5-6.
9. Tung EW, 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(6): 979-987.
10. Chaudhary S, Ganjoo P, Raiusddin S, et al. Nephroprotective activities of quercetin with potential relevance to oxidative stress induced by valproic acid. Protoplasma, 2015, 252(1): 209-217.
11. Son YR, Choi EH, Kim GT, et al. Bioefficacy of Graviola leaf extracts in scavenging free radicals and upregulating antioxidant genes. Food Funct, 2016, 7(2): 861-871.
12. Liu HH, Lu P, Guo Y, et al. An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity. Genome Res, 2010, 20(1): 28-35.
13. Tunali S, Kahraman S, Yanardag R. Vitamin U, a novel free radical scavenger, prevents lens injury in rats administered with valproic acid. Hum Exp Toxicol, 2015, 34(9): 904-910.
14. Sokmen BB, Tunali S, Yanardag R. Effects of vitamin U (S-methyl methionine sulphonium chloride) on valproic acid induced liver injury in rats. Food Chem Toxicol, 2012, 50(10): 3562-3566.
15. Vyas MV, Davidson BA, Escalaya L, et al. Antiepileptic drug use for treatment of epilepsy and dyslipidemia: systematic review. Epilepsy Res, 2015, 113: 44-67.
16. 赵晶, 冯伟, 罗新民, 等. 丙戊酸钠对成人癫痫患者脂质代谢的影响. 中国新药与临床杂志, 2010, 29(3): 203-206.
17. Seri K, Matsuo T, Taniguchi T, et al. Hypolipidemic effects of S-methylmethionine (vitamin U) using various experimental procedures. Arzneimittelforschung, 1980, 30(10): 1694-1703.
18. Seri K, Amemiya K, Sugimoto H, et al. Effects of S-methylmethionine (vitamin U) on experi-mental nephrotic hyperlipidemia. Arzneimittelforschung, 1979, 29(10): 1517-1520.
19. Gezginci-Oktayoglu S, Turkyilmaz IB, Ercin M, et al. Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. Protoplasma, 2016, 253(1): 127-135.
20. Raza M, Al-Shabanah OA, Al-Bekairi AM, et al. Pathomorphological changes in mouse liver and kidney during prolonged valproate administration. Int J Tissue React, 2000, 22(1): 15-21.
21. Raza M, Al-Bekairi AM, Ageel AM, et al. Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder: time dependence of peroxidative injury. Pharmacol Res, 1997, 35(2): 153-157.
22. Ben-Cherif W, Dridi I, Aouam K, et al. Chronotolerance study of the antiepileptic drug valproic acid in mice. J Circadian Rhythms, 2012, 10(1): 1-7.
23. Ranocha P, Mcneil S D, Ziemak M J, et al. The S-methylmethionine cycle in angiosperms: ubiq-uity, antiquity and activity. Plant J, 2001, 25(5): 575-84.
24. Oktay S, Bayrak G, Alev B, et al. The effect of vitamin U on the lung tissue of pentyleneterazole-induced seizures in rats. Naunyn Schmiedebergs Arch Pharmacol, 2018, 391(2): 177-184.
25. El-Shenawy NS, Hamza RZ. Nephrotoxicity of sodium valproate and protective role of L-cysteine in rats at biochemical and histological levels. J Basic Clin Physiol Pharmacol, 2016, 27(5): 497-504.

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