Mitochondrial protection and anti-inflammatory effect of curcumin in inhibiting reproductive toxicity induced by sodium valproate in male mice

Document Type : Original Article

Authors

1 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

2 Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran

3 Department of Anatomy, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran

10.22038/ijbms.2025.82254.17791

Abstract

Objective(s): Sodium valproate (VPA) has harmful effects on the male reproductive system. The present study aimed to investigate the influence of curcumin (CUR) in mitigating the VPA-induced reproductive toxicity in male mice.
Materials and Methods: The male mice (mean weight 20 g and 8 weeks old) were divided into six groups (n=6): control, VPA only (500 mg/kg, IP), VPA plus different doses of CUR (25, 50, and 100 mg/kg, IP), CUR alone (100 mg/kg, IP). After treatment for eight consecutive weeks, the mice were sacrificed, testicle tissues were separated, and mitochondria were isolated with different centrifuge techniques. Various biomarkers were evaluated in testis tissue, including the concentration of lipid peroxidation, glutathione, protein carbonyl,  nitric oxide, IL-6, and TNF-alpha. Also, mitochondrial toxicity, swelling, and membrane potential were assessed. Furthermore, sperm analysis and histopathological examination were done on testicular tissue.
Results: VPA injection increased the amount of nitric oxide, inflammatory factors, mitochondrial toxicity, and oxidative stress markers (P<0.05). Also, histopathological and sperm analysis showed significant damage to testis tissue and a significant reduction in sperm count, motility, and normal morphology after VPA administration. CUR led to a substantial reduction of the inflammatory and oxidative stress parameters(P<0.05), restored the VPA-induced testis toxicity, and increased sperm count and motility (P<0.05).
Conclusion: Our study demonstrates CUR’s ameliorative effects on mitochondrial oxidative damage and inflammation caused by VPA-induced reproductive toxicity, which can be suggested as a strategy for reducing the side effects caused by VPA. 

Keywords

Main Subjects


1. Zhong JG, Lan WT, Feng YQ, Li YH, Shen YY, Gong JH, et al. Associations between dysbiosis gut microbiota and changes of neurotransmitters and short-chain fatty acids in valproic acid model rats. Front Physiol 2023; 14: 1077821.
2. Qu D, Ge Y, Zhang L, Chen L, Xu Y, Chen J, et al. Efficacy and mechanisms of Dingxian pill combined with valproic acid on pentylenetetrazol-induced chronic epilepsy in rats. J Tradit Chin Med 2023; 43: 286-294.
3. De Caro V, Scaturro AL, Sutera FM, Avellone G, Schiera G, Ferrantelli E, et al. N-valproyl-L-phenylalanine as new potential antiepileptic drug: synthesis, characterization and in vitro studies on stability, toxicity and anticonvulsant efficacy. Med Chem 2014; 11: 30-40.
4. Merola C, Caioni G, Cimini A, Perugini M, Benedetti E. Sodium valproate exposure influences the expression of pparg in the zebrafish model. Birth Defects Res 2023; 115: 658-667.
5. Khaleseh F, Chahardori M, Samadi M. Methylnitrosourea. In: Encyclopedia of Toxicology (Fourth Edition), 2024; 6: 339-344.
6. Muralidharan A, Rahman J, Banerjee D, Mohammed ARH, Malik BH. Parkinsonism: A rare adverse effect of valproic acid. Cureus 2020; 12: e8782.
7. Safdar A, Ismail F. A comprehensive review on pharmacological applications and drug-induced toxicity of valproic acid. Saudi Pharm J 2023; 31: 265-278.
8. Chahardori M, Haghi-Aminjan H, Samadi M. Methyl disulfide. In: Encyclopedia of Toxicology (Fourth Edition), 2024; 6: 267-272.
9. Caracciolo L, Fumagalli F, Carelli S, Madaschi L, La Via L, Bonini D, et al. Kainate receptor RNA editing is markedly altered by acute spinal cord injury. J Mol Neurosci 2013; 51: 903–910.
10. Hoshi N. M-current suppression, seizures and lipid metabolism: A potential link between neuronal Kv7 channel regulation and dietary therapies for epilepsy. Front Physiol 2020; 11: 513.
11. Kessler SK, McGinnis E. A practical guide to treatment of childhood absence epilepsy. Paediatr Drugs 2019; 21: 15-24.
12. Shaki F, Amirkhanloo M, Jahani D, Chahardori M. Artificial intelligence in pharmaceuticals: exploring applications and legal challenges. Pharm Biomed Res 2024; 10: 1-10.
13. Reihani A, Marboutian F, Aghebat-bekheir S, Reyhani A, Akhgari M. Diagnostic aspects of paraquat in the forensic toxicology: A systematic review. Acad Forensic Pathol 2024; 14: 51-61.
14. Nishimura T, Sakai M, Yonezawa H. Effects of valproic acid on fertility and reproductive organs in male rats. J Toxicol Sci 2000; 25: 85-93.
15. Sukhorum W, Iamsaard S. Changes in testicular function proteins and sperm acrosome status in rats treated with valproic acid. Reprod Fertil Dev 2017; 29: 1585-1592.
16. Alsemeh AE, Ahmed MM, Fawzy A, Samy W, Tharwat M, Rezq S. Vitamin E rescues valproic acid-induced testicular injury in rats: Role of autophagy. Life Sci 2022; 296: 120434.
17. Reihani A, Shaki F, Azari A. Zinc oxide nanoparticles decrease acrylamide cytotoxicity and oxidative stress in HepG2 cells. Nutr Food Sci 2024; 55: 481-492.
18. Chaudhary S, Pinky, Parvez S. Neuroprotective effects of natural antioxidants against branched-chain fatty acid-induced oxidative stress in cerebral cortex and cerebellum regions of the rat brain. ACS Omega 2022; 7: 38269–38276.
19. Omidipour R, Zarei L, Boroujeni MB, Rajabzadeh A. Protective effect of thyme honey against valproic acid hepatotoxicity in Wistar rats. Biomed Res Int 2021; 2021: 8839898.
20. Ezhilarasan D, Mani U. Valproic acid induced liver injury: An insight into molecular toxicological mechanism. Environ Toxicol Pharmacol 2022; 95: 103967.
21. Lee M, Ahn C, Kim K, Jeung EB. Mitochondrial toxic effects of antiepileptic drug valproic acid on mouse kidney stem cells. Toxics 2023; 11: 471-482.
22. Kurwadkar S, Mandal PK, Soni S. Dioxin: Environmental fate and health/ecological consequences. CRC Press; 2020.
23. Qu C, Zhang S, Wang W, Li M, Wang Y, van der Heijde-Mulder M, et al. Mitochondrial electron transport chain complex III sustains hepatitis E virus replication and represents an antiviral target. FASEB J 2019; 33: 1008-1019.
24. Reihani A, Mohammadi H. Evaluation of methamphetamine, methadone, tramadol, diazinon, phosalone, trichlorfon, mancozeb, and penconazole in hand-made alcoholic beverages in North Khorasan Province, Iran. Asia Pac J Med Toxicol 2023; 12: 92-96.
25. Reale M, Pesce M, Priyadarshini M, Kamal MA, Patruno A. Mitochondria as an easy target to oxidative stress events in Parkinson’s disease. CNS Neurol Disord Drug Targets 2012; 11: 430-438.
26. Girish C, Shweta O, Raj V, Balakrishnan S, Varghese RG. Ellagic acid modulates sodium valproate induced reproductive toxicity in male Wistar rats. Indian J Physiol Pharmacol 2014; 58: 416-422.
27. Kumar N. Sperm mitochondria, the driving force behind human spermatozoa activities: Its functions and dysfunctions - A narrative review. Curr Mol Med 2023; 23: 332-340.
28. Vicente-Carrillo A, Edebert I, Garside H, Cotgreave I, Rigler R, Loitto V, et al. Boar spermatozoa successfully predict mitochondrial modes of toxicity: Implications for drug toxicity testing and the 3R principles. Toxicol in vitro 2015; 29: 582-591.
29. Wang P, Gong Q, Hu J, Li X, Zhang X. Reactive oxygen species (ROS)-responsive prodrugs, probes, and theranostic prodrugs: Applications in the ROS-related diseases. J Med Chem 2021; 64: 298-325.
30. Zuo L, Wijegunawardana D. Redox role of ROS and inflammation in pulmonary diseases. Adv Exp Med Biol 2021; 1304: 187-204.
31. Momeni HR, Eskandari N. Curcumin protects the testis against cadmium-induced histopathological damages and oxidative stress in mice. Hum Exp Toxicol 2020; 39: 653-661.
32. Noorafshan A, Karbalay-Doust S, Valizadeh A, Aliabadi E. Ameliorative effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in metronidazole-treated mice: a stereological approach. Exp Toxicol Pathol 2011; 63: 627-633.
33. Baharan O. Protective effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in methandienone treated mice. Res J Pharmacogn 2018; 5: 33-41.
34. Hayashi T. Laboratory animals published by the US National Institute were analyzed densitometrically by the National Institute of Health (NIH Publication No. 85-23, revised 1996). Health HMAGE Program 2010.
35. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248–254.
36. Zhang F, Xu Z, Gao J, Xu B, Deng Y. In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain. Environ Toxicol Pharmacol 2008; 26: 232–236.
37. Sadegh C, Schreck RP. The spectroscopic determination of aqueous sulfite using Ellman’s reagent. Murj 2003; 8: 39–43.
38. Harris ED. Regulation of antioxidant enzymes 1. FASEB J 1992; 6: 2675–2683.
39. Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, et al. Phase I clinical trial of oral curcumin: Biomarkers of systemic activity and compliance. Clin Cancer Res 2004; 10: 6847–6854.
40. Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G. Curcumin-from molecule to biological function. Angew Chem Int Ed Engl 2012; 51: 5308-5332.
41. Levine RL. Carbonyl modified proteins in cellular regulation, aging, and disease. Free Radic Biol Med 2002; 32: 790-796.
42. Butterfield DA, Stadtman ER. Protein oxidation processes in aging brain. Adv Cell Aging Gerontol 1997; 2: 161-191.
43. Hosseini MJ, Shaki F, Ghazi-Khansari M, Pourahmad J. Toxicity of arsenic (III) on isolated liver mitochondria: A new mechanistic approach. Iran J Pharm Res 2013; 12(Suppl): 121.
44. Kishikawa H, Tateno H, Yanagimachi R. Fertility of mouse spermatozoa retrieved from cadavers and maintained at 4 C. Reproduction 1999; 116: 217-222.
45. Hikim AS, Swerdloff RS. Hormonal and genetic control of germ cell apoptosis in the testis. Rev Reprod 1999; 4: 38-47.
46. Bairy L, Paul V, Rao Y. Reproductive toxicity of sodium valproate in male rats. Indian J Pharmacol 2010; 42: 90-94.
47. Ji Q, Shi X, Lin R, Mao Y, Zhai X, Lin Q, Zhang J. Participation of lipid transport and fatty acid metabolism in valproate sodium-induced hepatotoxicity in HepG2 cells. Toxicol in vitro 2010; 24: 1086-1091.
48. White HS, Smith MD, Wilcox KS. Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol 2007; 81: 85-110.
49. Mehmood T, Saleem M, Shah SSH. Frequency of valproate induced thrombocytopenia in epileptic children. J Univ Med Dent Coll 2014; 5: 52-56.
50. Prasad S, Tyagi AK, Aggarwal BB. Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: The golden pigment from golden spice. Cancer Res Treat 2014; 46: 2-18.
51. Anand P, Thomas SG, Kunnumakkara AB, Sundaram C, Harikumar KB, Sung B, et al. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol 2008; 76: 1590-1611.
52. Salem NA, Alnahdi HS, Ibrahim GS. Therapeutic effect of curcumin against nicotine-induced reproductive dysfunction in male rats. J Innov Pharm Biol Sci 2017; 4: 26-31.
53. Momeni H, Eskandari N. Curcumin protects the testis against cadmium-induced histopathological damages and oxidative stress in mice. Hum Exp Toxicol 2020; 39: 653-661.
54. Samarghandian S, Azimi-Nezhad M, Farkhondeh T, Samini F. Antioxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney. Biomed Pharmacother 2017; 87: 223-229.
55. José CMX, Emilio CLV, Maria dGN-M, Glauce SdBV. Valproic acid, a drug with multiple molecular targets related to its potential neuroprotective action. Neurosci Med 2012; 3: 17746-1760.
56. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med 2010; 49: 1603-1616.
57. Kandeda AK, Moto FCO, Ayissi REM, Omam JPO, Ojong L, Bum EN. Pergularia daemia hydro-ethanolic extract protects against pentylenetetrazole kindling-induced seizures, oxidative stress, and neuroinflammation in mice. J Ethnopharmacol 2021; 279: 114338.
58. Shah SA, Yoon GH, Ahmad A, Ullah F, Amin FU, Kim MO. Nanoscale-alumina induces oxidative stress and accelerates amyloid beta (Aβ) production in ICR female mice. Nanoscale 2015; 7: 15225-15337.
59. Calcerrada P, Peluffo G, Radi R. Nitric oxide-derived oxidants with a focus on peroxynitrite: Molecular targets, cellular responses and therapeutic implications. Curr Pharm Des 2011; 17: 3905-3932.
60. Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC, Ogle WO. Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res 2007; 1162: 9-18.
61. Aitken RJ, Curry BJ. Redox regulation of human sperm function: From the physiological control of sperm capacitation to the etiology of infertility and DNA damage in the germ line. Antioxid Redox Signal 2011; 14: 367-381.
62. Talebi A, Moridian M, Khorsandi L. The detrimental effects of zinc oxide nanoparticles on mouse spermatogenesis. Int J Reprod Biomed 2014; 12: 114-115.
63. Ganjkhani M, Nourozi S, Bigonah R, Rostami A, Shokri S. Ameliorating impacts of ginseng on the apoptosis of spermatogenic cells and sperm quality in temporal lobe epilepsy rat model treated with valproate. Andrologia 2019; 51: e13348.
64. Asadi A, Ghahremani R, Abdolmaleki A, Rajaei F. Role of sperm apoptosis and oxidative stress in male infertility: A narrative review. Int J Reprod Biomed 2021; 19: 493-504.
65. Agarwal A, Sharma RK, Nallella KP, Thomas AJ Jr, Alvarez JG, Sikka SC. Reactive oxygen species as an independent marker of male factor infertility. Fertil Steril 2006; 86: 878-885.
66. Agarwal A, Virk G, Ong C, Du Plessis SS. Effect of oxidative stress on male reproduction. World J Mens Health 2014; 32: 1-17.
67. Zowail M, El-Balshy R, Asran A, Khidr F, Amer N. Protective effect of Origanum majorana against the toxicity of bromadialone on adult male albino rat. Egypt J Exp Biol Zool 2019; 15: 263-285.
68. Rezvanfar MA, Rezvanfar MA, Shahverdi AR, Ahmadi A, Baeeri M, Mohammadirad A, Abdollahi M. Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles. Toxicol Appl Pharmacol 2013; 266: 356-365.