The Effects of Lipoic Acid on Markers of Oxidative Stress and Inflammation in the Lungs of Valproic Acid-Treated Rats

Year 2024, Volume: 11 Issue: 4, 1441 - 1448, 03.12.2024

Burcin Alev , İsmet Burcu Türkyılmaz , Hazal İpekçi , Ünsal Veli Üstündağ , Tuğba Tunalı-akbay , Ebru Emekli Alturfan , Refiye Yanardağ , Ayşen Yarat

https://doi.org/10.18596/jotcsa.1520611

Abstract

In this experimental study, the effect of lipoic acid (LA) on lung damage caused by valproic acid (VPA) was investigated. The antioxidant, oxidative stress, and inflammation indicators such as glutathione (GSH), lipid peroxidation (LPO), catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST), nitric oxide (NO), sialic acid (SA), myeloperoxidase (MPO), and tissue factor (TF) were examined. Sprague Dawley rats were used, and they were randomly divided into four groups as follows: Control group, LA group received 50 mg LA/kg/day for 15 days, VPA group received 500 mg VPA/kg/day for 15 days, and VPA+LA group received the same doses of VPA and LA for 15 days. On day 16, lung tissues were taken. VPA caused the decreases in GSH, SA and SOD values and the increases LPO, NO, and TF values. LA reversed the changes in GSH, SOD, and TF values. GST and CAT activities did not change significantly by the effect of VPA or LA. On the other hand, the inhibitory effect of VPA on MPO, which is an inflammatory marker, and the pro-oxidant effects of LA causing the increases in both LPO and MPO values were observed in lung tissue. These regulations may help LA to overcome oxidative stress caused by VPA in the lung. Further studies are needed to confirm the mechanism underlying VPA-induced MPO inhibition in the lung.

Keywords

Lung, lipoic acid, valproic acid, oxidative stress, antioxidant

References

• 1. Safdar A, Ismail F. A comprehensive review on pharmacological applications and drug-induced toxicity of valproic acid. Saudi Pharm J [Internet]. 2023 Feb 1;31(2):265–78. Available from: <URL>.
• 2. Oztay F, Tunali S, Kayalar O, Yanardag R. The protective effect of vitamin U on valproic acid‐induced lung toxicity in rats via amelioration of oxidative stress. J Biochem Mol Toxicol [Internet]. 2020 Dec 26;34(12):e22602. Available from: <URL>.
• 3. Hosakote YM, Rayavara K. Respiratory syncytial virus-induced oxidative stress in lung pathogenesis. In: Oxidative Stress in Lung Diseases [Internet]. Singapore: Springer Singapore; 2020. p. 297–330. Available from: <URL>.
• 4. Guo X, Wu S, Shang J, Dong W, Li Y, Peng Q, et al. The effects of lipoic acid on respiratory diseases. Int Immunopharmacol [Internet]. 2023 Mar 1;116:109713. Available from: <URL>.
• 5. Eser Faki H, Tras B, Uney K. Alpha lipoic acid and vitamin E improve atorvastatin-induced mitochon-drial dysfunctions in rats. Mitochondrion [Internet]. 2020 May 1;52:83–8. Available from: <URL>.
• 6. Moini H, Packer L, Saris NEL. Antioxidant and prooxidant activities of α-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol [Internet]. 2002 Jul 1;182(1):84–90. Available from: <URL>.
• 7. Beutler E. Glutathione in red blood cell metabolism. In: A manuel of biochemical methods. New York: Grune & Stratton; 1975. p. 112–4.
• 8. Ledwoż;yw A, Michalak J, Stȩpień A, Ka̧dziołka A. The relationship between plasma triglycerides, cholesterol, total lipids and lipid peroxidation products during human atherosclerosis. Clin Chim Acta [Internet]. 1986 Mar 28;155(3):275–83. Available from: <URL>.
• 9. 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>.
• 10. Aebi H. Catalase in vitro. In: Methods in enzymology [Internet]. Methods Enzymol; 1984. p. 121–6. Available from: <URL>.
• 11. 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>.
• 12. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide [Internet]. 2001 Feb 1;5(1):62–71. Available from: <URL>.
• 13. Warren L. The thiobarbituric acid assay of sialic acids. J Biol Chem [Internet]. 1959 Aug 1;234(8):1971–5. Available from: <URL>.
• 14. Wei H, Frenkel K. In vivo formation of oxidized DNA bases in tumor promoter-treated mouse skin. Cancer Res [Internet]. 1991 Aug 15;51(16):4443–9. Available from: <URL>.
• 15. Ingram GI, Hills M. Reference method for the one-stage prothrombin time test on hlman blood. International committee for standardization in hematology. Thromb Haemost [Internet]. 1976 Aug 31;36(1):237–8. Available from: <URL>.
• 16. Kim SJ, Jhun BW, Lee JE, Kim K, Choi HY. A case of drug-induced interstitial pneumonitis caused by valproic acid for the treatment of seizure disorders. Tuberc Respir Dis (Seoul) [Internet]. 2014 Sep 1;77(3):145. Available from: <URL>.
• 17. Şimşek F, Kızıldağ N. Eosinophilic pleuropericardial effusion due to valproic acid. Black Sea J Heal Sci [Internet]. 2022 Jan 1;5(1):104–6. Available from: <URL>.
• 18. Akaras N, Kandemir FM, Şimşek H, Gür C, Aygörmez S. Antioxidant, antiinflammatory, and antiapoptotic effects of rutin in spleen toxicity induced by sodium valproate in rats. Türk Doğa ve Fen Derg [Internet]. 2023 Jun 22;12(2):138–44. Available from: <URL>.
• 19. Oztay F, Kayalar O, Yildirim M. Pulmonary oxidative stress and antioxidant defence system in the lung ageing and fibrotic and diabetic lungs. In: Oxidative Stress in Lung Diseases [Internet]. Singapore: Springer Singapore; 2019. p. 325–53. Available from: <URL>.
• 20. Lee M, Ahn C, Kim K, Jeung EB. Mitochondrial toxic effects of antiepileptic drug valproic acid on mouse kidney stem cells. Toxics [Internet]. 2023 May 20;11(5):471. Available from: <URL>.
• 21. Hansen JM, Lucas SM, Ramos CD, Green EJ, Nuttall DJ, Clark DS, et al. Valproic acid promotes SOD2 acetylation: a potential mechanism of valproic acid-induced oxidative stress in developing systems. Free Radic Res [Internet]. 2021 Dec 2;55(11–12):1130–44. Available from: <URL>.
• 22. Cadirci E, Altunkaynak BZ, Halici Z, Odabasoglu F, Uyanik MH, Gundogdu C, et al. Alpha-lipoic acid as a potential target for the treatment of lung injury caused by cecal ligation and puncture-induced sepsis model in rats. Shock [Internet]. 2010 May;33(5): 479–84. Available from: <URL>.
• 23. Thimmulappa RK, Chattopadhyay I, Rajasekaran S. Oxidative stress mechanisms in the pathogenesis of environmental lung diseases. In: Oxidative Stress in Lung Diseases [Internet]. Singapore: Springer Singapore; 2020 [cited 2024 Sep 13]. p. 103–37. Available from: <URL>.
• 24. Mokra D, Mokry J. Oxidative stress in experimental models of acute lung injury. In: Oxidative Stress in Lung Diseases [Internet]. Singapore: Springer Singapore; 2020. p. 25–57. Available from: <URL>.
• 25. Turkyilmaz IB, Bilgin Sokmen B, Yanardag R. Alpha‐lipoic acid prevents brain injury in rats administered with valproic acid. J Biochem Mol Toxicol [Internet]. 2020 Nov 14;34(11):e22580. Available from: <URL>.
• 26. Cho DH, Park JH, Joo Lee E, Jong Won K, Lee SH, Kim YH, et al. Valproic acid increases NO production via the SH-PTP1–CDK5–eNOS-Ser116 signaling cascade in endothelial cells and mice. Free Radic Biol Med [Internet]. 2014 Nov 1;76:96–106. Available from: <URL>.
• 27. Hernández-Jiménez C, Martínez-Cortés J, Olmos-Zuñiga JR, Jasso-Victoria R, López-Pérez MT, Díaz-Martínez NE, et al. Changes in the levels of free sialic acid during ex vivo lung perfusion do not correlate with pulmonary function. Experimental model. BMC Pulm Med [Internet]. 2023 Sep 4;23(1):326. Available from: <URL>.
• 28. Martins M de F, Honório-Ferreira A, Martins P, Gonçalves CA. Presence of sialic acids in bronchioloalveolar cells and identification and quantification of N-acetylneuraminic and N-glycolylneuraminic acids in the lung. Acta Histochem [Internet]. 2019 Aug 1;121(6):712–7. Available from: <URL>.
• 29. Alev B, Tunalı S, Üstündağ ÜV, İpekçi H, Emekli Alturfan E, Tunalı Akbay T, et al. Chard extract increased gastric sialic acid and ameliorated oxidative stress in valproic acid-administered rats. Food Heal [Internet]. 2023;9(2):139–47. Available from: <URL>.
• 30. Berkan Ö, Göl MK, İçağasioğlu S, Çetınkaya Ö, Yildiz E, Doğan K, et al. Sialic acid is a marker of lung injury following lower extremities ischemia/ reperfusion. Eur J Vasc Endovasc Surg [Internet]. 2004 May 1;27(5):553–8. Available from: <URL>.
• 31. 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>.
• 32. Jomova K, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Arch Toxicol [Internet]. 2024 May 14;98(5):1323–67. Available from: <URL>.
• 33. 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>.
• 34. Türkyılmaz İB, Karatuğ Kaçar A, Bolkent Ş, Yanardağ R. Damage to liver tissue caused by valproic acid used for treating epilepsy: Protective effects of vitamin B6. Arch Epilepsy [Internet]. 2023 Mar 1;29(1):9–15. Available from: <URL>.
• 35. Wu SY, Tang SE, Ko FC, Wu GC, Huang KL, Chu SJ. Valproic acid attenuates acute lung injury induced by ischemia–reperfusion in rats. Anesthesiology [Internet]. 2015 Jun 1;122(6):1327–37. Available from: <URL>.
• 36. Kim K, Li Y, Jin G, Chong W, Liu B, Lu J, et al. Effect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion. Resuscita-tion [Internet]. 2012 Feb 1;83(2):243–8. Available from: <URL>.
• 37. Adcock IM. HDAC inhibitors as anti‐inflammatory agents. Br J Pharmacol [Internet]. 2007 Apr 29;150(7):829–31. Available from: <URL>.
• 38. Pai P, Vijeev A, Phadke S, Shetty MG, Sundara BK. Epi-revolution in rheumatology: The potential of histone deacetylase inhibitors for targeted rheumatoid arthritis intervention. Inflammopharm-acology [Internet]. 2024 Aug 7;32(4):2109–23. Available from: <URL>.
• 39. Alturfan AA, Alturfan EE, Dariyerli N, Zengin E, Aytac E, Yigit G, et al. Investigation of tissue factor and other hemostatic profiles in experimental hypothyroidism. Endocrine [Internet]. 2006;30(1): 63–8. Available from: <URL>.
• 40. van der Poll T. Tissue factor as an initiator of coagulation and inflammation in the lung. Crit Care [Internet]. 2008 Nov 26;12(Suppl 6):S3. Available from: <URL>.
• 41. Grover SP, Mackman N. Tissue Factor. Arterioscler Thromb Vasc Biol [Internet]. 2018 Apr 1;38(4):709–25. Available from: <URL>.
• 42. Mackman N, Antoniak S. Tissue factor and oxidative stress. Blood [Internet]. 2018 May 10;131(19):2094–5. Available from: <URL>.
• 43. Hasanoğlu C, Karalök Z, Kalenderoğlu M, Haspolat Ş. A rare cause of hemorrhage from valproic acid—induced hypofibrinogenemia and review of literature. Ann Clin Case Reports [Internet]. 2021;6:1910. Available from: <URL>.
• 44. Oktay Ş, Alev B, Koç Öztürk L, Tunalı S, Demirel S, Emekli Alturfan E, et al. Edaravone ameliorates valproate-induced gingival toxicity by reducing oxidative-stress, inflammation and tissue damage. Marmara Pharm J [Internet]. 2016 May 10;20(3): 232–40. Available from: <URL>.
• 45. Çakatay U. Pro-oxidant actions of α-lipoic acid and dihydrolipoic acid. Med Hypotheses [Internet]. 2006 Jan 1;66(1):110–7. Available from: <URL>.
• 46. Mohammed MA, Gharib DM, Reyad HR, Mohamed AA, Elroby FA, Mahmoud HS. Antioxidant and anti-inflammatory properties of alpha-lipoic acid protect against valproic acid–induced liver injury. Can J Physiol Pharmacol [Internet]. 2021 May;99(5):499–505. Available from: <URL>.
• 47. Rezaei Zonooz S, Hasani M, Morvaridzadeh M, Beatriz Pizarro A, Heydari H, Yosaee S, et al. Effect of alpha-lipoic acid on oxidative stress parameters: A systematic review and meta-analysis. J Funct Foods [Internet]. 2021 Dec 1;87:104774. Available from: <URL>.
• 48. Peng P, Zhang X, Qi T, Cheng H, Kong Q, Liu L, et al. Alpha‐lipoic acid inhibits lung cancer growth via mTOR‐mediated autophagy inhibition. FEBS Open Bio [Internet]. 2020 Apr 18;10(4):607–18. Available from: <URL>.
• 49. Oktay S, Çalışkan Ş. Potential therapeutic effect of lipoic acid on methotrexate-induced oxidative stress in rat heart. Eur J Biol [Internet]. 2023 Sep 27;82(2):306–10. Available from: <URL>.
• 50. Piechota-Polanczyk A, Zielińska M, Piekielny D, Fichna J. The influence of lipoic acid on caveolin-1-regulated antioxidative enzymes in the mouse model of acute ulcerative colitis. Biomed Pharmacother [Internet]. 2016 Dec 1;84:470–5. Available from: <URL>.
• 51. AL-Rasheed NM, Al-Rasheed NM, Attia HA, Hasan IH, Al-Amin M, Al-Ajmi H, et al. Adverse cardiac responses to alpha-lipoic acid in a rat-diabetic model: Possible mechanisms? J Physiol Biochem [Internet]. 2013 Dec 18;69(4):761–78. Available from: <URL>.
• 52. Ali YF, Desouky OS, Selim NS, Ereiba KM. Assessment of the role of α-lipoic acid against the oxidative stress of induced iron overload. J Radiat Res Appl Sci [Internet]. 2015 Jan 1;8(1):26–35. Available from: <URL>.
• 53. Wang X, Qiu M, Qi J, Li J, Wang H, Li Y, et al. Impact of anemia on long-term ischemic events and bleeding events in patients undergoing percutaneous coronary intervention: a system review and meta-analysis. J Thorac Dis [Internet]. 2015;7(11):2041–52. Available from: <URL>.
• 54. Marsh SA, Coombes JS. Vitamin E and a-Lipoic acid supplementation increase bleeding tendency via an intrinsic coagulation pathway. Clin Appl Thromb [Internet]. 2006 Apr 1;12(2):169–73. Available from: <URL>.