Effects of intravenous lipid solution on spexin and meteorin-like protein expression in the liver of rats with systemic toxicity induced by bupivacaine: an immunohistochemical study

Yıl 2025, Cilt: 18 Sayı: 3, 437 - 446, 22.12.2025

Fadime Tosun , Gulsen Bayrak , Nezir Yılmaz , Mevlüt Doğukan , Mehmet Duran , Seda Koçak , Zeliha Bozkurt

Öz

Aim: The aim of this research was to investigate the effects of intravenous lipid solution on Spexin and Meteorin-Like Protein (Metrnl) levels in the liver tissue of rats with systemic toxicity induced by the local anesthetic agent bupivacaine, and to determine the possible effects of bupivacaine on these markers, which are effective in energy metabolism. Methods: Twenty-eight adult male Wistar-Albino rats were divided into four equal groups. Group 1 (Control group): No agent was administered. Group 2 (Local anesthesia group (LA): After intravenous 3 µg/kg/min bupivacaine infusion, bupivacaine infusion was withdrawn at the onset of cardiac toxicity. Group 3 (LA+ILE group): 1.5 mL/kg 20% bolus + 0.25 μg/kg/min (15 minutes) ILE infusion was given when signs of cardiac toxicity developed after 3 μg/kg/min intravenous bupivacaine infusion. Group 4 (ILE group): 1.5 mL/kg 20% bolus + 0.25 μg/kg/min (15 minutes) ILE infusion. Following these procedures, rats were decapitated under anesthesia. liver tissues were removed, put in 10% neutral formaldehyde, and preserved for immunohistochemical analysis. Results: Analysis of Speksin and Metrnl immunoreactivity revealed that, Group 1 and Group 4 were similar (p=0.323, p=0.442). Compared to Group 1, Spexin and Metrnl immunoreactivity was significantly increased in Group 2 (p=0.001, p=0.000). However, in Group 3, Spexin and Metrnl immunoreactivity in liver tissue was decreased compared to Group 2 (p=0.041, p=0.048). Conclusion: Bupivacaine increased the levels of Spexin and Metrnl, which are effective in energy metabolism, whereas administration of intravenous lipid emulsion reduced these marker levels.. It was concluded that further investigations are needed to determine the cytotoxin effects of local anesthetic agents, such as bupivacaine, on energy metabolism.

Anahtar Kelimeler

Bupivacaine , Intravenous Lipid Emulsion , spexin , meteorin-like Protein

Bupivakain ile sistemik toksisite oluşturulan sıçanlarda intravenöz lipid solüsyonunun karaciğerde speksin ve meteorin-like protein ekspresyonu üzerindeki etkileri: bir immüohistokimyasal çalışma

Öz

Amaç: Bu çalışmada, yüksek doz bupivakainin sistemik toksisiteye yol açtığı sıçanlarda, intravenöz lipid solüsyonunun (ILE) karaciğer dokusu üzerindeki korunma ve tedavi edici etkilerini araştırmak ve Speksin ile Meteorin-Like Protein (Metrnl) gibi biyobelirteçlerin bu süreçteki rollerini değerlendirmek amaçlanmıştır. Yöntem: 28 yetişkin erkek Wistar-Albino rat dört gruba ayrıldı. Grup 1 (Kontrol): herhangi bir ajan uygulanmadı. Grup 2 (Lokal anestezi (LA): İntravenöz 3 µg/kg/dk bupivakain infüzyonu sonrası kardiyak toksisite bulgularının başlangıcında bupivakain infüzyonu durduruldu. Grup 3 (LA+ILE grubu): 3 µg/kg/dk intravenöz bupivakain infüzyonu sonrası kardiyak toksisite bulguları geliştiğinde 1.5 mL/kg %20 bolus + 0.25 μg/kg/dk (15 dakika) ILE infüzyonu verildi. Grup 4 (ILE grubu): 1.5 mL/kg %20 bolus + 0.25 μg/kg/dk (15 dakika) ILE infüzyonu verildi. İmmunohistokimyasal inceleme için karaciğer doku örnekleri alındı. Bulgular: Gruplar arasında Speksin ile Metrnl immünreaktivitesine bakıldığında; Grup 1 ve Grup 4 benzerdi (p=0.323, p=0.442). Grup 1 ile kıyaslandığında Grup 2’de Speksin ve Metrnl immünreaktivitesinin anlamlı şekilde arttığı görüldü (p<0.05). Ancak Grup 2 ile kıyaslandığında Grup 3’te Speksin ve Metrnl immünreaktivitesi istatistiksel olarak azaldığı tespit edildi. Sonuç: Speksin ve Metrnl’nin immünreaktivitesinde gözlenen belirgin artışlar, yüksek doz bupivakainin yol açtığı hepatotoksik etkilere karşı moleküler ve hücresel savunma mekanizmalarının aktivasyonunu göstermektedir. Ayrıca, lipit infüzyonunun yüksek doz bupivakainin neden olduğu karaciğer hasarını azaltarak organ koruyucu etkiler sağlayabildiği ortaya konmuştur.

Anahtar Kelimeler

Bupivakain , intravenöz lipid emülsiyonu , speksin , meteorin-like protein

Etik Beyan

30.11.2023 tarih 2023/0016 sayılı

Destekleyen Kurum

Adıyaman Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu

Kaynakça

• Dillane D, Finucane BT. Local anesthetic systemic toxicity. Can J Anaesth. 2010;57(4):368-380.
• Chowdhury O, Upendran I. S2940 bupivacaine-induced hepatotoxicity in a healthy patient without chronic liver disease after shoulder arthroscopy. Official journal of the American College of Gastroenterology| ACG. 2022;117.10S: e1911-e1912.
• Han D, Dara L, Win S, et al. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. Trends Pharmacol Sci. 2013;34(4):243-253.
• Scutari G, Marian M, Bindoli A, et al. Mitochondrial effects of L-ropivacaine, a new local anesthetic. Biochem Pharmacol. 1998;56(12):1633-1637.).
• Sun X, Yu Z, Xu Y, Pu S, Gao X. The role of spexin in energy metabolism. Peptides. 2023;164:170991.
• Kaya S, Yalçın T, Kuloğlu T. Resveratrol may reduce oxidative stress and apoptosis in doxorubicin-induced cardiotoxicity by regulating Meteorin-like and TRPM2 levels. Comp Clin Pathol. 2023;32(3): 393-404.
• Türkel İ, Memi G, Yazgan B. Impact of spexin on metabolic diseases and inflammation: An updated minireview. Exp Biol Med (Maywood). 2022;247(7):567-573.
• Chen Z, Li J, Peng H, et al. Meteorin-like/Meteorin-β protects LPS-induced acute lung injury by activating SIRT1-P53-SLC7A11 mediated ferroptosis pathway. Mol Med. 2023;29(1):144.
• Weinberg GL, Ripper R, Murphy P, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med. 2006;31(4):296-303.
• Yang L, Bai Z, Lv D, Liu H, Li X, Chen X. Rescue effect of lipid emulsion on bupivacaine-induced cardiac toxicity in cardiomyocytes. Mol Med Rep. 2015;12(3):3739-3747.
• Esen M, Uysal M. Protective effects of intravenous lipid emulsion on malathion-induced hepatotoxicity. Bratisl Lek Listy. 2018;119(6):373-378.
• Turk A, Metin TO. Effects of Vitamin D on asprosin and meteorin-like protein in liver tissue of diabetic rats. Medicine. 2023;12(4):1036-1041.
• Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981;29:577–580.
• Chintamaneni P, Stevenson HL, Malik SM. Bupivacaine drug-induced liver injury: a case series and brief review of the literature. J Clin Anesth. 2016;32:137-141.
• Lee JE, Kwak KH. A liver transplant recipient with possible bupivacaine-induced liver injury caused by intra-articular injection after total knee arthroplasty: A case report. Medicine (Baltimore). 2018;97(38):e12481.
• Billström R, Blomberg HM. Cholestasis after interpleural bupivacaine for chronic upper limb pain. Anesth Analg. 1993;76(5):1158-1159.
• Yokoyama M, Ohashi I, Nakatsuka H, et al. Drug-induced liver disease during continuous epidural block with bupivacaine. Anesthesiology. 2001;95(1):259-261.
• Chowdhury O, Upendran I. S2940 Bupivacaine-induced hepatotoxicity in a healthy patient without chronic liver disease after shoulder arthroscopy. Official journal of the American College of Gastroenterology| ACG. 2022;117.10S: e1911-e1912.
• Ma A, Bai J, He M, Wong AOL. Spexin as a neuroendocrine signal with emerging functions. Gen Comp Endocrinol. 2018;265:90-96.
• Zhang L, Li G, She Y, Zhang Z. Low levels of spexin and adiponectin may predict insulin resistance in patients with non-alcoholic fatty liver. Pract Lab Med. 2021;24:e00207.
• Özgürlük İ, Kavak RP, Turhan B, et al. The relationship between spexin and liver steatosis in polycystic ovary syndrome: a novel analysis using ultrasound-guided attenuation parameter. Rev Assoc Med Bras (1992). 2025;71(2):e20241313.
• Kolodziejski PA, Leciejewska N, Chmurzynska A, et al. 30-Day spexin treatment of mice with diet-induced obesity (DIO) and type 2 diabetes (T2DM) increases insulin sensitivity, improves liver functions and metabolic status. Mol Cell Endocrinol. 2021;536:111420.
• El-Saka MH, Abo El, Gheit RE, et al. Effect of spexin on renal dysfunction in experimentally obese rats: potential mitigating mechanisms via galanin receptor-2. Arch Physiol Biochem. 2023;129(4):933-942.
• Said MA, Nafeh NY, Abdallah HA. Spexin alleviates hypertension, hyperuricaemia, dyslipidemia and insulin resistance in high fructose diet induced metabolic syndrome in rats via enhancing PPAR-ɣ and AMPK and inhibiting IL-6 and TNF-α. Arch Physiol Biochem. 2023;129(5):1111-1116.
• Baht GS, Bareja A, Lee DE, et al. Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism. Nat Metab. 2020;2(3):278–289.
• Hu C, Zhang X, Song P, et al. Meteorin-like protein attenuates doxorubicin-induced cardiotoxicity via activating cAMP/PKA/SIRT1 pathway. Redox Biol. 2020;37:101747.
• Xu L, Cai Y, Wang Y, Xu C. Meteorin-like (METRNL) attenuates myocardial Ischemia/Reperfusion injury-induced cardiomyocytes apoptosis by alleviating endoplasmic reticulum stress via activation of AMPK-PAK2 signaling in H9C2 cells. Med Sci Monit. 2020;26:e924564.
• Du YN, Teng JM, Zhou TH, Du BY, Cai W. Meteorin-like protein overexpression ameliorates fulminant hepatitis in mice by inhibiting chemokine-dependent immune cell infiltration. Acta Pharmacol Sin. 2023;44(7):1404-1415.
• Chen J, Li ZY, Xu F, et al. low levels of metrnl are linked to the deterioration of diabetic kidney disease. Diabetes Metab Syndr Obes. 2024;17:959-967.
• Liu ZX, Ji HH, Yao MP, et al. Serum Metrnl is associated with the presence and severity of coronary artery disease. J Cell Mol Med. 2019;23(1):271–280.
• Ushach I, Arrevillaga-Boni G, Heller GN, et al. Meteorin-like/Meteorin-β is a novel immunoregulatory cytokine associated with inflammation. J Immunol. 2018;201(12):3669–3676.
• Kaya S, Yalcın T, Tektemur A, Kuloğlu T. N-Acetylcysteine may exert hepatoprotective effect by regulating Meteorin-Like levels in Adriamycin-induced liver injury. Cell Stress Chaperones. 2023;28(6):849-859.