Iranian Journal of Veterinary Surgery

Iranian Journal of Veterinary Surgery

Effect of N-Acetylcysteine on Acute Hyperglycemia Induced by Urethane in Rats: Role of α2-Adrenergic Receptor

Document Type : Original Article

Authors
Nazanin Zahra Rouzkhosh 1
Esmaeal Tamaddonfard 2
Amir Erfanparast 2
1 PhD candidate, Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.
2 Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.
10.30500/ivsa.2025.512508.1440
Abstract
N-acetylcysteine (NAC) is used to treat respiratory, neurodegenerative, and metabolic disorders. In the present study, the effect of NAC was investigated on acute hyperglycemia induced by urethane (URE) in rats. The possible mechanisms including α2-adrenergic receptors and insulin (INS) involvements were explored by intraperitoneal (IP) injection of yohimbine (YOH, an α2-adrenergic receptor antagonist) and determination of serum INS level, respectively. Thirty-five rats were divided into seven groups with equal number to receive IP injections of normal saline (NS), NAC, YOH, and a low dose combination of NAC and YOH before IP injection of URE. Another 20 rats were treated with NS, high doses of NAC, YOH, and their combination without receiving urethane. Time-dependent and percentage alterations in blood glucose level were measured and calculated, respectively. Serum INS level was measured with an enzyme-linked immune-sorbent assay (ELISA) kit and expressed as percentage. Time-dependent and percentage alterations of acute hyperglycemia induced by URE were reduced by 25 and 50 mg/kg NAC, 1 mg/kg YOH, and a combination treatment with low doses of NAC (12.5 mg/kg) and YOH (0.25 mg/kg). The urethane alone did not affect INS percentage, but NAC, YOH, and their combination increased it. Conscious rats showed no significant differences in blood glucose and serum INS levels. It is concluded that NAC produced an anti-hyperglycemic effect. This antihyperglycemic action of NAC might be mediated by α2-adrenergic receptors and pancreatic insulin.
Keywords
Alpha-2 adrenergic receptor
Hyperglycemia
Insulin
N-acetylcysteine
Rats
Subjects
  1. La Fleur SE, Fliers E, Kalsbeek A. Neuroscience of glucose homeostasis. Handbook of Clinical Neurology. 2014; 126: 341-351. doi: 10.1016/B978-0-444-53480-4.00026-6
  2. Liu MZ, He HY, Luo JQ, He FZ, Chen ZR, Liu YP, Xiang DS, ZHOU HH, Zhang W. Drug-induced hyperglycaemia and diabetes: pharmacogenomics perspectives. Archives of Pharmacal Research. 2018; 41(7): 725-736. doi: 10.1007/s12272-018-1039-x
  3. Palermo NE, Gianchandani RY, McDonnell ME, Alexanian SM. Stress hyperglycemia during surgery and anesthesia: pathogenesis and clinical implications. Current Diabetes Reports. 2016; 16(3): 33. doi:10.1007/s11892-016-0721-y
  4. Raghu G, Berk M, Campochiaro PA, Jaeschke H, Marenzi G, Richeldi L, Wen FQ, Nicoletti F, Calverley PMA. The multifaceted therapeutic role of n-acetylcysteine (NAC) in disorders characterized by oxidative stress. Current Neuropharmacology. 2021; 19(8): 1202-1224. doi: 10.2174/1570159X19666201230144109
  5. Samuni Y, Goldstein S, Dean OM, Berk M. The chemistry and biological activities of N-acetylcysteine. Biochimica et Biophysica Acta. 2013; 1830(8): 4117-4129. doi: 10.1016/j.bbagen.2013.04.016
  6. Kamboj SS, Vasishta RK, Sandhir R. N-acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy. Journal of Neurochemistry. 2010; 112(1): 77-91. doi: 10.1111/j.1471-4159.2009.06435.x
  7. Lasram MM, Dhouib IB, Annabi A, El Fazaa S, Gharbi N. A review on the possible molecular mechanism of action of N-acetylcysteine against insulin resistance and type-2 diabetes development. Clinical Biochemistry. 2015; 48(16-17): 1200-1208. doi: 10.1016/j.clinbiochem.2015.04.017
  8. Nowacka A, Śniegocka M, Śniegocki M, Ziółkowska E, Bożiłow D, Smuczyński W. Multifaced nature of yohimbine-A promising therapeutic potential or a risk? International Journal of Molecular Sciences. 2024; 25(23): 12856. doi: 10.3390/ijms252312856
  9. Jabir NR, Firoz CK, Zughaibi TA, Alsaadi MA, Abuzenadah AM, Al-Asmari AI, Alsaieedi A, Ahmed BA, Ramu AK, Tabrez S. A literature perspective on the pharmacological applications of yohimbine. Annals of Medicine. 2022; 54(1): 2861-2875. doi: 10.1080/07853890.2022.2131330
  10. Porrill SL, Rogers RR, Ballmann CG. Ergogenic and sympathomimetic effects of yohimbine: a review. Neurology International. 2024; 16(6): 1837-1848. doi: 10.3390/neurolint16060131
  11. Norton L, Shannon C, Gastaldelli A, DeFronzo RA. Insulin: The master regulator of glucose metabolism. Metabolism. 2022; 129: 155142. doi: 10.1016/j.metabol.2022.155142
  12. Faillie JL, Heurtebize MA. Drug-induced hyperglycemia and diabetes. Therapie. 2024; 79(2): 221-238. doi: 10.1016/j.therap.2023.09.010
  13. Høyer KF, Nielsen TS, Risis S, Treebak JT, Jessen N. Sevoflurane impairs insulin secretion and tissue-specific glucose uptake in vivo. Basic and Clinical Pharmacology and Toxicology. 2018; 123(6): 732-738. doi: 10.1111/bcpt.13087
  14. Mansano AM, Vianna PT, Fabris VE, Silva LM, Braz LG, Castiglia YM. Prevention of renal ischemia/reperfusion injury in rats using acetylcysteine after anesthesia with isoflurane. Acta Cirurgica Brasileira. 2012; 27(4): 340-345. doi: 10.1590/s0102-86502012000400010
  15. Lebourgeois S, González-Marín MC, Antol J, Naassila M, Vilpoux C. Evaluation of N-acetylcysteine on ethanol self-administration in ethanol-dependent rats. Neuropharmacology. 2019; 150: 112-120. doi: 10.1016/j.neuropharm.2019.03.010
  16. Safaei F, Tamaddonfard E, Nafisi S, Imani M. Effects of intraperitoneal and intracerebroventricular injection of cinnamaldehyde and yohimbine on blood glucose and serum insulin concentrations in ketamine-xylazine induced acute hyperglycemia. Veterinary Research Forum. 2021; 12(2): 149-156. doi: 10.30466/vrf.2019.106805.2538
  17. Tamaddonfard E, Erfanparast A, Tamaddonfard S, Nagshbandi N, Naderi S. Effect of curcumin, an active substance of turmeric, on acute hyperglycemia induced by ketamine-xylazine: role of α2-adrenergic receptor. Iranian Journal of Veterinary Surgery. 2020; 15(1): 53-61. doi: 10.30500/ivsa.2020.189763.1186
  18. Abdulhamid Kadhim R, Erfanparast A, Tamaddonfard E, Amirkashani D, Imani M. Effects of linalool on acute hyperglycemia and hypoinsilinemia induced by ketamine-xylazine in rats: the role of alpha 2 adrenergic receptors. Iranian Journal of Physiology and Pharmacology. 2025; 8: 183-194. [Persian].
  19. Silver NRG, Ward-Flanagan R, Dickson CT. Long-term stability of physiological signals within fluctuations of brain state under urethane anesthesia. PLoS One. 2021; 16(10): e0258939. doi: 10.1371/journal.pone.0258939
  20. Wang MY, Ren LM, Du ZJ, Fu SX. Urethane-induced hyperglycemia. Acta Pharmacologica Sinica. 2000; 21(3): 271-275.
  21. Takeuchi K, Niida H, Ohuchi T, Okabe S. Influences of urethane anesthesia on indomethacin-induced gastric mucosal lesions in rats. Relation to blood glucose levels. Digestive Diseases Sciences. 1994; 39(12): 2536-2542. doi: 10.1007/BF02087687
  22. Gourcerol G, Coskun T, Craft LS, Mayer JP, Heiman ML, Wang L, Million M, St-Pierre DH, Taché Y. Preproghrelin-derived peptide, obestatin, fails to influence food intake in lean or obese rodents. Obesity (Silver Spring). 2007; 15(11): 2643-2652. doi: 10.1038/oby.2007.316
  23. Horii Y, Fujisaki Y, Fuyuki R, Misonou Y, Nagai K. Effect of Lactobacillus delbrueckii LAB4 on hepatic and pancreatic sympathetic nerve activity and blood glucose levels in rats. Beneficial Microbes. 2019; 10(3): 293-300. doi: 10.3920/BM2018.0083
  24. Holscher C, van Aalten L, Sutherland C. Anaesthesia generates neuronal insulin resistance by inducing hypothermia. BMC Neurosciences. 2008; 9: 100. doi: 10.1186/1471-2202-9-100
  25. Kim SP, Broussard JL, Kolka CM. Isoflurane and sevoflurane induce severe hepatic insulin resistance in a canine model. PLoS One. 2016; 11(11): e0163275. doi: 10.1371/journal.pone.0163275
  26. Yasuda Y, Fukushima Y, Kaneki M, Martyn JA. Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats. Biochemical and Biophysical Research Communications. 2013; 431(1): 81-85. doi: 10.1016/j.bbrc.2012.12.084
  27. Wilson PR, Bridges KH, Scofield M, Wilson SH. Perioperative n-acetylcysteine: evidence and indications. Pain Management. 2024; 14(7): 385-396. doi: 10.1080/17581869.2024.2388504
  28. Beyaz SG, Yelken B, Kanbak G. The effects of n-acetylcysteine on hepatic function during isoflurane anaesthesia for laparoscopic surgery patients. Indian Journal of Anaesthesia. 2011; 55(6): 567-572. doi: 10.4103/0019-5049.90610
  29. Paskal W, Paskal AM, Pietruski P, Stachura A, Pełka K, Woessner AE, Quinn KP, Kopka M, Galus R, Wejman J, Włodarski P. N-Acetylcysteine added to local anesthesia reduces scar area and width in early wound healing-an animal model study. International Journal of Molecular Sciences. 2021; 22(14): 7549. doi: 10.3390/ijms22147549
  30. Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE. The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. Journal of Biological Chemistry. 2005; 280(6): 4617-4626. doi: 10.1074/jbc.M411863200
  31. Cui ZH, Yuan Q, Mao L, Chen FL, Ji F, Tao S. Insulin resistance in vitamin D-deficient mice is alleviated by n-acetylcysteine. Oncotarget. 2017; 8(38): 63281-63289. doi: 10.18632/oncotarget.18793
  32. Aisaka K, Kihara T, Koike M, Kuroki M, Ishihara T. Effect of yohimbine on urethane-induced hyperglycemia in rats. Japanese Journal of Pharmacology. 1989; 49(4): 523-527. doi: 10.1254/jjp.49.523
  33. Kang YJ, Sim YB, Park SH, Sharma N, Suh HW. Involvement of α(2)-adrenergic receptor in the regulation of the blood glucose level induced by immobilization stress. Archives of Pharmacal Research. 2015; 38(5): 921-929. doi: 10.1007/s12272-014-0430-5
  34. Lindh E, Meller A, Raekallio M. Effects of vatinoxan in rats sedated with a combination of medetomidine, midazolam and fentanyl. Acta Veterinaria Scandinavica. 2024; 66(1): 23. doi: 10.1186/s13028-024-00744-y
  35. Takahashi T, Kawano T, Eguchi S, Chi H, Iwata H, Yokoyama M. Effects of dexmedetomidine on insulin secretion from rat pancreatic β cells. Journal of Anesthesia. 2015; 29(3): 396-402. doi: 10.1007/s00540-014-1943-2
  36. Xiao YF, Wang B, Wang X, Du F, Benzinou M, Wang YX. Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys. BMC Anesthesiology. 2013; 13(1): 33. doi: 10.1186/1471-2253-13-33
  37. Wang XL, Wang JX, Chen JL, Hao WY, Xu WZ, Xu ZQ, Jiang YT, Luo PQ, Chen Q, Li YH, Zhu GQ, Li XZ. Asprosin in the paraventricular nucleus induces sympathetic activation and pressor responses via cAMP-dependent ROS production. International Journal of Molecular Sciences. 2022; 23(20): 12595. doi: 10.3390/ijms232012595
  38. Xu XY, Wang JX, Chen JL, Dai M, Wang YM, Chen Q, Li YH, Zhu GQ, Chen AD. GLP-1 in the hypothalamic paraventricular nucleus promotes sympathetic activation and hypertension. Journal of Neuroscience. 2024; 44(21): e2032232024. doi: 10.1523/JNEUROSCI.2032-23.2024
  39. Jouett NP, Moralez G, White DW, Eubank WL, Chen S, Tian J, Smith ML, Zimmerman MC, Raven PB. N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects. Experimental Physiology. 2016; 101(3): 387-396. doi: 10.1113/EP085546
  40. Russell-Guzmán J, Américo-Da Silva L, Cadagan C, Maturana M, Palomero J, Estrada M, Barrientos G, Buvinic S, Hidalgo C, Llanos P. Activation of the ROS/TXNIP/NLRP3 pathway disrupts insulin-dependent glucose uptake in skeletal muscle of insulin-resistant obese mice. Free Radical Biology and Medicine. 2024; 222:187-198. doi: 10.1016/j.freeradbiomed.2024.06.011

  • Receive Date 15 March 2025
  • Revise Date 14 May 2025
  • Accept Date 16 July 2025
  • First Publish Date 16 July 2025