Anti-Inflammatory Effect of Dopamine D2 Receptor Agonist Cabergoline Against L-Arginine-Induced Acute Pancreatitis in Rats.

Anti-Inflammatory Effect of Dopamine D2 Receptor Agonist Cabergoline Against L-Arginine-Induced Acute Pancreatitis in Rats Randa A. Zaghloul Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt Search for more papers by this authorDalia H. El-Kashef Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt Search for more papers by this authorMedhat Taha Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt Department of Anatomy, Al-Qunfudah Medical College, Umm Al-Qura University, Al-Qunfudah, Saudi Arabia Search for more papers by this authorCorresponding Author Noha Abdel-Rahman Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt Correspondence: Noha Abdel-Rahman ([email protected]) Search for more papers by this authorRanda A. Zaghloul Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt Search for more papers by this authorDalia H. El-Kashef Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt Search for more papers by this authorMedhat Taha Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt Department of Anatomy, Al-Qunfudah Medical College, Umm Al-Qura University, Al-Qunfudah, Saudi Arabia Search for more papers by this authorCorresponding Author Noha Abdel-Rahman Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt Correspondence: Noha Abdel-Rahman ([email protected]) Search for more papers by this authorABSTRACT Severe acute pancreatitis (SAP) is an inflammatory disorder of the pancreas that may extend to other organs resulting in systemic injury. Unfortunately, there is no specific treatment beyond supportive management. Therefore, the current study explores the role of cabergoline (CAB) against l-arginine (l-arg)-induced SAP and systemic injury. Thirty male, adult, Sprague−Dawley rats were arbitrarily allocated into five groups; Normal, CAB (rats received CAB [0.5 mg/kg, orally], SAP [rats were intraperitoneally injected with 50% l-arg at 250 mg/100 g, 50% w/v, pH 7.4, twice with 1 h interval]), SAP + CAB-L, and SAP + CAB-H (rats received CAB [0.1 and 0.5 mg/kg, orally, respectively, for 7 days then were injected with l-arg twice with 1 h interval]). The results indicated that CAB significantly mitigated l-arg-induced damage to the pancreas, lung, liver, and kidney as observed through histopathological examination. Oral administration of CAB (0.5 mg/kg) significantly reduced the serum activities of amylase, lipase, ALT, AST, and the level of creatinine (p < 0.001), and ameliorated pancreatic oxidative stress marked by pancreatic levels of MDA and GSH (p < 0.001), compared to the SAP group. Moreover, CAB (0.5 mg/kg) significantly reduced inflammation as indicated by reduced levels of TNF-α, IL-6, -1β, and NLRP3 (p < 0.001, 0.001, 0.01, and 0.001, respectively). Additionally, CAB reduced the levels of TLR4, NF-κB, NLRP3, and caspase-1 in the pancreatic tissues upon comparison with the SAP group. In conclusion, CAB could offer a new avenue for the prevention of SAP and systemic inflammation mitigation. Conflicts of Interest The authors declare no conflicts of interest. Data Availability Statement Data is available upon request from the authors. References - 1D. H. El-Kashef, A. A. Shaaban, and D. S. El-Agamy, “Protective Role of Pirfenidone Against Experimentally-Induced Pancreatitis,” Pharmacological Reports 71, no. 5 (2019): 774–781. - 2A. T. Chatila, M. Bilal, and P. Guturu, “Evaluation and Management of Acute Pancreatitis,” World Journal of Clinical Cases 7, no. 9 (2019): 1006–1020. - 3T. Mizunuma, S. Kawamura, and Y. Kishino, “Effects of Injecting Excess Arginine on Rat Pancreas,” Journal of Nutrition 114, no. 3 (1984): 467–471. - 4P. Hegyi, “L-Arginine-Induced Experimental Pancreatitis,” World Journal of Gastroenterology 10, no. 14 (2004): 2003–2009. - 5A. L. Shifrin, N. Chirmule, Y. Zhang, and S. E. Raper, “Macrophage Ablation Attenuates Adenoviral Vector-Induced Pancreatitis,” Surgery 137, no. 5 (2005): 545–551. - 6X. Han, B. Li, X. Ye, et al., “Dopamine D(2) Receptor Signalling Controls Inflammation in Acute Pancreatitis via a PP2A-Dependent Akt/NF-κB Signalling Pathway,” British Journal of Pharmacology 174, no. 24 (2017): 4751–4770. - 7S. Basu and P. S. Dasgupta, “Dopamine, a Neurotransmitter, Influences the Immune System,” Journal of Neuroimmunology 102, no. 2 (2000): 113–124. - 8Y. Yan, W. Jiang, L. Liu, et al., “Dopamine Controls Systemic Inflammation Through Inhibition of NLRP3 Inflammasome,” Cell 160, no. 1–2 (2015): 62–73. - 9W. Shao, S. Zhang, M. Tang, et al., “Suppression of Neuroinflammation by Astrocytic Dopamine D2 Receptors via αB-Crystallin,” Nature 494, no. 7435 (2013): 90–94. - 10Y. Zhang, X. Jiang, C. Qin, S. Cuevas, P. A. Jose, and I. Armando, “Dopamine D2 Receptors' Effects onRenal Inflammation Are Mediated by Regulation of PP2A Function,” American Journal of Physiology-Renal Physiology 310, no. 2 (2016): F128–F134. - 11H. Odaka, T. Numakawa, N. Adachi, et al., “Cabergoline, Dopamine D2 Receptor Agonist, Prevents Neuronal Cell Death Under Oxidative Stress via Reducing Excitotoxicity,” PLoS One 9, no. 6 (2014): e99271. - 12S. J. Lin, Z. R. Wu, L. Cao, et al., “Pituitary Tumor Suppression by Combination of Cabergoline and Chloroquine,” Journal of Clinical Endocrinology & Metabolism 102, no. 10 (2017): 3692–3703. - 13Y. T. Liu, F. Liu, L. Cao, et al., “The KBTBD6/7-DRD2 Axis Regulates Pituitary Adenoma Sensitivity to Dopamine Agonist Treatment,” Acta Neuropathologica 140, no. 3 (2020): 377–396. - 14P. K. Anokhin, A. G. Veretinskaya, V. V. Pavshintsev, and I. Y. Shamakina, “The Effect of the Dopamine D2 Receptor Agonist Cabergoline on the Content of Catecholamines and Expression of BDNF mRNA in the Rat Midbrain and Hypothalamus,” Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova 119, no. 11 (2019): 54–59. - 15H. Nishijima, F. Mori, T. Kimura, et al., “Cabergoline, a Long-Acting Dopamine Agonist, Attenuates L-Dopa-Induced Dyskinesia Without L-Dopa Sparing in a Rat Model of Parkinson's Disease,” Neuroscience Research 178 (2022): 93–97. - 16C. Y. Rao, L. Y. Fu, C. L. Hu, et al., “H2S Mitigates Severe Acute Pancreatitis Through the PI3K/AKT-NF-κB Pathway In Vivo,” World Journal of Gastroenterology 21, no. 15 (2015): 4555–4563. - 17A. Ozdulger, I. Cinel, O. Koksel, et al., “The Protective Effect of N-Acetylcysteine on Apoptotic Lung Injury in Cecal Ligation and Puncture-Induced Sepsis Model,” Shock 19, no. 4 (2003): 366–372. - 18J. Schmidt, D. W. Rattner, K. Lewandrowski, et al., “A Better Model of Acute Pancreatitis for Evaluating Therapy,” Annals of Surgery 215, no. 1 (1992): 44–56. - 19D. H. El-Kashef and R. A. Zaghloul, “Ameliorative Effect of Montelukast Against Carbon Tetrachloride-Induced Hepatotoxicity: Targeting NLRP3 Inflammasome Pathway,” Life Sciences 304 (2022): 120707. - 20H. Ohkawa, N. Ohishi, and K. Yagi, “Assay for Lipid Peroxides in Animal Tissues by Thiobarbituric Acid Reaction,” Analytical Biochemistry 95, no. 2 (1979): 351–358. - 21G. L. Ellman, “Tissue Sulfhydryl Groups,” Archives of Biochemistry and Biophysics 82, no. 1 (1959): 70–77. - 22Z. J. Farino, T. J. Morgenstern, A. Maffei, et al., “New Roles for Dopamine D(2) and D(3) Receptors in Pancreatic Beta Cell Insulin Secretion,” Molecular Psychiatry 25, no. 9 (2020): 2070–2085. - 23S. C. Moore, P. A. S. Vaz de Castro, D. Yaqub, P. A. Jose, and I. Armando, “Anti-Inflammatory Effects of Peripheral Dopamine,” International Journal of Molecular Sciences 24, no. 18 (2023): 13816. - 24X. Han, B. Li, X. Ye, et al., “Dopamine D2 Receptor Signalling Controls Inflammation in Acute Pancreatitisviaa PP2A-dependent Akt/NF-κB Signalling Pathway,” British Journal of Pharmacology 174, no. 24 (2017): 4751–4770. - 25P. K. Garg and V. P. Singh, “Organ Failure Due to Systemic Injury In Acute Pancreatitis,” Gastroenterology 156, no. 7 (2019): 2008–2023. - 26Q. Ruan, H. Lu, H. Zhu, Y. Guo, and Y. Bai, “A Network-Regulative Pattern in the Pathogenesis of Kidney Injury Following Severe Acute Pancreatitis,” Biomedicine & Pharmacotherapy 125 (2020): 109978. - 27M. T. Zhou, “Acute Lung Injury and ARDS in Acute Pancreatitis: Mechanisms and Potential Intervention,” World Journal of Gastroenterology 16, no. 17 (2010): 2094–2099. - 28P. Liu, D. Qin, H. Lv, et al., “Activation of Dopamine D2 Receptor Alleviates Neuroinflammation in a Mouse Model of Allergic Rhinitis With Olfactory Dysfunction,” Allergy, Asthma & Immunology Research 13, no. 6 (2021): 882–895. - 29M. Wang, F. Gorelick, and A. Bhargava, “Sex Differences in the Exocrine Pancreas and Associated Diseases,” Cellular and Molecular Gastroenterology and Hepatology 12, no. 2 (2021): 427–441. - 30O. Z. Ismail and V. Bhayana, “Lipase or Amylase for the Diagnosis of Acute Pancreatitis?,” Clinical Biochemistry 50, no. 18 (2017): 1275–1280. - 31X. Zhang, C. Zhu, D. Wu, and X. Jiang, “Possible Role of Toll-Like Receptor 4 in Acute Pancreatitis,” Pancreas 39, no. 6 (2010): 819–824. - 32W. He, O. Rebello, R. Savino, et al., “TLR4 Triggered Complex Inflammation in Human Pancreatic Islets,” Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1865, no. 1 (2019): 86–97. - 33A. S. Gukovskaya, I. Gukovsky, V. Zaninovic, et al., “Pancreatic Acinar Cells Produce, Release, and Respond to Tumor Necrosis Factor-Alpha. Role in Regulating Cell Death and Pancreatitis,” Journal of Clinical Investigation 100, no. 7 (1997): 1853–1862. - 34Z. Jambrik, M. Gyöngyösi, P. Hegyi, et al., “Plasma Levels of IL-6 Correlate With Hemodynamic Abnormalities in Acute Pancreatitis in Rabbits,” Intensive Care Medicine 28, no. 12 (2002): 1810–1818. - 35M. A. Fouad Shalaby, H. A. Abd El Latif, M. El Yamani, et al., “Therapeutic Activity of Sarpogrelate and Dopamine D(2) Receptor Agonists on Cardiovascular and Renal Systems in Rats With Alloxan-Induced Diabetes,” BMC Pharmacology and Toxicology 22, no. 1 (2021): 64. - 36T. Karslıoglu, A. F. G. Karasu, and P. Yildiz, “The Effects of Micronized Progesterone and Cabergoline on a Rat Autotransplantation Endometriosis Model: A Placebo Controlled Randomized Trial,” Journal of Investigative Surgery 34, no. 8 (2021): 897–901. - 37S. Das, B. Shapiro, E. A. Vucic, S. Vogt, and D. Bar-Sagi, “Tumor Cell–Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer,” Cancer Research 80, no. 5 (2020): 1088–1101. - 38F. G. Bauernfeind, G. Horvath, A. Stutz, et al., “Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression,” Journal of Immunology 183, no. 2 (2009): 787–791. - 39R. Hoque, M. Sohail, A. Malik, et al., “TLR9 and the NLRP3 Inflammasome Link Acinar Cell Death With Inflammation in Acute Pancreatitis,” Gastroenterology 141, no. 1 (2011): 358–369. - 40F. Algaba-Chueca, E. de-Madaria, B. Lozano-Ruiz, et al., “The Expression and Activation of the AIM2 Inflammasome Correlates With Inflammation and Disease Severity in Patients With Acute Pancreatitis,” Pancreatology 17, no. 3 (2017): 364–371. - 41A. F. Pike, F. Longhena, G. Faustini, et al., “Dopamine Signaling Modulates Microglial NLRP3 Inflammasome Activation: Implications for Parkinson's Disease,” Journal of Neuroinflammation 19, no. 1 (2022): 50. - 42Y. Wang, H. Lv, Q. Cui, P. Tu, Y. Jiang, and K. Zeng, “Isosibiricin Inhibits Microglial Activation by Targeting the Dopamine D1/D2 Receptor-Dependent NLRP3/Caspase-1 Inflammasome Pathway,” Acta Pharmacologica Sinica 41, no. 2 (2020): 173–180. - 43D. M. Booth, J. A. Murphy, R. Mukherjee, et al., “Reactive Oxygen Species Induced by Bile Acid Induce Apoptosis and Protect Against Necrosis in Pancreatic Acinar Cells,” Gastroenterology 140, no. 7 (2011): 2116–2125. - 44T. Salomone, P. Tosi, N. Di Battista, et al., “Impaired Alveolar Gas Exchange in Acute Pancreatitis,” Digestive Diseases and Sciences 47, no. 9 (2002): 2025–2028. - 45E. I. Ekici, M. Güney, and M. Nazıroğlu, “Protective Effect of Cabergoline on Mitochondrial Oxidative Stress-Induced Apoptosis Is Mediated by Modulations of TRPM2 in Neutrophils of Patients With Endometriosis,” Journal of Bioenergetics and Biomembranes 52, no. 3 (2020): 131–142. - 46M. Yoshioka, K. Tanaka, I. Miyazaki, et al., “The Dopamine Agonist Cabergoline Provides Neuroprotection by Activation of the Glutathione System and Scavenging Free Radicals,” Neuroscience Research 43, no. 3 (2002): 259–267. - 47P. K. Garg, K. Madan, G. K. Pande, et al., “Association of Extent and Infection of Pancreatic Necrosis With Organ Failure and Death in Acute Necrotizing Pancreatitis,” Clinical Gastroenterology and Hepatology 3, no. 2 (2005): 159–166. - 48S. Yue, T. Wang, Y. Yang, et al., “Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Injury Could Be Attenuated by Dopamine Receptor Agonist Rotigotine via Regulating NF-κB Signaling Pathway,” International Immunopharmacology 96 (2021): 107798. - 49M. Li, C. Zhang, L. Zhou, X. Sun, T. Wang, and F. Fu, “Continuous Activation of Dopamine Receptors Alleviates LPS-Induced Liver Injury in Mice via β-Arrestin2 Dependent Akt/NF-κB Pathway,” Frontiers in Pharmacology 13 (2022): 853834. - 50E. Kaya, A. Arslan, Y. Aliyazicioglu, H. Güven, O. Aydin, and K. Ozkan, “Low Dose Dopamine Prevents End Organ Damage in Experimentally Induced Pancreatitis,” Hepato-gastroenterology 52, no. 64 (2005): 1250–1254.