Kynurenic Acid and Its Analogue SZR-72 Ameliorate the Severity of Experimental Acute Necrotizing Pancreatitis
| Autor: | Vilmos Tubak, Péter Hegyi, József Maléth, Attila Gácser, Tamara Madácsy, Emese Réka Bálint, Béla Iványi, Balázs Kui, László Vécsei, András Harazin, Erik Márk Orján, Csaba Gergő Papp, Ferenc Fülöp, Gabriella Fűr, Eszter S. Kormányos, Viktória Venglovecz, Gabriella Varga, Mária A. Deli, Loránd Kiss, Zoltán Rakonczay, Zsolt Balla |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
N-Methylaspartate acute pancreatitis Neutrophil granulocyte Immunology Interleukin-1beta tryptophan pathway NMDA receptor-1 Pharmacology Kynurenic Acid Receptors N-Methyl-D-Aspartate Rats Sprague-Dawley chemistry.chemical_compound Kynurenic acid medicine Acinar cell Immunology and Allergy Animals Receptor Original Research Chemistry Pancreatitis Acute Necrotizing Microcirculation Patient Acuity RC581-607 medicine.disease Pathophysiology Rats medicine.anatomical_structure NMDA SZR-72 N-methyl-D-aspartate Toxicity Acute pancreatitis NMDA receptor Immunologic diseases. Allergy |
| Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 12 (2021) |
| ISSN: | 1664-3224 |
| Popis: | The pathophysiology of acute pancreatitis (AP) is not well understood, and the disease does not have specific therapy. Tryptophan metabolite L-kynurenic acid (KYNA) and its synthetic analogue SZR-72 are antagonists of the N-methyl-D-aspartate receptor (NMDAR) and have immune modulatory roles in several inflammatory diseases. Our aims were to investigate the effects of KYNA and SZR-72 on experimental AP and to reveal their possible mode of action. AP was induced by intraperitoneal (i.p.) injection of L-ornithine-HCl (LO) in SPRD rats. Animals were pretreated with 75-300 mg/kg KYNA or SZR-72. Control animals were injected with physiological saline instead of LO, KYNA and/or SZR-72. Laboratory and histological parameters, as well as pancreatic and systemic circulation were measured to evaluate AP severity. Pancreatic heat shock protein-72 and IL-1β were measured by western blot and ELISA, respectively. Pancreatic expression of NMDAR1 was investigated by RT-PCR and immunohistochemistry. Viability of isolated pancreatic acinar cells in response to LO, KYNA, SZR-72 and/or NMDA administration was assessed by propidium-iodide assay. The effects of LO and/or SZR-72 on neutrophil granulocyte function was also studied. Almost all investigated laboratory and histological parameters of AP were significantly reduced by administration of 300 mg/kg KYNA or SZR-72, whereas the 150 mg/kg or 75 mg/kg doses were less or not effective, respectively. The decreased pancreatic microcirculation was also improved in the AP groups treated with 300 mg/kg KYNA or SZR-72. Interestingly, pancreatic heat shock protein-72 expression was significantly increased by administration of SZR-72, KYNA and/or LO. mRNA and protein expression of NMDAR1 was detected in pancreatic tissue. LO treatment caused acinar cell toxicity which was reversed by 250 µM KYNA or SZR-72. Treatment of acini with NMDA (25, 250, 2000 µM) did not influence the effects of KYNA or SZR-72. Moreover, SZR-72 reduced LO-induced H2O2 production of neutrophil granulocytes. KYNA and SZR-72 have dose-dependent protective effects on LO-induced AP or acinar toxicity which seem to be independent of pancreatic NMDA receptors. Furthermore, SZR-72 treatment suppressed AP-induced activation of neutrophil granulocytes. This study suggests that administration of KYNA and its derivative could be beneficial in AP. |
| Databáze: | OpenAIRE |
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