Kynurenic Acid and Its Analogue SZR-72 Ameliorate the Severity of Experimental Acute Necrotizing Pancreatitis

• Published in: Frontiers in immunology 2021-10, Vol.12, p.702764-702764
• Main Authors: Balla, Zsolt, Kormányos, Eszter Sára, Kui, Balázs, Bálint, Emese Réka, Fűr, Gabriella, Orján, Erik Márk, Iványi, Béla, Vécsei, László, Fülöp, Ferenc, Varga, Gabriella, Harazin, András, Tubak, Vilmos, Deli, Mária A, Papp, Csaba, Gácser, Attila, Madácsy, Tamara, Venglovecz, Viktória, Maléth, József, Hegyi, Péter, Kiss, Lóránd, Rakonczay, Jr, Zoltán
• Format: Article
• Language: English
• Subjects: acute pancreatitis; Animals; Immunology; Interleukin-1beta - analysis; kynurenic acid; Kynurenic Acid - analogs & derivatives; Kynurenic Acid - pharmacology; Kynurenic Acid - therapeutic use; Male; Microcirculation - drug effects; N-Methylaspartate - pharmacology; NMDA; NMDA receptor-1; Pancreatitis, Acute Necrotizing - drug therapy; Pancreatitis, Acute Necrotizing - physiopathology; Patient Acuity; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - analysis; SZR-72; tryptophan pathway
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.702764

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 H O 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.