The pharmacological blockade of P2X4 receptors has shown potential benefits in the management of several immune/inflammatory diseases. However, data regarding the involvement of P2X4 receptors in the pathophysiological mechanisms of action in intestinal inflammation are not well defined. We aimed to evaluate the anti-inflammatory effects of two novel and selective P2X4 receptor antagonists, NC-2600 and NP-1815-PX, and characterize the molecular mechanisms of their action in a murine model of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis. These two drugs and dexamethasone (DEX) were administered orally for 6 days, immediately after the manifestation of DNBS. The body weight decrease, resulting from colitis, was attenuated by NC-2600 and NP-1815-PX, but not DEX. However, all three drugs attenuated the increase in spleen weight and ameliorated macroscopic and microscopic colonic tissue damage. Furthermore, all three compounds decreased tissue IL-1 beta levels and caspase-1 expression and activity. Colonic tissue increase of tumor necrosis factor was downregulated by DEX, while both NC-2600 and NP-1815-PX were ineffective. The reduction of occludin associated with colitis was ameliorated by NC-2600 and NP-1815-PX, but not DEX. In THP-1 cells, lipopolysaccharide and ATP upregulated IL-1 beta release and NLRP3, caspase-1, caspase-5, and caspase-8 activity, but not of caspase-4. These changes were prevented by NC-2600 and NP-1815-PX treatment. For the first time, the above findings show that the selective inhibition of P2X4 receptors represents a viable approach to manage bowel inflammation via the inhibition of NLRP3 inflammasome signaling pathways.

Anti-inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis / D'Antongiovanni, Vanessa; Pellegrini, Carolina; Benvenuti, Laura; Fornai, Matteo; Di Salvo, Clelia; Natale, Gianfranco; Ryskalin, Larisa; Bertani, Lorenzo; Lucarini, Elena; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Nemeth, Zoltan H; Haskó, György; Antonioli, Luca. - In: INFLAMMATION. - ISSN 0360-3997. - ELETTRONICO. - 45:(2022), pp. 1829-1847. [10.1007/s10753-022-01663-8]

Anti-inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis

D'Antongiovanni, Vanessa;Lucarini, Elena;Di Cesare Mannelli, Lorenzo;Ghelardini, Carla;
2022

Abstract

The pharmacological blockade of P2X4 receptors has shown potential benefits in the management of several immune/inflammatory diseases. However, data regarding the involvement of P2X4 receptors in the pathophysiological mechanisms of action in intestinal inflammation are not well defined. We aimed to evaluate the anti-inflammatory effects of two novel and selective P2X4 receptor antagonists, NC-2600 and NP-1815-PX, and characterize the molecular mechanisms of their action in a murine model of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis. These two drugs and dexamethasone (DEX) were administered orally for 6 days, immediately after the manifestation of DNBS. The body weight decrease, resulting from colitis, was attenuated by NC-2600 and NP-1815-PX, but not DEX. However, all three drugs attenuated the increase in spleen weight and ameliorated macroscopic and microscopic colonic tissue damage. Furthermore, all three compounds decreased tissue IL-1 beta levels and caspase-1 expression and activity. Colonic tissue increase of tumor necrosis factor was downregulated by DEX, while both NC-2600 and NP-1815-PX were ineffective. The reduction of occludin associated with colitis was ameliorated by NC-2600 and NP-1815-PX, but not DEX. In THP-1 cells, lipopolysaccharide and ATP upregulated IL-1 beta release and NLRP3, caspase-1, caspase-5, and caspase-8 activity, but not of caspase-4. These changes were prevented by NC-2600 and NP-1815-PX treatment. For the first time, the above findings show that the selective inhibition of P2X4 receptors represents a viable approach to manage bowel inflammation via the inhibition of NLRP3 inflammasome signaling pathways.
2022
45
1829
1847
D'Antongiovanni, Vanessa; Pellegrini, Carolina; Benvenuti, Laura; Fornai, Matteo; Di Salvo, Clelia; Natale, Gianfranco; Ryskalin, Larisa; Bertani, Lorenzo; Lucarini, Elena; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Nemeth, Zoltan H; Haskó, György; Antonioli, Luca
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1296000
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