Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test

Marta Szandruk-Bender,1 Anna Merwid-L&aogon;d,1 Benita Wiatrak,1 Maciej Danielewski,1 Stanis&lstrok;aw Dzimira,2 Danuta Szkudlarek,3 &Lstrok;ukasz Szczukowski,4 Piotr &Sacute;wi&aogon;tek,4 Adam Szel&aogon;g1 1Department of Pharmacology, Wroclaw Medical University, Wroc&l...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Szandruk-Bender M, Merwid-Ląd A, Wiatrak B, Danielewski M, Dzimira S, Szkudlarek D, Szczukowski Ł, Świątek P, Szeląg A
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	carrageenan anti-inflammatory agents pyrrolo[3 4-d]pyridazinone 1 3 4-oxadiazole inflammatory mediators toxicity Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/d90f1bb5903e43d280d94fe8e9e79b5f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d90f1bb5903e43d280d94fe8e9e79b5f
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	carrageenan anti-inflammatory agents pyrrolo[3 4-d]pyridazinone 1 3 4-oxadiazole inflammatory mediators toxicity Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	carrageenan anti-inflammatory agents pyrrolo[3 4-d]pyridazinone 1 3 4-oxadiazole inflammatory mediators toxicity Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Szandruk-Bender M Merwid-Ląd A Wiatrak B Danielewski M Dzimira S Szkudlarek D Szczukowski Ł Świątek P Szeląg A Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test
description	Marta Szandruk-Bender,1 Anna Merwid-L&aogon;d,1 Benita Wiatrak,1 Maciej Danielewski,1 Stanis&lstrok;aw Dzimira,2 Danuta Szkudlarek,3 &Lstrok;ukasz Szczukowski,4 Piotr &Sacute;wi&aogon;tek,4 Adam Szel&aogon;g1 1Department of Pharmacology, Wroclaw Medical University, Wroc&lstrok;aw, Poland; 2Department of Pathology, Wroclaw University of Environmental and Life Sciences, Wroc&lstrok;aw, Poland; 3Foundation of the Wroclaw Medical University, Wroclaw Medical University, Wroc&lstrok;aw, Poland; 4Department of Chemistry of Drugs, Wroclaw Medical University, Wroc&lstrok;aw, PolandCorrespondence: Marta Szandruk-BenderDepartment of Pharmacology, Wroclaw Medical University, Mikulicza-Radeckiego 2, Wroc&lstrok;aw, 50-345, PolandTel +48717841438Fax +48717840094Email marta.szandruk@umed.wroc.plBackground and Purpose: Due to the risk of gastrointestinal damage and various tissue toxicity associated with non-steroidal anti-inflammatory drugs (NSAIDs) use, investigating new anti-inflammatory agents with efficacy comparable to that of NSAIDs but reduced toxicity is still a major challenge and a clinical need. Based on our previous study, new 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 6-butyl-3,5,7-trimethyl-1-[[4-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]methoxy]pyrrolo[3,4-d]pyridazin-4-one and 6-butyl-1-[[4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]methyl]-2-thioxo-1,3,4-oxadiazol-5-yl]methoxy]-3,5,7-trimethyl-pyrrolo[3,4-d]pyridazin-4-one (hereafter referred to as the compounds 10b and 13b, respectively) seem to be promising anti-inflammatory agents. This study aimed to elucidate the effects of these two new derivatives on the course of experimental rat inflammation, liver and kidney function, and gastric mucosa.Methods: The anti-inflammatory effect of compounds 10b and 13b was evaluated using the carrageenan-induced paw edema test in rats. The increase in paw volume (paw edema), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) levels, histological alterations, and inflammatory cell infiltration in paw tissue were determined. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities, serum urea and creatinine levels, as well as changes in gastric mucosa, were measured as indicators of hepatic, renal, and gastric toxicity.Results: Pretreatment with both novel derivatives at 10 mg/kg and 20 mg/kg doses reduced paw edema, counteracted the increased PGE2 and TNF-α levels, reduced the influx of inflammatory cells, and decreased histopathological alterations in paw tissue. Compound 13b at a dose of 20 mg/kg was more effective than indomethacin in reversing the increased TNF-α levels and reducing the influx of inflammatory cells. Only compound 13b at all studied doses (5, 10, or 20 mg/kg) counteracted the increased MPO level in paw tissue. Both compounds neither caused alterations in ALT, AST, urea, creatinine parameters nor gastric mucosal lesions.Conclusion: New compounds exert an anti-inflammatory effect, presumably via inhibiting inflammatory mediators release and inflammatory cell infiltration. Moreover, both possess a more favorable benefit–risk profile than indomethacin, especially compound 13b.Keywords: carrageenan, anti-inflammatory agents, pyrrolo[3,4-d]pyridazinone, 1,3,4-oxadiazole, inflammatory mediators, toxicity
format	article
author	Szandruk-Bender M Merwid-Ląd A Wiatrak B Danielewski M Dzimira S Szkudlarek D Szczukowski Ł Świątek P Szeląg A
author_facet	Szandruk-Bender M Merwid-Ląd A Wiatrak B Danielewski M Dzimira S Szkudlarek D Szczukowski Ł Świątek P Szeląg A
author_sort	Szandruk-Bender M
title	Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test
title_short	Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test
title_full	Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test
title_fullStr	Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test
title_full_unstemmed	Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test
title_sort	novel 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone exert anti-inflammatory activity without acute gastrotoxicity in the carrageenan-induced rat paw edema test
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/d90f1bb5903e43d280d94fe8e9e79b5f
work_keys_str_mv	AT szandrukbenderm novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest AT merwidlada novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest AT wiatrakb novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest AT danielewskim novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest AT dzimiras novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest AT szkudlarekd novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest AT szczukowskił novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest AT swiatekp novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest AT szelaga novel134oxadiazolederivativesofpyrrolo34dpyridazinoneexertantiinflammatoryactivitywithoutacutegastrotoxicityinthecarrageenaninducedratpawedematest
_version_	1718376408572493824
spelling	oai:doaj.org-article:d90f1bb5903e43d280d94fe8e9e79b5f2021-12-02T19:31:58ZNovel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test1178-7031https://doaj.org/article/d90f1bb5903e43d280d94fe8e9e79b5f2021-11-01T00:00:00Zhttps://www.dovepress.com/novel-134-oxadiazole-derivatives-of-pyrrolo34-dpyridazinone-exert-anti-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Marta Szandruk-Bender,1 Anna Merwid-L&aogon;d,1 Benita Wiatrak,1 Maciej Danielewski,1 Stanis&lstrok;aw Dzimira,2 Danuta Szkudlarek,3 &Lstrok;ukasz Szczukowski,4 Piotr &Sacute;wi&aogon;tek,4 Adam Szel&aogon;g1 1Department of Pharmacology, Wroclaw Medical University, Wroc&lstrok;aw, Poland; 2Department of Pathology, Wroclaw University of Environmental and Life Sciences, Wroc&lstrok;aw, Poland; 3Foundation of the Wroclaw Medical University, Wroclaw Medical University, Wroc&lstrok;aw, Poland; 4Department of Chemistry of Drugs, Wroclaw Medical University, Wroc&lstrok;aw, PolandCorrespondence: Marta Szandruk-BenderDepartment of Pharmacology, Wroclaw Medical University, Mikulicza-Radeckiego 2, Wroc&lstrok;aw, 50-345, PolandTel +48717841438Fax +48717840094Email marta.szandruk@umed.wroc.plBackground and Purpose: Due to the risk of gastrointestinal damage and various tissue toxicity associated with non-steroidal anti-inflammatory drugs (NSAIDs) use, investigating new anti-inflammatory agents with efficacy comparable to that of NSAIDs but reduced toxicity is still a major challenge and a clinical need. Based on our previous study, new 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 6-butyl-3,5,7-trimethyl-1-[[4-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]methoxy]pyrrolo[3,4-d]pyridazin-4-one and 6-butyl-1-[[4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]methyl]-2-thioxo-1,3,4-oxadiazol-5-yl]methoxy]-3,5,7-trimethyl-pyrrolo[3,4-d]pyridazin-4-one (hereafter referred to as the compounds 10b and 13b, respectively) seem to be promising anti-inflammatory agents. This study aimed to elucidate the effects of these two new derivatives on the course of experimental rat inflammation, liver and kidney function, and gastric mucosa.Methods: The anti-inflammatory effect of compounds 10b and 13b was evaluated using the carrageenan-induced paw edema test in rats. The increase in paw volume (paw edema), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) levels, histological alterations, and inflammatory cell infiltration in paw tissue were determined. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities, serum urea and creatinine levels, as well as changes in gastric mucosa, were measured as indicators of hepatic, renal, and gastric toxicity.Results: Pretreatment with both novel derivatives at 10 mg/kg and 20 mg/kg doses reduced paw edema, counteracted the increased PGE2 and TNF-α levels, reduced the influx of inflammatory cells, and decreased histopathological alterations in paw tissue. Compound 13b at a dose of 20 mg/kg was more effective than indomethacin in reversing the increased TNF-α levels and reducing the influx of inflammatory cells. Only compound 13b at all studied doses (5, 10, or 20 mg/kg) counteracted the increased MPO level in paw tissue. Both compounds neither caused alterations in ALT, AST, urea, creatinine parameters nor gastric mucosal lesions.Conclusion: New compounds exert an anti-inflammatory effect, presumably via inhibiting inflammatory mediators release and inflammatory cell infiltration. Moreover, both possess a more favorable benefit–risk profile than indomethacin, especially compound 13b.Keywords: carrageenan, anti-inflammatory agents, pyrrolo[3,4-d]pyridazinone, 1,3,4-oxadiazole, inflammatory mediators, toxicitySzandruk-Bender MMerwid-Ląd AWiatrak BDanielewski MDzimira SSzkudlarek DSzczukowski ŁŚwiątek PSzeląg ADove Medical Pressarticlecarrageenananti-inflammatory agentspyrrolo[34-d]pyridazinone134-oxadiazoleinflammatory mediatorstoxicityPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 5739-5756 (2021)

Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test

Ejemplares similares