The Antihypersensitive and Antiinflammatory Activities of a Benzofuranone Derivative in Different Experimental Models in Mice: The Importance of the Protein Kinase C Pathway

Benzofuranone (BF1) was synthesized and its effects evaluated on mechanical hypersensitivity and paw edema models induced by different agents and on neuropathic pain induced by partial ligation of the sciatic nerve. An attempt was also made to elucidate the mechanism of action. Swiss mice were used...

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Published in:	Anesthesia and analgesia Vol. 119; no. 4; pp. 836 - 846
Main Authors:	de Souza Nunes, Juliana Paula, da Silva, Kathryn Ana Bortolini, da Silva, Gislaine Francieli, Quintão, Nara Lins Meira, Corrêa, Rogério, Cechinel-Filho, Valdir, de Campos-Buzzi, Fátima, Niero, Rivaldo
Format:	Journal Article
Language:	English
Published:	United States International Anesthesia Research Society 01-10-2014
Subjects:	Animals Anti-Inflammatory Agents - pharmacology Anti-Inflammatory Agents - therapeutic use Antihypertensive Agents - pharmacology Antihypertensive Agents - therapeutic use Benzofurans - chemistry Benzofurans - pharmacology Benzofurans - therapeutic use Disease Models, Animal Edema - drug therapy Edema - enzymology Female Male Mice Pain - drug therapy Pain - enzymology Protein Kinase C - antagonists & inhibitors Protein Kinase C - metabolism Signal Transduction - drug effects Signal Transduction - physiology
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Summary:	Benzofuranone (BF1) was synthesized and its effects evaluated on mechanical hypersensitivity and paw edema models induced by different agents and on neuropathic pain induced by partial ligation of the sciatic nerve. An attempt was also made to elucidate the mechanism of action. Swiss mice were used for the tests. Hypersensitivity was induced by intraplantar injection of carrageenan, bradykinin (BK), prostaglandin E2 (PGE2), epinephrine, lipopolysaccharide, or complete Freund adjuvant or by using a neuropathic pain model (evaluated with von Frey filament 0.6 g). The antiinflammatory effects were investigated in a paw edema model induced by carrageenan, PGE2, and BK (measured with a plethysmometer). The involvement of protein kinase C (PKC) was investigated through a nociception model induced by phorbol myristate acetate. BF1 inhibited the hypersensitivity and paw edema induced by intraplantar injection of carrageenan, BK, and PGE2 (P < 0.001), and it was effective in reducing the hypersensitivity evoked by complete Freund adjuvant or epinephrine (P < 0.001) but not by lipopolysaccharide (P = 0.2570). BF1 inhibited the licking behavior induced by phorbol myristate acetate (P < 0.001), suggesting involvement of the PKC pathway. A reduction in hypersensitivity of mice submitted to partial ligation of the sciatic nerve (P < 0.001) was observed, with inhibition of neutrophil migration and interleukin-1β production into the spinal cord. BF1 treatment did not interfere with locomotor activity (P = 0.0783) and thermal withdrawal threshold (P = 0.5953), which are important adverse effects of other analgesics. BF1 has dose-dependent antihypersensitive and antiinflammatory effects in both acute and chronic models of pain and inflammation, possibly mediated through interference with the PKC activation pathway. The easy and fast synthesis of this compound, low-cost, low-concentration-requirement, and once-daily-administration drug suggest it as a candidate for future clinical studies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0003-2999 1526-7598
DOI:	10.1213/ANE.0000000000000351