title: The antihypersensitive and antiinflammatory activities of a benzofuranone derivative in different experimental models in mice: the importance of the protein kinase C pathway.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Programa de Pós-Graduação em Ciências Farmacêuticas and Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí, Rua Uruguai, Itajaí, SC, Brazil.
authors.forename: Juliana Paula
authors.initials: JP
authors.lastname: de Souza Nunes
authors.forename: Kathryn Ana Bortolini
authors.initials: KAB
authors.lastname: da Silva
authors.forename: Gislaine Francieli
authors.initials: GF
authors.lastname: da Silva
authors.forename: Nara Lins Meira
authors.initials: NLM
authors.lastname: Quintão
authors.forename: Rogério
authors.initials: R
authors.lastname: Corrêa
authors.forename: Valdir
authors.initials: V
authors.lastname: Cechinel-Filho
authors.forename: Fátima
authors.initials: F
authors.lastname: de Campos-Buzzi
authors.forename: Rivaldo
authors.initials: R
authors.lastname: Niero
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy / Q000201:enzymology; D005260:Female; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D001572:Benzofurans; D011493:Protein Kinase C