title: Valproic acid: an anticonvulsant drug with potent antinociceptive and anti-inflammatory properties.
abstract: Valproic acid (VA) is a major antiepileptic drug, used for several therapeutic indications. It has a wide activity spectrum, reflecting on mechanisms of action that are not fully understood. The objectives of this work were to study the effects of VA on acute models of nociception and inflammation in rodents. VA (0.5, 1, 10, 25, and 50 mg/kg, p.o.) effects were evaluated on the carrageenan-induced paw edema, carrageenan-induced peritonitis, and plantar tests in rats, as well as by the formalin test in mice. The HE staining and immunohistochemistry assay for TNF-α in carrageenan-induced edema, from paws of untreated and VA-treated rats, were also carried out. VA decreased paw edema after carrageenan, and maximum effects were seen with doses equal to or higher than 10 mg/kg. VA also preserved the tissue architecture as assessed by the HE staining. Immunohistochemical studies revealed that VA significantly reduced TNF-α immunostaining in carrageenan-inflamed rat paws. In addition, the anti-inflammatory action of VA was potentiated by pentoxifylline (a phosphodiesterase inhibitor, known to inhibit TNF-α production), but not by sodium butyrate or by suberoylanilide hydroxamic acid (SAHA), nonspecific and specific inhibitors, respectively, of histone deacetylase. However, the decrease in the number of positive TNF-α cells in the rat paw was drastically potentiated in the VA + SAHA associated group. VA also reduced leukocytes and myeloperoxidase (MPO) releases to the peritoneal exudate, in the carrageenan-induced peritonitis. Although in the formalin test, VA inhibited both phases, the inhibition was mainly on the second phase. Furthermore, VA significantly increased the reaction time to thermal stimuli, as assessed by the plantar test. VA is a multi-target drug, presenting potent antinociceptive and anti-inflammatory properties at a lower dose range. These effects are partly dependent upon its inhibitory action on TNF-α-related pathways. However, the participation of the HDAC inhibition with the VA anti-inflammatory action cannot be ruled out. Inflammatory processes are associated with free radical damage and oxidative stress, and their blockade by VA could also explain the present results.
authors.affiliation: Federal University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: José Christian Machado
authors.initials: JC
authors.lastname: Ximenes
authors.forename: Danilo
authors.initials: D
authors.lastname: de Oliveira Gonçalves
authors.forename: Rafaelly Maria Pinheiro
authors.initials: RM
authors.lastname: Siqueira
authors.forename: Kelly Rose Tavares
authors.initials: KR
authors.lastname: Neves
authors.forename: Gilberto
authors.initials: G
authors.lastname: Santos Cerqueira
authors.forename: Alyne Oliveira
authors.initials: AO
authors.lastname: Correia
authors.forename: Francisco Hélder Cavalcante
authors.initials: FH
authors.lastname: Félix
authors.forename: Luzia Kalyne Almeida Moreira
authors.initials: LK
authors.lastname: Leal
authors.forename: Gerly Anne
authors.initials: GA
authors.lastname: de Castro Brito
authors.forename: Maria
authors.initials: M
authors.lastname: da Graça Naffah-Mazzacorati
authors.forename: Glauce Socorro de Barros
authors.initials: GS
authors.lastname: Viana
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000927:Anticonvulsants / Q000008:administration & dosage*; D020148:Butyric Acid / Q000008:administration & dosage; D002351:Carrageenan; D004357:Drug Synergism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005528:Foot / Q000473:pathology; D005557:Formaldehyde; D006358:Hot Temperature; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000473:pathology; D010431:Pentoxifylline / Q000008:administration & dosage; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D009195:Peroxidase / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014635:Valproic Acid / Q000008:administration & dosage*; D000077337:Vorinostat
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D006877:Hydroxamic Acids; D014409:Tumor Necrosis Factor-alpha; D020148:Butyric Acid; D005557:Formaldehyde; D000077337:Vorinostat; D014635:Valproic Acid; D002351:Carrageenan; D009195:Peroxidase; D010431:Pentoxifylline