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Valproic acid: an anticonvulsant drug with potent antinociceptive and anti-inflammatory properties

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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.

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Acknowledgments

The authors are grateful to the financial support of CNPq and CAPES (Brazilian Government Agencies for financial support and coordination of higher education personnel). They also thank the technical assistance of Ms. Xênia Maria de S. Serra and the orthographic revision of Prof. M.O.L. Viana.

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Authors and Affiliations

  1. Faculty of Medicine of the Federal University of Ceará (UFC), Fortaleza, Brazil

    Danilo de Oliveira Gonçalves, Rafaelly Maria Pinheiro Siqueira, Kelly Rose Tavares Neves, Gilberto Santos Cerqueira, Luzia Kalyne Almeida Moreira Leal, Gerly Anne de Castro Brito & Glauce Socorro de Barros Viana

  2. Faculty of Medicine Estácio of Juazeiro do Norte (FMJ), Ceará, Brazil

    Alyne Oliveira Correia & Glauce Socorro de Barros Viana

  3. Federal University of São Paulo, São Paulo (UNIFESP), São Paulo, Brazil

    José Christian Machado Ximenes & Maria da Graça Naffah-Mazzacorati

  4. Albert Sabin Hospital, Fortaleza, Brazil

    Francisco Hélder Cavalcante Félix

  5. Rua Barbosa de Freitas, 130/1100, Fortaleza, Brazil

    Glauce Socorro de Barros Viana

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  1. José Christian Machado Ximenes
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  2. Danilo de Oliveira Gonçalves
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Ximenes, J.C.M., de Oliveira Gonçalves, D., Siqueira, R.M.P. et al. Valproic acid: an anticonvulsant drug with potent antinociceptive and anti-inflammatory properties. Naunyn-Schmiedeberg's Arch Pharmacol 386, 575–587 (2013). https://doi.org/10.1007/s00210-013-0853-4

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