title: Ameliorative potential of standardized fruit extract of Pterodon pubescens Benth on neuropathic pain in mice: Evidence for the mechanisms of action.
abstract: BACKGROUND
  The medicinal plant Pterodon pubescens Benth has been traditionally used for a long time to treat rheumatic diseases due to its anti-inflammatory and analgesic activities. The present study aims to evaluate the antinociceptive effect of ethanolic extract from P. pubescens fruits (EEPp) in a model of neuropathic pain in mice.
  
  
  METHODS
  The phytochemical analysis of EEPp was performed through GC-MS, HPLC and colorimetric analysis. The antinociceptive effects of EEPp (30-300 mg/kg, i.g.) were evaluated on mechanical and thermal (cold or heat) hyperalgesia in neuropathic pain induced by partial sciatic nerve ligation (PSNL) in mice. We also investigated the effects of EEPp on the nociceptive response induced by intrathecal injection (i.t.) of ionotropic (AMPA, NMDA and kainate) and metabotropic (trans-ACPD) glutamate receptor agonists, proinflammatory cytokines such as IL-1β and TNF-α, as well as TRPV1 and TRPA1 agonists. In addition, we also investigated the safety profile of prolonged treatment with EEPp in mice.
  
  
  RESULTS
  The phytochemical analysis showed a higher amount terpenes, being nine sesquiterpenes and seven diterpenes with vouacapan skeletons, as well as a small amount of phenols and flavonoids. The exact mechanism by which EEPp promotes its antinociceptive effect is not yet fully understood, but its oral administration causes significant inhibition of glutamate-, kainate-, NMDA-, trans-ACPD-induced biting responses, as well as of proinflammatory cytokines (TNF-α and IL-1β) and TRPV1 and TRPA1 channels activators (capsaicin and cinnamaldehyde, respectively). These results may indicate, at least in part, some of the mechanisms that are involved in this effect. In particular, EEPp decreases neuropathic pain and clearly shows, for the first time, a thermal and mechanical hyperalgesia reduction in the model of partial sciatic nerve ligation (PSNL), without inducing tolerance. Furthermore, the prolonged treatment with EEPp (300 mg/kg, i.g.) showed a cumulative effect over 24h, in the 15th day, after last treatment. In addition, the open-field test showed that doses up to 300 mg/kg in both treatments, acute and/or prolonged, did not affect the motor activity of mice. Also, EEPp showed no toxicity according to the serum levels of the renal and hepatic injury indicators or observed macroscopic organs, after PSNL.
  
  
  CONCLUSIONS
  Taken together, these results provide the first experimental evidence of the significant antinociceptive effect of EEPp on neuropathic pain without causing side effects, such as sedation or locomotor dysfunction. Moreover, these results appear to be mediated, at least in part, by the inhibition of glutamatergic receptors, TRPV1 and TRPA1 channels and proinflammatory cytokines. Thus, this study adds new scientific evidence and highlights the therapeutic potential of the medicinal plant P. pubescens in the development of phytomedicines for the management of neuropathic pain.
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil; Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Catharina
authors.initials: C
authors.lastname: Nucci-Martins
authors.affiliation: Laboratory of Experimental Neuroscience, Graduate Program in Health Sciences, University of Southern Santa Catarina, Pedra Branca, Palhoça, SC 88137-270, Brazil.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Martins
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil; Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Nascimento
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade Florianópolis, SC 88040-900, Brazil.
authors.forename: Dalila
authors.initials: D
authors.lastname: Venzke
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade Florianópolis, SC 88040-900, Brazil.
authors.forename: Aldo S
authors.initials: AS
authors.lastname: Oliveira
authors.affiliation: Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil; Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Marisa J S
authors.initials: MJ
authors.lastname: Frederico
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Fátima R M B
authors.initials: FR
authors.lastname: Silva
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade Florianópolis, SC 88040-900, Brazil.
authors.forename: Inês M C
authors.initials: IM
authors.lastname: Brighente
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade Florianópolis, SC 88040-900, Brazil.
authors.forename: Moacir G
authors.initials: MG
authors.lastname: Pizzolatti
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil; Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil. Electronic address: adair.santos@ufsc.br.
authors.forename: Adair R S
authors.initials: AR
authors.lastname: Santos
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D007887:Fabaceae; D005260:Female; D005638:Fruit; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D012584:Sciatic Nerve / Q000293:injuries; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000700:Analgesics; D053583:Interleukin-1beta; D010936:Plant Extracts; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D014409:Tumor Necrosis Factor-alpha
keywords: Glutamate; Mice; Neuropathic pain; Pterodon pubescens; TRPA1; TRPV1