Hydroalcoholic crude extract of Casearia sylvestris Sw. reduces chronic post-ischemic pain by activation of pro-resolving pathways
Graphical abstract
Introduction
We have previously reported that the hydroalcoholic crude extract from Casearia sylvestris Sw. (HCE-CS) exert several actions on specific responses of pain and inflammation. Antinociceptive actions were evident in animal models of nociceptive, inflammatory and immune mediated pain (De Mattos et al., 2017); furthermore, the HCE-CS was also endowed with anti-inflammatory properties in the model of carrageenan-paw edema in mice, as well as in pleurisy model in rats reducing neutrophil recruitment and nitrite/nitrate production in pleural exsudate (Albano et al., 2013).
The Casearia sylvestris specie was recently related to the family of Salicaceae (Ferreira et al., 2011) and contains phytochemicals from different classes of medicinal interest such as sesqui- (Bou et al., 2013) and diterpenes (Meesakul et al., 2016). Among this last class, Dos Santos and colleagues (Dos Santos et al., 2010) recently reported the isolation of five new compounds, termed casearins and casearvestrins. Together with other coumpounds, casearins can be able to inhibit the activity of phospholipase A2 (PLA2) (Borges et al., 2000, Borges et al., 2001), which seems to be a property in agreement with the ethnopharmacological use of the plant in popular medicine for the treatment of wounds and ulcers or against snake bites (Ferreira et al., 2011). Collectively, these results raise the possibility that the plant could exert antinociceptive and anti-inflammatory effects based on mechanisms relied on resolution of inflammation pathways in other unexplored models of pain and inflammation, since PLA2 is also targeted by others pro-resolving mediators.
The resolution of inflammation is a programmed response from the organism to enable the end of the inflammatory process and ensure that the affected organ goes back to its pre-inflammatory settings and function (Perretti, 2015). Specific pro-resolving mediators and pathways are operative to enact resolution including those centred on annexin A1 (AnxA1) and lipoxin A4 (LXA4) (Cash et al., 2014). Accumulating evidence from diverse animal models indicate modulatory properties for pro-resolving mediators on nociception (Pei et al., 2011; Pierretti et al., 2001) and hyperalgesia (Abdelmoaty et al., 2013, Hu et al., 2012, Huang et al., 2011), through mechanisms that involve modulation of the expression of transcriptional factors and cytokines (Liu et al., 2016, Sun et al., 2012, Wang et al., 2014). Similarly, pivotal roles for the endogenous local signals that govern resolution to impact on pain processes have already defined (for review: Serhan, 2008). Against this background, we speculated a possible synergism of action for both HCE-CS and pro-resolving mediators on pain associated with inflammatory processes, the main example here being chronic post-ischemic pain (CPIP) typical of the Complex Regional Pain Syndrome-Type I (CRPS-I).
CRPS-I model is able to faithfully reproduce many of the symptoms related to this syndrome in humans such as hyperalgesia, edema, vasomotor dysfunction and trophic changes (Laferrière et al., 2008). Using this model, after induction of ischemia and reperfusion (I/R) in the hindpaw of animals, is possible to evaluate an initial phase of paw edema and inflammatory pain (up to 3 days after reperfusion) followed by a form of neuropatic pain (from 7 to 21 days after reperfusion) (Martins et al., 2013, Millecamps et al., 2010). Studies have elucidated few aspects of the histology of the skin and microvasculature of the paw tissues after I/R (Coderre and Bennett, 2010; Millecamps, 2010), yet joints and skeletal muscle have not been investigated, both in the absence or presence of specific pharmacological treatments. Herein, we aimed to investigate the effect of HCE-CS or pro-resolving mediators on mechanical hyperalgesia observed in CRPS-I through behavioral and histological analysis, as well as establish a possible influence of resolution of inflammation pathways to the effects of the plant extract.
Section snippets
Preparation and characterization of the hydroalcoholic crude extract of Casearia sylvestris (HCE-CS)
Extract was obtained from leaves of the plant collected at the botanical Horto at the campus of University Southern Santa Catarina (UNISUL), in the municipality of Tubarão, Santa Catarina, Brazil (latitude 28°28'00" south and longitude 49°00'25" west) and prepared as previously described (Albano et al., 2013) and the plant was identified by direct comparison with a voucher specimen (SRS-174) deposited at the herbarium Laelia Purpurata (SRS) at this university. Concentrated HCE of Casearia
Influence of pro-resolving mediators in the CRPS-I model
Treatment of the animals with different pro-resolving mediators at 10 min, 24 and 48 h after I/R, reduced the mechanical hyperalgesia quantified in this model (Fig. 2). At 26 h after I/R, or 2 h after second treatment, RvD1 (21.7±7.6% frequency of response), 15-epi-LXA4 (22.7±7.3%) and BML-111 (1 µg/animal: 31.4±5.0%) reduced frequency of response to von Frey filaments stimulus when compared to vehicle treated animals (52.7±7.3% frequency of response).
WRW4 prevents antihyperalgesic effect of HCE-CS or BML-111 during inflammatory phase of CRPS-I model
We then tested the treatment with HCE-CS which
Discussion
The present study demonstrated that HCE from the leaves of Casearia sylvestris displayed powerful anti-hyperalgesic effect during the inflammatory phase of experimental CRPS-I. These data also indicate, likely for the first time, an involvement of the mechanisms of the resolution of inflammation in the properties of the plant extract leading to the suggestion that both classes of compounds (HCE-CS and pro-resolving mediators) can provide pharmacological tools for the treatment of this condition
Conclusion
We presented evidence that demonstrate the involvement of a pathway of resolution of inflammation centred on LXA4 and the receptor ALX/FPR2 in the antihyperalgesic effect for HCE-CS and BML-111 during the inflammatory phase of CPIP model. These results also suggest a potential role for endogenous pro-resolving mediators in the pharmacological properties of Casearia sylvestris extract, a conclusion that may have dual implications with respect to innovative therapies for this debilitating
Authors and contributions
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Anna P. Piovezan: author make substantial contributions to conception and design, and/or acquisition of data, and/or analysis and interpretation of data, participate in drafting the article or revising it critically for important intellectual contente and give final approval of the version to be submitted and any revised version.
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Ana P. Batisti: author make substantial contributions to acquisition of data, participate in drafting the article and give final approval of the version to be submitted.
Conflict of interest
The authors declare that they have no conflicts of interest.
Acknowledgements
This work was supported by CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico -, FAPESC - Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina-, UNISUL (Brazil) and European Union's Seventh Framework Programme (FP7/2007–2013) CoFund (Marie Curie Actions; WHRI Academy) under REA grant agreement n° 608765”. Contents reflect only the author's views and not the views of the European Commission. Maria L.A.C.S. Benevides received PIBIC-CNPq/UNISUL scholarship.
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