Role of peripheral and central sensitization in the anti-hyperalgesic effect of hecogenin acetate, an acetylated sapogenin, complexed with ß-cyclodextrin: Involvement of NFκB and p38 MAPK pathways.

Neuropathic pain develops due to injury to the somatosensory system, affecting the patient's quality of life. In view of the ineffectiveness of the current pharmacotherapy, substances obtained from natural products (NPs) are a promising alternative. One NP that has been discussed in the literature is hecogenin acetate (HA), a steroidal sapogenin with anti-inflammatory and antinociceptive activity. However, HA has low water solubility, which affects its bioavailability. Thus, the objective of this study was to evaluate the anti-hyperalgesic activity of pure and complexed hecogenin acetate (HA/ßCD) in an animal model of chronic neuropathic and inflammatory pain. The inclusion complex was prepared at a molar ratio of 1:2 (HA:ßCD) by the lyophilization method. For the induction of chronic inflammatory pain, the mice received an intraplantar injection of CFA (complete Freund's adjuvant), and were evaluated for mechanical hyperalgesia and for the levels of myeloperoxidase (MPO) in the skin of the paw after eight days of treatment. HA and HA/ßCD reduced mechanical hyperalgesia in relation to the vehicle group until the fourth and fifth hours, respectively, in the acute evaluation, with a superior effect of the complexed form over the pure form in the second and third hour after treatment (p < 0.001). In the chronic evaluation, HA and HA/ßCD reduced hyperalgesia in relation to the vehicle in the eight days of treatment (p < 0.001). Both pure (p < 0.01) and complexed (p < 0.001) forms reduced myeloperoxidase activity in the skin of the animals' paw. Groups of animals subjected to the same pharmacological protocol were submitted to the partial sciatic nerve ligation (PSNL) model and evaluated for mechanical and thermal hyperalgesia, and cold allodynia. HA and HA/ßCD reduced mechanical hyperalgesia until the fourth and sixth hours, respectively, and both reduced hyperalgesia in relation to the vehicle in the chronic evaluation (p < 0.001). HA and HA/ßCD also reduced thermal hyperalgesia and cold allodynia (p < 0.05 and p < 0.001, respectively). The analysis of the spinal cord of these animals showed a decrease in the levels of the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 and a reduction in the phosphorylation of NFκB and p38MAPK, as well as a decrease in microglioses compared to the vehicle group. In addition, HA/ßCD reduced the nociception induced by intraplantar injection of agonist TRPA1 (p < 0.01) and TRPM8 (p < 0.05). Treatment for eight days with HA and HA/ßCD showed no signs of gastric or liver damage. HA and HA/ßCD were, therefore, shown to have antinociceptive effects in chronic pain models. Based on our exploration of the mechanisms of the action of HA, these effects are likely to be related to inhibited leukocyte migration, interaction with the TRPA1 and TRPM8 receptors, reduced pro-inflammatory cytokines levels, microglial expression and suppression of NF-κB p65 and p38 MAPK pathway signaling. Therefore, HA/ßCD has great potential for use in the treatment of chronic pain.

Dereplication and quantification of the ethanol extract of Miconia albicans (Melastomaceae) by HPLC-DAD-ESI-/MS/MS, and assessment of its anti-hyperalgesic and anti-inflammatory profiles in a mice arthritis-like model: Evidence for involvement of TNF-α, IL-1ß and IL-6.

ETHNOPHARMACOLOGICAL RELEVANCE: Miconia albicans (Sw) Triana (Melastomataceae), a medicinal plant widely used by practitioners of folk medicine in the northeast of Brazil, has been used to treat chronic inflammatory disorders, such as rheumatoid arthritis (RA) and other joint conditions. Oddly, there is little research on the species. AIM OF THE STUDY: We aimed to evaluate the anti-arthritic and anti-inflammatory profile of the ethanolic leaf extract of M. albicans (EEMA), as well as to perform dereplication and quantification by HPLC-DAD-ESI-/MS/MS. MATERIALS AND METHODS: The compounds present in the extracts were identified by HPLC-DAD-ESI-MS/MS. The possible anti-inflammatory effect of EEMA (50 and 100 mg/kg, p.o) was evaluated using the pleurisy model induced by carrageenan and its action on IL-1ß and TNF-α levels was also evaluated. The RA model was induced through the intra-articular injection of complete Freund's adjuvant (CFA). RESULTS: HPLC-DAD-ESI-MS/MS analysis identified 23 compounds, with glycoside flavonoids mainly derived from quercetin, and rutin being the main compounds. EEMA significantly reduced (p < 0.001) leukocyte migration in the pleurisy model and reduced TNF-α and IL-1ß levels in pleural lavage (p < 0.001). In the CFA animal model, EEMA significantly reduced the nociceptive and hyperalgesic behaviors demonstrated by the rearing test (p < 0.01 or p < 0.05) and decreased mechanical hyperalgesia (p < 0.001). EEMA produced a significant improvement in mobility in the open-field test (only at the higher dose, p < 0.05). EEMA significantly (p < 0.01) increased hindpaw grip strength. The diameter of CFA-induced ipsilateral knee edema was significantly reduced (p < 0.001) by EEMA, which was related to reduced levels of IL-6 and TNF-α in the joint knee (p < 0.01). No indication of hepatic injury after chronic treatment was found. CONCLUSION: Taken together, these results contribute to the chemical and pharmacological knowledge of M. albicans and demonstrated that this medicinal plant appears to be able to mitigate deleterious symptoms of RA, which supports its use in folk medicine.