The leaves of Bougainvillea spectabilis suppressed inflammation and nociception in vivo through the modulation of glutamatergic, cGMP, and ATP-sensitive K+ channel pathways

Abstract

Ethnopharmacological relevance: Bougainvillea spectabilis is an ornamental shrub from Nyctaginaceae family, widely used in the traditional medicine in the treatment of pain, inflammation, and ulcer. Some research investigated the analgesic potential of this plant, however, the in-depth analysis of its antinociceptive properties and molecular mechanism(s) are yet to be revealed.

Purpose of the study: This study, therefore, investigated the antinociceptive potential of methanol extract of the leaves of B. spectabilis (MEBS) with possible molecular mechanism(s) of action using several pre-clinical models of acute and chronic pain in mice.

Materials and methods: The dry leaf powder of B. spectabilis was macerated with 100% methanol, and then dried crude extract was used for in vivo experiments. Following the acute toxicity test with 500, 1000, and 2000 mg/kg b.w. doses of MEBS, the central antinociceptive activities of the extract (50, 100, and 200 mg/kg b.w.) were evaluated using hot plate and tail immersion tests, whereas the peripheral activities were investigated using acetic acid-induced writhing, formalin-induced licking and oedema, and glutamate-induced licking tests. Moreover, the possible involvements of cGMP and ATP-sensitive K+ channel pathways in the observed antinociceptive activities were also investigated using methylene blue (20 mg/kg b.w.) and glibenclamide (10 mg/kg b.w.), respectively. We also performed GC/MS-MS analysis of MEBS to identify the phyto-constituents and in silico modelling of the major compounds for potential molecular targets.

Results: Our results demonstrated that MEBS at 50, 100, and 200 mg/kg b.w. doses were not effective enough to suppress centrally mediated pain in the hot plate and tail immersion models. However, the extract was potent (at 100 and 200 mg/kg b.w. doses) in reducing peripheral nociception in the acetic acid-induced writhing and inflammatory phase of the formalin tests. Further analyses revealed that MEBS could interfere with glutamatergic system, cGMP and ATP-sensitive K⁺ channel pathways to show its antinociceptive properties. GC/MS-MS analysis revealed 35 different phytochemicals with potent anti-inflammatory and antinociceptive properties including phytol, neophytadiene, 2,4-Di-tert-butylphenol, fucoxanthin, and Vit-E. Prediction analysis showed high intestinal absorptivity and low toxicity profiles of these compounds with capability to interact with glutamatergic system, inhibit JAK/STAT pathway, scavenge nitric oxide and oxygen radicals, and inhibit expression of COX3, tumor necrosis factor, and histamine.

Conclusion: Taken together, these results suggested the antinociceptive potentials of MEBS which were mediated through the modulation of glutamatergic, cGMP, and ATP-sensitive K⁺ channel pathways. These also suggested that MEBS could be beneficial in the treatment of complications associated with nociceptive pain.

Keywords: 13-Docosenamide (PubChem CID: 5365371); 2,4-Di-tert-butylphenol (PubChem CID: 7311); ATP-Sensitive K(+) channel pathway; Antinociceptive; Bougainvillea spectabilis; Fucoxanthin (PubChem CID: 5281239); GC/MS-MS; Nyctaginaceae; Phytol (PubChem CID: 5280435); Squalene (PubChem CID: 638072); Stigmasta-7,25-dien-3-ol (PubChem CID: 623142); Stigmasterol (PubChem CID: 5280794); cGMP pathway; α-Tocopheryl acetate (PubChem CID: 2117).