| Summary: | ObjectiveMoringa oleifera possesses multiple biological effects and the 4-[(4′-O-acetyl-α-L- rhamnosyloxy) benzyl] isothiocyanate accounts for them. Based on the original isothiocyanate molecule we obtained a semisynthetic derivative, named 4-[(2′,3′,4′-O-triacetyl-α-L-rhamnosyloxy) N-benzyl] hydrazine carbothioamide (MC-H) which was safe and effective in a temporomandibular joint (TMJ) inflammatory hypernociception in rats. Therefore, considering that there is still a gap in the knowledge concerning the mechanisms of action through which the MC-H effects are mediated, this study aimed to investigate the involvement of the adhesion molecules (ICAM-1, CD55), the pathways heme oxygenase-1 (HO-1) and NO/cGMP/PKG/K+ATP, and the central opioid receptors in the efficacy of the MC-H in a pre-clinical study of TMJ pain.MethodsMolecular docking studies were performed to test the binding performance of MC-H against the ten targets of interest (ICAM-1, CD55, HO-1, iNOS, soluble cGMP, cGMP-dependent protein kinase (PKG), K+ATP channel, mu (μ), kappa (κ), and delta (δ) opioid receptors). In in vivo studies, male Wistar rats were treated with MC-H 1 μg/kg before TMJ formalin injection and nociception was evaluated. Periarticular tissues were removed to assess ICAM-1 and CD55 protein levels by Western blotting. To investigate the role of HO-1 and NO/cGMP/PKG/K+ATP pathways, the inhibitors ZnPP-IX, aminoguanidine, ODQ, KT5823, or glibenclamide were used. To study the involvement of opioid receptors, rats were pre-treated (15 min) with an intrathecal injection of non-selective inhibitor naloxone or with CTOP, naltrindole, or norbinaltorphimine.ResultsAll interactions presented acceptable binding energy values (below −6.0 kcal/mol) which suggest MC-H might strongly bind to its molecular targets. MC-H reduced the protein levels of ICAM-1 and CD55 in periarticular tissues. ZnPP-IX, naloxone, CTOP, and naltrindole reversed the antinociceptive effect of MC-H.ConclusionMC-H demonstrated antinociceptive and anti-inflammatory effects peripherally by the activation of the HO-1 pathway, as well as through inhibition of the protein levels of adhesion molecules, and centrally by μ and δ opioid receptors.
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