Resveratrol formulated with a natural deep eutectic solvent inhibits active matrix metalloprotease‐9 in hormetic conditions

Abstract

Despite the promising anti-oxidant and anti-inflammatory effects of resveratrol (RES) on human health, pre-clinical and clinical studies are frequently disappointing, probably due to its low water-solubility and poor bioavailability. Even though a hormetic mode of action was clearly established for RES, the high doses commonly used to mitigate these issues, lead to adverse effects. Common hallmarks of multiple pathologies results from pathological-enhanced endothelial permeability due to both enhanced inflammation and matrix metalloprotease-9 (aMMP-9) activities. The main aim of this work was to optimize the RES capacity to inhibit aMMP-9 by using a new class of solvents, natural deep eutectic solvents (NADES) for a new RES formulation as compared with dimethyl-sulfoxide (DMSO). To obtain the appropriate NADES, 18 compounds combinations were prepared to select those exhibiting the optimized capacity to dissolve RES. The RES-NADES 1,2-propanediol:choline-chloride:water (PCW, 1:1:1 molar ratio) and compared with RES-DMSO for their aMMP-9-inhibitory capacities. Low concentrations of RES-NADES/PCW formulation exhibited both a biocompatible solubility and a strong increased aMMP-9-inhibitory activity, at least 10-fold, higher than RES-DMSO, reaching its hormetic mode of action. Following in vivo validations, some particular NADES could potentially be considered as the new generation of formulation for druggable compounds. Practical applications: Formulation of resveratrol in Natural Deep Eutectic solvents (NADES) optimizes its capacity to inhibit active matrix metalloprotease-9. The Resveratrol-NADES 1,2-propanediol:choline-was the most efficient and low concentrations exhibited both a biocompatible solubility and an increased aMMP-9-inhibitory activity, at least 10-fold, higher than RES-DMSO. Consequently, the NADES/PCW formulation allowed resveratrol to reach its hormetic mode of action. Following in vivo validations, some particular NADES could potentially be considered as the new generation of formulation for druggable compounds. The effect of resveratrol (RES) dissolved in either NADES/PCW or DMSO was assessed on the TNFa-activated human monocytes (THP-1). NADES/PCW was able to confer a significant increase of the MMP-9 inhibitory activity of RES, at low doses (at least 10-fold higher) than DMSO, Thus, these data on RES-NADES/PCW formulation support the hormetic effect of resveratrol in preserving the endothelial monolayer integrity by decreasing the exacerbated vascular permeability induced by the overproduction of active MMP-9, during inflammation resulting from infections, cancer, or other pathologies. (Résumé d'auteur

Resveratrol-Linoleate protects from exacerbated endothelial permeability via a drastic inhibition of the MMP-9 activity

“…Afterward, we assessed the cytotoxicity assay of most active and soluble lipophenol derivative, RES-LA, on THP-1 and HUVEC ( Figure 3 ). Our data revealed a less cytotoxic profile of RES-LA as compared with the parent compound RES as assessed in our previous study [ 14 ]. Additionally, we chose NADES as a solvent, since it is believed to be less toxic than other organic solvents due to its natural composition [ 13 ].…”

“…Additionally, we chose NADES as a solvent, since it is believed to be less toxic than other organic solvents due to its natural composition [ 13 ]. However, in our previous study, the compared cytotoxicity levels between NADES (1,2-propanediol:choline chloride:water, 1:1:1) and DMSO were not different [ 14 ]. We also demonstrated in that same study that NADES was able to improve the MMP-9 inhibitory activity of RES by at least ten fold higher than DMSO, thus permitting to evidence the hormetic mode of action of RES.…”

“…The emerging use of this new solvent class has been particularly observed in the field of green chemistry, for the extraction of different plant bioactive compounds and much less applied to the extraction of organic solvents (which are more toxic and volatile) [ 13 ]. In our previous study [ 14 ], we found that a particular NADES, consisting of an equimolar 1,2-propanediol:choline chloride:water mix (PCW), was not only able to solubilize RES, but also to increase its capacity to inhibit MMP-9 activity, by at least a ten-fold factor as compared with DMSO. Thus, NADES-PCW enabled us to reach the RES hormetic mode of action.…”

The perspectives of natural deep eutectic solvents in agri-food sector

“…Additionally, formulation of resveratrol with NADES increased its matrix metalloproteinase-9 (MMP-9) inhibition activity (Shamseddin et al 2017), while dissolution of salsalate in NADES allowed in vitro evaluation of its bioactivity (Rozema et al 2015).…”

Solubility and Stability of Some Pharmaceuticals in Natural Deep Eutectic Solvents-Based Formulations

“…Manyfold increases were found if compared with solubility in water. Recently some publications reported the successful applications of NADES for improving solubilities of some medicines, e.g., salsalate [ 30 ], rutin [ 31 ], berberine [ 32 ], and resveratrol [ 33 ]. The term “therapeutic deep eutectic system” (THEDES) was introduced recently [ 34 ], where an API is one of the components of the deep eutectic system, making a delivery vehicle of the bioactive compound to improve bioavailability.…”