Preparation and characterization of nano-isoliquiritigenin, molecular dynamics simulations and in vitro studies to evaluate potential TrkB activation

Natural bioactive compounds are increasingly recognized for their therapeutic potential. Among them, isoliquiritigenin is known for its promising pharmacological potential such as anti-inflammatory, antioxidant, antiobesity, neuroprotective and antitumoral properties. However, its clinical translation is often limited by poor solubility, and consequently, low bioavailability. To overcome these limitations, after the construction of the space of knowledge, using the Design of Experiments approach, we designed and optimized a nano-isoliquiritigenin formulation, produced by nanonization technology. We identified the concentration (0.5 %w/v) and the type (PVP) of stabilizer (independent variables) to obtain a stable formulation with uniform and monodisperse particle size (mean size'100 nm and PDI' 0.2). The interaction between isoliquiritigenin and TrkB receptor was investigated through the molecular dynamic simulations using 7,8-dihydroxyflavone, a well-known TrkB agonist, as a positive control. These preliminary computational findings were validated in SH-SY5Y neuronal-like cells, where isoliquiritigenin and nano-isoliquiritigenin significantly attenuated rotenone-induced toxicity, an effect abrogated by the selective TrkB antagonist ANA-12. Overall, these results revealed that Design of experiment approach, in particular D-optimal design, is a useful and reliable approach to design and optimized an innovative formulation of nano-isoliquiritigenin obtained by sonoprecipitation technique. In addition, computational and in vitro studies showed promising evidence about the isoliquiritigenin activity as TrkB agonist in neuroprotection, supporting their potential as a novel class of small-molecule TrKB agonist .