Investigations On Anti-depressant Effect Of Thermo-sensitive Hydrogel System Loaded With Resveratrol By Intranasal Administration

Depression is a central nervous system（CNS）disease.The bioavailability of anti-depressants is reduced because of the blood-brain barrier（BBB）.Resveratrol（Res）is a natural polyphenol compound derived from the Polygonum cuspidatum of Chinese Traditional Medicine（TCM）.Studies have shown that Res can bypass the BBB and reach the brain tissue to preventing and treating depression.However,due to its low stability,poor water solubility and low bioavailability,Res has seriously affected its physiological activity and clinical application.In this study,the design and construction of THS carrier can not only effectively improve the bioavailability of Res,but also investigate the anti-depressant effect of Res-THS by intranasal administration.According to the physiological features between the nasal cavity and the brain,the temperature of the nasal cavity was used as the investigation index.GCS,β-GP and HP-β-CD were used as matrix materials to design and prepare a THS by single-factor and response surface methodology.Using THS as the carrier and Res as model drug,the anti-depressant effect of Res-THS on CUMS depression model rats was evaluated.First,the Res/HP-β-CD complex was prepared by freeze-drying method.The structure of Res/HP-β-CD complex was analyzed by FT-IR,DSC,XRD and ¹H-NMR.The phase solubility curve indicated that the inclusion ratio of the Res/HP-β-CD complex was 1:1,the inclusion constant was 1621 M^-1,and the drug loading of Res was 72.84 mg/g.Secondly,the THS was prepared by cold method with GCS,β-GP and HP-β-CD.The physiological temperature of the nasal cavity as the investigation index,optimal concentration ratio of the THS was 2.5%GCS+6.5%β-GP+1.0%HP-β-CD（%,w/w）by single factor and response surface experiment.The results of in vitro properties showed that the THS had good temperature response and biocompatibility.In vitro release behavior of the Res-THS was consistent with the Higuchi equation,which belonged to the Fickian mechanism and had sustained release characteristics.Thirdly,the anti-depressant effects of Res-THS on CUMS depression model rat was investigated by intranasal administration.The results showed that intranasal administration of Res-TSH could significantly improve the behavior in the CUMS depression model rats,increase the concentration of DA,NE and 5-HT in the hippocampus and hypothalamus in rats,and reduce CORT concentrations serum of rats.All tests exhibited that Res-TSH had good brain targeting and anti-depressant effects.In conclusion,Res-THS by intranasal administration can significantly improve the depressive-like behavior and the concentration of neurotransmitters in the CUMS model rats,showing the characteristic of trace and high-efficiency.THS is expected to be a novel nasal formulation for brain-targeted treatment of depression.