Intranasal delivery of icariin via a nanogel-thermoresponsive hydrogel compound system to improve its antidepressant-like activity.

Although icariin has been reported to have antidepressant-like effects in different animal models, its poor oral bioavailability and low efficiency of delivery to the brain limit its application. In this study, icariin nanogels were prepared by reverse microemulsion methods to improve its poor water solubility. Then, we developed an icariin nanogel loaded self-assembled thermosensitive hydrogel system (icariin-NGSTH) to deliver icariin via a noninvasive, direct nose-to-brain delivery route for the treatment of depression. The in vivo distribution was investigated by fluorescence imaging with rhodamine B-labeled nanogels. The antidepressant efficacy of icariin-NGSTH was evaluated in behavioral despair tests and the chronic unpredictable mild stress (CUMS) model. The results showed that icariin-NGSTH had a zero-order kinetics release in the first 10 h. Icariin-NGSTH led to rapid brain distribution within 30 min. Icariin-NGSTH significantly reduced the duration of immobility in the tail suspension test (TST) and forced swim test (FST). Compared with oral administration, intranasally administered icariin-NGSTH had a fast-acting antidepressant effect in the TST and FST. Moreover, icariin-NGSTH increased body weight and sucrose preference, reversed abnormal plasma levels of testosterone, interleukin-6 (IL-6) and prostaglandin E2 (PGE2), and repaired neuronal damage in the hippocampi of CUMS rats. These results indicated that icariin-NGSTH at a low dose produced a significant antidepressant effect. As a complex drug delivery system, intranasally administered icariin-NGSTH is a rapid and effective treatment for depression, increasing the antidepressant-like activity of icariin.