The aim of this study was to develop a novel antidepressant with high activity. Based on the findings of molecular docking, eight novel curcumin analogues were evaluated in vitro to check for antidepressant efficacy. Among them, CACN136 had the strongest antidepressant effect. Firstly, CACN136 had a stronger 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonate) radical ion scavenging ability (IC 50 : 17.500 ± 0.267 μg/mL) compared to ascorbic acid (IC 50 : 38.858 ± 0.263 μg/mL) and curcumin (27.189 ± 0.192 μg/mL). Secondly, only CACN136 demonstrated clear protective effects on cells damaged by glutamate and oxidative stress at all concentrations. Finally, only CACN136 showed ASP + inhibition and was more effective than fluoxetine hydrochloride (FLU) at low concentrations. To further confirm the antidepressant effect of CACN136 in vivo, the CUMS model was established. Following 28 days of oral administration of CUMS mice, CACN136 increased the central area residence time in the open-field test, significantly increased the sucrose preference rate in the sucrose preference test ( P < 0.001) and significantly reduced the immobility period in the tail suspension test ( P < 0.0001), all of which were more effective than those of FLU. Subsequent research indicated that the antidepressant properties of CACN136 were linked to a decrease in the metabolism of 5-HT and the modulation of oxidative stress levels in vivo. In particular, the activation of the Keap1-Nrf2/BDNF-TrkB signaling pathway by CACN136 resulted in elevated levels of antioxidant enzymes, enhancing the antioxidant capability in mice subjected to CUMS. In conclusion, CACN136 has the potential to treat depression and could be an effective antidepressant. Graphical Abstract
CACN136-SD increased CACN136 solubility and rapid dissolution. • Solid dispersion enhanced CACN136 oral bioavailability in rats. • CACN136-SD improved depression-like behaviors in CUMS mice. • CACN136-SD regulated brain 5-HT and MAO without obvious toxicity. Objective CACN136 is a novel curcumin analogue with antidepressant potential, but its poor aqueous solubility may restrict oral absorption. This study aimed to develop a rapidly dissolving solid dispersion of CACN136 (CACN136-SD) to further enhance its oral bioavailability and antidepressant efficacy. Methods CACN136-SD was prepared using a solvent method with PVP and mannitol as composite carriers. Physicochemical characterization was performed through in vitro experiments, followed by pharmacokinetic and antidepressant behavioral evaluations. Results CACN136-SD increased the apparent aqueous solubility of CACN136 approximately 20-fold. Cumulative dissolution at 10 min reached 95.69%, versus 6.64% for the active pharmaceutical ingredient (API). Differential scanning calorimetry and X-ray powder diffraction showed markedly reduced drug crystallinity, with CACN136 present predominantly in an amorphous or highly disordered state within the carrier matrix. Fourier-transform infrared spectroscopy showed changes in the local vibrational environment of CACN136 after incorporation into the matrix. The apparent terminal half-life of CACN136-SD was approximately 23 times that of the API, and its systemic exposure (AUC-t) was 8.95 times higher. In the chronic unpredictable mild stress (CUMS) model, CACN136-SD significantly alleviated depression-like behaviors and produced greater changes in serum and hippocampal 5-hydroxytryptamine (5-HT) and monoamine oxidase (MAO) levels than unformulated CACN136. Preliminary safety assessments detected no obvious cardiac, hepatic, or renal toxicity under the tested conditions. Conclusion CACN136-SD improved the solubility, dissolution, and oral exposure of CACN136 and showed enhanced antidepressant-like activity associated with changes in monoamine-related markers. This solid dispersion represents a promising antidepressant candidate with potential for clinical translation. Download: Download high-res image (159KB) Download: Download full-size image
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