Novel chlorine-containing curcumin analogue CAK06 promotes neuroprotection and rapid antidepressant through Nrf2-induced anti-inflammatory and antioxidant effects

Currently, conventional antidepressants are often limited by poor efficacy and delayed onset, and there is an urgent need for the development of rapid acting antidepressant alternatives. The aim of this study was to develop novel antidepressants with a rapid onset of action by inhibiting inflammation and oxidative stress. A series of chlorine-containing curcumin analogues were designed and synthesized. Among them, compound CAK06 exhibited the highest potency and most robust antidepressant activity, as demonstrated through ABTS free radical ion scavenging assays, relative proliferation rate measurements, and both hydrogen peroxide and corticosterone injury models. In the lipopolysaccharide-induced BV2 cell stress model, treatment with CAK06 resulted in a 69 ​% decrease in nitric oxide levels and a 52 ​% reduction in the fluorescence intensity of reactive oxygen species compared to the model group. qRT-PCR results showed that CAK06 upregulated the expression of anti-inflammatory and antioxidant genes while downregulating the expression of pro-inflammatory genes. In the CUMS depression model, CAK06 exerted rapid antidepressant effects after 14 days of oral administration. Notably, after 28 days, CAK06 produced a more pronounced improvement in depression-like behaviors compared to the widely used antidepressant fluoxetine. Mechanistically, molecular docking, Western blot, and Elisa results indicated that CAK06 may alleviate oxidative stress, inflammatory responses, and enhance synaptic plasticity in CUMS mice via the Nrf2-HO-1/BDNF-TrkB pathway. These results suggest that the new compound CAK06 exhibits rapid antidepressant effects, positioning it as a promising novel antidepressant candidate.