Integrative Target Prediction, Molecular docking and Experimental Evaluation of the Antidepressant-like effects of Doxycycline

Compelling evidence demonstrated neuroprotective properties of tetracyclines. Recent studies have reported the antidepressant properties of doxycycline (DOXY)1,2. However, it is unclear which molecular targets are underlying DOXY effects. Our in silico target prediction approach pointed the metalloproteases MMP1, MMP3, MMP13, and the receptors dopamine D2 (D2R), sigma 1 and serotonin (5-HT) 1A as potential targets for DOXY. After docking studies, the best docking scores and binding poses for DOXY were observed with MMP3 and D2R. Experimentally, we observed that DOXY reversed the depression-like behavior induced by repeated lipopolysaccharide injection. Also, DOXY reduced the MMP activity in mice hippocampus and the expression of Iba1 (microglial activation) and pro-inflammatory cytokines IL-1β and TNFα. In the radioligand assay, DOXY showed no binding affinity to D2R or 5-HT1A receptors. This study identified the potential molecular targets underlying DOXY antidepressant action and highlighted the involvement of MMP inhibition for the protective effects of this drug.