Bafilomycin A1 alleviates depression‑like symptoms in chronic unpredictable mild stress rats

Abstract

Major depression is a multifactorial disease. Emerging evidence has suggested that autophagy is involved in the pathological process of depressive disorders. Bafilomycin A1 (Baf A1), is an inhibitor of vacuolar H+‑ATPase that is frequently used at high concentrations to block late‑phase autophagy. However, whether Baf A1 has antidepressant effects remains to be elucidated. The current study aimed to evaluate the antidepressant effects of Baf A1 in rats with chronic unpredictable mild stress (CUMS) and its potential mechanism. The CUMS animal model was established. The sucrose preference test, open‑field test (OFT) and forced swim test (FST) were applied to evaluate the depressive behavior. Synaptic plasticity‑associated proteins synaptophysin and postsynaptic density protein 95 were measured by western blotting and immunofluorescence. Apoptosis‑ and autophagy‑associated proteins in addition to pro‑inflammatory cytokines, including interleukin‑1β and tumor necrosis factor‑α, were detected by western blotting, reverse transcription‑quantitative polymerase chain reaction or ELISA. A 4‑week treatment period with Baf A1 markedly ameliorated CUMS‑induced behavioral abnormalities, including increasing sucrose intake, improving locomotor activity in the OFT, and decreasing immobility time in the FST. In addition, treatment with Baf A1 restored the dysregulation of synaptic plasticity and inhibited neuroinflammation in rats exposed to CUMS. Furthermore, Baf A1 decreased the levels of apoptosis‑ and autophagy‑associated proteins induced by CUMS. The present study demonstrated that Bafilomycin A1 resulted in antidepressant effects in rats, which may be mediated by the reversal of apoptosis, autophagy and neuroinflammation in the hippocampus.

Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression

“…Finally, inhibiting hyperactive neuronal autophagy in the DG significantly improved CORT-induced depression-like behaviors and hippocampal-dependent cognitive deficits, including reductions in immobility duration in the TST and FST and increases in the preference index in the NOR test. These results are consistent with those of previous studies that used the stress-induced depression model 20 , 21 .…”

Quercitrin Rapidly Alleviated Depression-like Behaviors in Lipopolysaccharide-Treated Mice: The Involvement of PI3K/AKT/NF-κB Signaling Suppression and CREB/BDNF Signaling Restoration in the Hippocampus

“…Therefore, the downregulation of IL-10 by Qc may result from its inhibiting effect on AKT in the LPS model. A few previous studies revealed that some antidepressant agents both improved the neuroinflammation and neuroplasticity in the chronic mild stress model . A few previous studies showed that some antidepressant agents improved both the neuroinflammation and neuroplasticity in the chronic mild stress model, although the contribution of neuroinflammation to depression and the antidepressant response remains unclear.…”

Autophagy in Neuronal Development and Plasticity

“…While serum levels of the autophagy mediator Beclin appear to be higher in responders to selective serotonin reuptake inhibitors, the study was small and needs replication in a larger cohort [65]. Furthermore, while many studies show correlations supporting the idea that autophagy induction may have antidepressant effects, the lysosomal inhibitor bafilomcyin A1, which blocks autophagic flux, also has such properties in rats exposed to chronic unpredictable mild stress [66].…”