Baicalin ameliorates CUMS-induced depression-like behaviors through activating AMPK/PGC-1α pathway and enhancing NIX-mediated mitophagy in mice

Depression is a common mental disease, which manifested as persistent low mood, delayed thinking, decreased volitional activity and sleep disturbance (Menard et al., 2016). Increasing evidence has shown that the pathogenesis of depression is extremely complicated (Malhi and Mann, 2018). In recent years, numerous studies have shown that mitochondrial dysfunction is closely related to depression (Bansal and Kuhad, 2016; Allen et al., 2021; Mishra et al., 2021; Simon et al., 2021). Previous studies have shown mitochondrial dysfunction in the brains of patients with depression and in animal models (Rezin et al., 2008; Karabatsiakis et al., 2014; Sahafi et al., 2018; Chung et al., 2019). The antidepressants improve depression-like behaviors by repairing mitochondrial function (Maes et al., 2012; Shu et al., 2019; Limanaqi et al., 2020). Therefore, these studies suggested that improving mitochondrial function may be a new strategy for treating depression.

Mitophagy is a vital pathway for cells to achieve mitochondrial quality control and is involved in maintaining the integrity of mitochondrial network function and cellular homeostasis (Pickles et al., 2018). Previous study showed that basic-level mitophagy is mainly mediated by receptor pathways, especially in high-energy organs such as the brain (McWilliams et al., 2018). Nip-like protein (NIX), also named BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L), is an essential autophagy receptor located on the outer membrane of mitochondria (Novak et al., 2010; Yazdankhah et al., 2021). Recently, a study showed that glucocorticoids inhibit NIX-mediated mitophagy, leading to impaired mitochondrial function and synaptic function in hippocampal neurons, and Phorbol 12-Myristate 13-acetate (PMA) can reverse these effects (Choi et al., 2021). PMA also ameliorated depression-like behaviors such as the decreased immobility times in Forced swimming test (Ito et al., 2020). These reports suggest that enhancing NIX-mitophagy can restore mitochondrial function and improve depression-like behaviors.

Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α has been shown to be a vital regular of mitochondrial quality control (Tadaishi et al., 2011). It is reported that basal mitophagy activated by the PGC-1α/NIX axis is more strongly and selectively impaired by glucocorticoids in hippocampus (Choi et al., 2021). Adenylate activated protein kinase (AMPK) is an important regulatory kinase in bioenergy metabolism, and it can directly phosphorylate and activate PGC-1α protein on Thr177 and Ser538, and also promote PGC-1α transcription (Jager et al., 2007). Therefore, activation of AMPK/PGC-1α is an effective pathway to improve NIX-mediated mitophagy and restore mitochondrial function.

Baicalin, the main active ingredient in Scutellaria baicalensis Georgi, exhibits antidepression-like effect in many rodent model depression (Li et al., 2013, 2015). Previous studies showed the mitochondrial protective effect of baicalin against hyperglycemia-exacerbated ischemia/reperfusion injury in an AMPK-dependent manner (Li et al., 2017). However, it is unclear whether the antidepressant effect of baicalin is related to the regulation of mitophagy and improving mitochondrial function in the brain. Therefore, the present study aimed to investigate the effects of baicalin on the mitochondrial structure and function, and mitophagy in the hippocampus of mice exposed to CUMS, and explore its mechanism based on AMPK/PGC-1α pathway.

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