Schisandra chinensis produces the antidepressant-like effects in repeated corticosterone-induced mice via the BDNF/TrkB/CREB signaling pathway

Highlights

• SC produces an antidepressant-like effect in CORT-induced depression in mice.

• The antidepressant-like effect exert by rectifying the HPA axis dysfunction.

• SC could upregulate the BDNF/TrkB/CREB signaling pathway in depressed mice.

Abstract

The present study aimed to examine the antidepressant-like effects and the possible mechanisms of Schisandra chinensis on depressive-like behavior induced by repeated corticosterone injections in mice. Here we evaluated the effect of an ethanol extract of the dried fruit of S. chinensis (EESC) on BDNF/TrkB/CREB signaling in the hippocampus and the prefrontal cortex. Three weeks of corticosterone injections in mice resulted in depressive-like behavior, as indicated by the significant decrease in sucrose consumption and increase the immobility time in the forced swim test, but without any influence on the locomotor activity. Further, there was a significant increase in serum corticosterone level and a significant downregulation of BDNF/TrkB/CREB signaling pathway in the hippocampus and prefrontal cortex in CORT-treated mice. Treatment of mice with EESC (600 mg/kg) significantly ameliorated all the behavioral and biochemical changes induced by corticosterone. Moreover, pharmacological inhibition of BDNF signaling by K252a abolished entirely the antidepressant-like effect triggered by chronic EESC treatment. These results suggest that EESC produces an antidepressant-like effect in CORT-induced depression in mice, which is possibly mediated, at least in part, by rectifying the stress-based hypothalamic–pituitary–adrenal (HPA) axis dysfunction paradigm and upregulation of BDNF/TrkB/CREB signaling pathway.

Introduction

Major depression has been recognized as long as human records have existed, and research shows that it continues to be a widespread major threat to public health, which afflicts one in six people at some point in life, also it is one of the main causes of human suffering and the leading global cause of years of life lived with disability (Ingram, 2016). It is generally assumed that multiple mechanisms are responsible for the development of depression. Despite recent progress in understanding the molecular, cellular, and circuit-level correlates of depression, the biological mechanisms that causally underlie this disease are still unclear. Previous studies have shown a causal relationship between the incidence of major depressive disorders and the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis (Ali et al., 2015, Mizuki et al., 2014). The HPA axis is activated in response to stress, which results in an overproduction of glucocorticoid hormones in the circulating blood. High concentration of blood glucocorticoids is reportedly maintained in patients with depression as compared to healthy controls due to a dysfunction in the feedback mechanism (Chen et al., 2016; Li et al., 2015b). Stimulation and sustained action of the HPA axis are attenuated via the negative feedback action of circulating glucocorticoid following exogenous corticosterone (CORT) administration, and this is closely associated with the development of psychosomatic disorders, which produce serious changes in affective behavior that are indicative of, or consistent with depressive-like symptoms (Lee et al., 2015). These findings suggested that a chronic corticosterone treated rodent model is suitable for evaluating the efficacy of potential antidepressant candidates and to explore the mechanism of action of antidepressants.

In addition to hyperactivity of the HPA axis, neurotrophin dysfunction is also involved in the pathogenesis of depression. Brain-derived neurotrophic factor (BDNF) is one of the most extensively investigated targets with respect to brain plasticity. Moreover, BDNF has been proposed to participate in stress response by modifying the HPA axis activity (Nowacka et al., 2015). Reduced BDNF expression by adverse stressors contributes to structural anomalies and functional impairment in the central nervous system (CNS). After binding with and activating tropomyosin-related kinase receptor B (TrkB), BDNF is thought to underlie the pathophysiology and treatment of depression. Further, BDNF increases phosphorylation of cAMP response element binding protein (CREB) via TrkB (Liu et al., 2015b). And CREB is involved in social isolation stress-induced emotional deficits (Li et al., 2015a). BDNF–TrkB signaling plays a critical role in the modulation of several functions, such as neurotransmitter release and postsynaptic responses to neurotransmitters, which are closely related to antidepressant therapy (Yi et al., 2014).

Due to a prevalent belief that “natural is better,” a significant amount of public interest in antidepressant development has focused on plant material or natural products extracted from plant sources. Schisandra chinensis (Turcz.) Baill., as a traditional Chinese medicine, is a functional food, and is extensively used in the clinic with the functions of inducing astringency, replenishing and promoting the production of body fluid and tonifying the kidney to relieve mental strain (Ahn et al., 2015, Chan, 2012). And the most reported are lignans, an antioxidant component of S. chinensis (Chiu et al., 2002, Li et al., 1996). Based on the previous studies of our group, we found that lignans could ameliorate learning and memory deficits, cognitive declines, exert sedative and hypnotic effects, and mitigate other neurodegenerative symptoms (Li et al., 2014, Mao et al., 2015, Yan et al., 2016, Zhang et al., 2014, Zhao et al., 2016). Moreover, the results of numerous studies implicate the involvement of the HPA axis and CNS in the effects exerted by Schizandra preparations (Panossian and Wikman, 2008). However, the mechanisms of the above effects for S. chinensis are still unclear.

The aim of the present study was to investigate the antidepressant-like effect of an ethanol extract of the dried fruit of S. chinensis (EESC) in mice that were repeatedly exposed to exogenous corticosterone. Firstly, we examined the effect of EESC on depressive-like behavior and BDNF, TrkB and CREB protein expression in the hippocampus and prefrontal cortex of CORT-treated mice; secondly, we used K252a, an inhibitor of the BDNF receptor TrkB, to further investigate the direct link between BDNF/TrkB/CREB signaling and the antidepressant-like effect of EESC in mice following repeated corticosterone administration.