Abstract
The leaves of Vaccinium bracteatum Thunb. are a source of traditional herbal medicines found in East Asia. The present study aimed to evaluate the mechanisms underlying the antidepressant-like effects of water extract of V. bracteatum Thunb. leaves (VBLW) in a mouse model of chronic restraint stress (CRS) and to identify the possible molecular in vitro mechanisms of the neuroprotective effects. The CRS-exposed mice were orally administered VBLW (100 and 200 mg/kg) daily for 21 days consecutively. The behavioral effects of VBLW were assessed through the forced swim test (FST) and the open field test (OFT). The levels of serum corticosterone (CORT), corticotropin releasing hormone (CRH), and adrenocorticotropin hormone (ACTH), brain monoamines, such as serotonin, dopamine, and norepinephrine, and serotonin turnover by tryptophan hydroxylase 2 (TPH2), serotonin reuptake (SERT), and monoamine oxidase A (MAO-A) were evaluated, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway. CRS-exposed mice treated with VBLW (100 and 200 mg/kg) showed significantly reduced immobility time and increased swimming and climbing times in the FST, and increased locomotor activity in the OFT. Moreover, CRS mice treated with VBLW exhibited significantly decreased CORT and ACTH, but enhanced brain monoamine neurotransmitters. In addition, CRS mice treated with VBLW had dramatically decreased protein levels of MAO-A and SERT, but increased TPH2 protein levels in the hippocampus and the PFC. Similarly, VBLW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and the PFC. Furthermore, VBLW showed neuroprotective effects via increased CREB phosphorylation in CORT-induced cell injury that were mediated through the ERK/Akt/mTOR signaling pathways. These results suggested that the antidepressant-like effects of VBLW might be mediated by the regulation of the HPA axis, glucocorticoids, and serotonin turnover, such as TPH2, SERT, and MAO-A, as well as the concentration of monoamine neurotransmitters, and the activities of ERK and Akt phosphorylation, which were possibly associated with neuroprotective effects.
Highlights
We previously reported that the efficacy of the antidepressant-like effects of V. bracteatum fruit extract might be mediated through the regulation of monoaminergic systems and glucocorticoids, which is possibly associated with neuroprotective effects and the antagonism of the 5-HT2A receptor (Oh et al, 2018)
3, 10, and 30 μg/mL VBL water extract (VBLW) significantly reduced CORT- and H2O2induced cytotoxicity in a dose-dependent manner (∗∗P < 0.01 and ∗∗∗P < 0.001, respectively). These results indicated that VBLW exerted significant neuroprotective effects against CORTinduced cytotoxicity, as well as H2O2-induced oxidative stress in SH-SY5Y cells
We demonstrated the antidepressantlike effects of V. bracteatum fruit extract might be the regulation of monoaminergic systems and serum CORT that was possibly associated with the neuroprotective effects through the downstream extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/cyclic AMP-responsive element-binding protein (CREB) signaling pathways as well as the antagonism of the 5-HT2A receptor (Oh et al, 2018)
Summary
Depressive disorders are characterized by changes in mental status induced by hyperactivity of the HPA axis and neurotrophin dysfunction (Radley et al, 2004; Angelucci et al, 2005). Stress is known to be a risk factor for the development of major depression. Stress models (e.g., restraint stress and unpredictable mild stress) is common in animal studies to mimic the development of depressive-like symptoms, such as altered weight gain, changed of the physical state, cognitive deficits and locomotor activity deficit. The restraint stress models has two known conditions, acute (30 min for 1 day) and chronic (6 h per day for 21 days), widely used physical stressors (Chattarji et al, 2015). CRS model of developing clinical depression, are associated with the dysregulation of the HPA axis (Chiba et al, 2012). CRS may activate the HPA axis, which includes a feedback loop composed of the hypothalamus, pituitary, and adrenal glands, which is thought to be closely related to the inhibition of negative feedback by endogenous hormones, such as CRH, ACTH, and CORT (Chang et al, 2015; Franco et al, 2016)
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