Abstract
There is an urgent need to find antidepressants that can be administered for long periods without inducing severe side effects to replace conventional antidepressants that control monoamine levels, such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRI). We sought to determine the antidepressant effects of Fraxinus rhynchophylla Hance (F. rhynchophylla Hance, FX) and its components on a reserpine-induced mouse model. One hour after oral administration of FX (30, 50, and 100 mg/kg), esculin (50 mg/kg), esculetin (50 mg/kg), fraxin (50 mg/kg), and fluoxetine (20 mg/kg), reserpine was delivered intraperitoneally to mice. Behavioral experiments were conducted to measure anxiety and depressive-like behaviors after 10 days of administration. FX and its components increased the number of entries into the center of an open field as well as distance traveled within it and decreased immobility duration in the forced swim and tail suspension tests. Reserpine-induced increases in plasma corticosterone concentrations were attenuated by the administration of FX and its components, which were also found to decrease the reserpine-induced enhancement of mRNA levels of interleukin (IL)-12 p40, IL-6, and tumor necrosis factor (TNF)-α, pro-inflammatory cytokines. Finally, the diminished expressions of hippocampal phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) by reserpine were increased by FX and its components. Our results suggest that FX and its components regulate anxiety and depressive-like behaviors through stress hormones, immune regulation, and the activation of neuroprotective mechanisms, further supporting the potential of FX and its components as antidepressants.
Highlights
Despite having a global prevalence of 350 million people and a long time-course, depression is not being treated effectively due to stigma and lack of effective therapeutic modalities (Smith, 2014)
Coumarin-based components isolated from Fraxinus rhynchophylla have been reported to have anti-inflammatory effects such as inhibiting tumor necrosis factor (TNF)-α release by peritoneal macrophages induced by LPS and attenuating the production of inflammatory mediators in BV2 microglia (Niu et al, 2012; Song et al, 2014)
Corticosterone, a stress-related hormone, was significantly decreased in the plasma of the mice in the FX 50, 100, EC, ECT, FR, and FXT-treated groups (Reserpine: 55.81 ± 44.98; FX 50: 15.95 ± 15.92, p = 0.0062; FX 100: 14.01 ± 15.35, p = 0.0033; EC: 10.18 ± 5.68, p < 0.0009; ECT: 16.81 ± 18.16, p = 0.008; FR: 7.457 ± 2.92, p = 0.0002; and FXT: 11.51 ± 4.88, p = 0.0015; Figure 4B). These results suggest that FX extract affects body weight, and FX extract and its component decrease the concentrations of plasma stress-related hormone levels on reserpine-induced mouse model
Summary
Despite having a global prevalence of 350 million people and a long time-course, depression is not being treated effectively due to stigma and lack of effective therapeutic modalities (Smith, 2014). Antidepressants currently treating depression, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRI), which control existing monoamine levels, have side effects such as constipation, decreased vision, high blood pressure, cognitive impairment, and anticholinergic effects (Donoghue and Tylee, 1996; Feighner, 1999; Tarleton et al, 2016). While such early antidepressants are fast-acting and inexpensive, clinical studies have associated their use with low recovery rates, only 22–40% of patients with depression (Anthes, 2014). FX and its components improve depressive-like behavior and anti-inflammatory effects have been studied in several studies as above
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