Rhodioloside ameliorates depressive behavior via up-regulation of monoaminergic system activity and anti-inflammatory effect in olfactory bulbectomized rats

https://doi.org/10.1016/j.intimp.2016.05.008Get rights and content

Highlights

  • Rhodioloside exhibits antidepressant-like effect in the OBX model.

  • Rhodioloside up-regulate the monoaminergic system activity in OBX rats.

  • Rhodioloside's antidepressant effect is related to its anti-inflammatory effects.

Abstract

Rhodioloside, a major constituent from roots of Rhodiola rosea, has been previously confirmed to alleviate the hyperactivity in olfactory bulbectomized (OBX) rats exposed to the open field and to decrease the immobility time in the forced swimming test (FST) and tail suspension test (TST). However, its antidepressant effects and mechanisms remain unclear. This study aimed to evaluate the antidepressant effect and the potential mechanisms of rhodioloside in OBX rats. ELISA kits, HPLC-MS and western blot analysis were applied to explore the underlying antidepressant mechanisms of rhodioloside. Rhodioloside (20, 40 mg/kg) significantly reversed OBX-induced reduction in sucrose consumption. It was also observed that administration of rhodioloside (20, 40 mg/kg) decreased pro-inflammatory cytokines interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) levels and inhibits nuclear factor-kappa B (NF-κB) activation, as well as normalized the monoaminergic system changes in prefrontal cortex (PFC) of OBX rats. These results confirmed the antidepressant-like effect of rhodioloside, which might be primarily based on its up-regulation of the monoaminergic system activity and anti-inflammatory effect.

Introduction

Rhodioloside (RH) (p-hydroxy-phenethyl-β-D-glucoside, C14H20O7, Fig. 1) is a major bioactive marker substance in the standardized extracts (SHR-5) from Rhodiola rosea. And Rhodiola rosea (also known as golden root) is mentioned as the most commonly used psychostimulant for a range of conditions such as depression and anxiety, fatigue, anaemia etc. in the Europe and Asia [1], [2]. Previous studies showed that RH has lots of biological activities such as anti-stress, anti-fatigue and anti-oxidative [3], [4], [5], and RH also have antidepressant-like effect on behavior in rats [6], [7]. Moreover, another recent report showed that RH could improve LPS-induced depressive behavior in mice [8]. These evidences indicated that RH might become a potential therapeutic agent for depression. However, its antidepressant effects and mechanisms remain unclear as yet.

It is widely accepted that a defect in monoamine system plays an important role in the pathogenesis of OBX-induced depression, especially the reduction of neurotransmitters such as serotonin (5-HT) and norepinephrine (NE) levels, which are qualitatively similar to those occurring in patients with major depression [9], [10]. The abnormalities in the monoaminergic system were most apparent in the prefrontal cortex (PFC) of OBX rats, and could be reversed by chronic antidepressant treatments [11]. It has also been reported that activation of inflammatory responses and release of pro-inflammatory cytokines (PICs) were increased by OBX and decreased by antidepressant treatment [12], which indicated that inflammation may be involved in the therapeutic action of antidepressants.

In this study, the OBX model, a well-documented animal model for evaluating antidepressant action of compounds, was used to investigate the antidepressant-like effect of RH. Furthermore, the possible molecular mechanisms were clarified by measuring the 5-HT and NE levels, IL-1β and IL-6 levels, p-NF-kB P65 protein expression in PFC of OBX rats.

Section snippets

Animals

Male Sprague-Dawley rats weighting 200–220 g were from the Laboratory Animal Center of Zhejiang Province, China. The animals were kept in polypropylene cages remained at 22 ± 1 °C temperature and 12-h light/dark cycle with free access to food and water. All procedures and animal welfare were performed strongly in agreement with the National Institute of Health Guide (NIH publication No. 80–23, revised 1996) and the PR China legislation for the care and use of laboratory animals.

Drugs

Rhodioloside (RH)

Effects of RH on sucrose intake in SPT

Sucrose preference is a measure of anhedonia. As shown in Fig. 2, there were no significant difference between groups during the pretest [F(4,35) = 0.0813, p > 0.05]. At the end of recovery phase, OBX rats showed a noteworthy reduction in sucrose intake compared with sham-operated rats [F(4,35) = 18.070, p < 0.01]. Administration of AMI (10 mg/kg) (p < 0.01) or RH (20, 40 mg/kg) (p < 0.05, p < 0.05, respectively) for 1 week (in the 3th week after OBX surgery) improved the lower sucrose consumption in OBX group

Discussion

Surgical ablation of bilateral olfactory bulbs has been widely proven as a reliable and valuable animal model of depression. OBX induces numerous behavior changes, including hyperactivity, increased despair behavior, and anhedonia symptoms. Interestingly, these behavioral abnormalities are not related to anosmia [15], but may rely on the disrupted connections in the olfactory-limbic circuitry and enlarged third ventricles [16]. These alterations are similar to those observed in patients with

Conflict of interest

There is no conflict of interest.

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