Research Article
(+)-Sesamin attenuates chronic unpredictable mild stress-induced depressive-like behaviors and memory deficits via suppression of neuroinflammation

https://doi.org/10.1016/j.jnutbio.2018.10.006Get rights and content

Abstract

Depression is a mood disorder that is related to neuroinflammation and cognition loss. This study is aimed to determine the potential antidepressant effects of (+)-sesamin, a lignan component of sesame, in a mild stress-induced depression mouse model. CD-1 mice were treated with chronic unpredictable mild stress (CUMS) process and orally administrated with sesamin (50 mg/kg/d) for 6 weeks. Behavioral tests including forced swimming test, tail suspension test, open field test, and elevated plus maze test demonstrated that sesamin treatment inhibited CUMS-induced mice depressant-like behaviors and anxiety, without changing immobility. It was found that sesamin prevented stress-induced decease levels of 5-HT and NE in striatum and serum. Cognitive deficits were assessed using Y-maze and Morris water maze test. Sesamin treatment also prevented stressed-induced memory impairments and neuronal damages. Consistently, sesamin also enhanced synapse ultrastructure and improved expressions of PSD-95 in stressed mice hippocampus with improving neurotrophic factors expression including BDNF and NT3. Moreover, sesamin treatment significantly prevented CUMS-induced neuroinflammation by inhibiting over-activation of microglia and expressions of inflammatory mediators including iNOS, COX-2, TNF-α and IL-1β in stressed mice hippocampus and cortex. These results illustrated that sesamin markedly improved CUMS-induced depression and memory loss via inhibiting neuroinflammation, which indicate that as food component, sesamin might be also a novel potential therapeutic for depression.

Graphical abstract

Supplementation of sesamin, a lignan from sesame seed, improved chronic unpredictable mild stress (CUMS)-induced anxiety, depressive-like behaviors and memory deficits. Sesamin treatment also enhanced levels of monoamine neurotransmitter and neurotrophic factor BDNF in hippocampus. The ultrastructure of synapses was rescued by sesamin with the enhancement of PSD expression in depressed mice. Moreover, sesamin suppressed stress-induced neuroinflammation by decreasing overexpression of IBA-1 and inhibiting COX-2, iNOS, TNF-α, and IL-1β levels in mice brain.

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Introduction

Depression is one of the most common mental disorders [1], and the major depressive disorder (MDD) affects over 350 million people worldwide [2]. Numerous research has indicated that depression and anxiety secondary to chronic stress are associated with decreased levels of dopamine, norepinephrine (NE), and serotonin (or 5-hydroxytryptamine, 5-HT) in the brain [3]. Besides, depression could also lead to cognitive deficits via aggravating the hippocampus, prefrontal cortex and other emotion regulation key brain region nerve atrophy, and decrease synapse function. It is believed that depression is mainly caused by the decrease of NE and 5-HT in the central nervous system, and the decline of synaptic content [4], [5]. The clinical treatments or drugs for depression, such as fluoxetine, paroxetine, and citalopram, are inhibitors of the reuptake of 5-HT and NE (SNRIs). However, the side effects of these drugs [6] including headaches, weight gain or loss, agitation and cognitive impairments need to be solved by new and safe therapeutics.

Neuroinflammatory responses are highly associated with the pathology of depression [7], [8] and depression-related cognitive impairment. It has been reported that 5-HT and NE levels were observed declined in inflammation-induced mice [9]. Moreover, over-expressions of proinflammatory cytokines including TNF-α, IL-6 and IL-1β have been found to relate to disorders of neuroendocrine function, neurotransmitter metabolism and synaptic plasticity and behaviors in depression [10]. Over-activation of microglia, the major immune cell in central nervous system (CNS), has also been reported to be participated in the pathogenesis of MDD [11], [12]. Therefore, to suppress the acute or chronic neuroinflammation might be one clue to alleviate depression process. The animal models preformed in current study, i.e. the chronic unpredictable mild stress (CUMS) model has already contributed to the elucidation of the pathophysiological mechanisms of depression [13]. CUMS represents an acute inflammatory stimulus, and produces depressive-like behaviors in mice that are associated with microglial activation in various regions of the mouse brain [13].

(+)-Sesamin is one of the most abundant lignans in sesame (Sesamum indicum L.) seed and oil [14]. It has been reported that sesamin possesses beneficial effects on improving lipid metabolism and liver damages in animal and human study [15], [16], [17]. Importantly, sesamin also has anti-inflammatory and potential neuroprotective effects. A previous study demonstrated that sesamin inhibited LPS-induced cytokines production in murine microglia and BV-2 cells [14]. Sesamin could also prevent blood–brain barrier disruption in a traumatic brain injury mice model [18]. Moreover, a latest clinical study indicated that treatment of sesamin with astaxanthin could improve mild cognitive impairment (MCI) [19]. The same Japanese research group also found that dietary supplementation of sesamin also promoted healthy volunteers recovery from mental fatigue [20]. Our previous research found that sesame crude extract and sesamol, other lignan in sesame oil, could prevent CUMS-induced mice depressive-like behaviors and synapse functions [21]. Interestingly, a series of research also demonstrated that (−)-sesamin, which is an epimeric isomer lignans with (+)-sesamin, extracted from Asiasari radix, could reduce anxiety-like behaviors and memory deficits induced by chronic electric foot shock in mice [3], [22]. To summarize, sesamin might be a potential candidate to prevent stress-induced mental disorders and cognitive impairments. However, there is little research to demonstrate this hypothesis.

The present study was aimed at uncovering the effects of dietary sesamin supplementation on CUMS-induced depression in a mice model by (a) characterizing the effects of sesamin on mice anxiety and depression behavioral tests including forced swimming test, tail suspension test, open field test and elevated plus maze test; (b) examining the effects of sesamin on cognitive function of CUMS treated mice including Y-maze test and Morris water maze test; (c) uncovering the effects of sesamin on expressions of monoamine neurotransmitter neurotrophic factors and hippocampal synapse morphology alterations in the brain; (d) determining the effects of sesamin on expressions of postsynaptic dense protein and protein related to synapse function in the brain; (e) measuring the effects of sesamin on expressions of inflammatory cytokines in the brain. Above all, it provides novel insights into the effects and mechanisms of sesamin on the regulation CUMS-induced depression and cognitive impairments.

Section snippets

Animals

Male CD-1 mice (weight: 28–32 g) were obtained from medical laboratory animal center of Xi'an Jiaotong University (Xi'an, Shanxi, China). Mice were single-housed per cage for bedding at 22±2 °C under a relative humidity of 50±10% and a 12-hour light/dark cycle. All mice were fed with a standard diet (AIN-93 M) and respectively randomized into four groups (n=10/group): Control, SE, CUMS, CUMS + SE. Different groups of animals were provided with vehicle (0.01 mL/g), SE (50 mg/kg/day, dissolved in

Effects of sesamin on depressive like behaviors and anxiety in CUMS-treated mice

In order to examine potential antidepressant effects of sesamin, the CUMS-induced depression-like mice model was employed in present study (Fig. 1A). During the experiment, mice showed no changes in bodyweight (Fig. 1B). Results showed that 42-days CUMS elicited depressive like behavior. The assessments of depression related behaviors were performed by forced swimming test and tail suspension test (Fig. 1C&D). Sesamin significantly decreased the CUMS-induced rise of immobility time (P<.05)

Discussion

In the current study, it demonstrated that sesamin treatment improved CUMS-induced anxiety and depressive-like behaviors by forced swimming test, tail suspension test and elevated plus maze test. Morris water maze test and Y-maze test also revealed that sesamin rescued spatial learning abilities, reference memory and working memory in stress-induced mice. Consistently, the monoamine neurotransmitter NE was improved in striatum. The level of neurotrophic factor BDNF in hippocampus was also

Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (No. 2016YFD0400601), National Natural Science Foundation of China (No.81803231), Key Research and Development Plan of Shaanxi, China (2018NY-100), China postdoctoral science foundation (2018 T111104), and the Fundamental research funds for the central universities (2452017141) supported this research.

Author contributions

Conception and design of research: ZL, XL; Performed experiments: YZ, QW, MJ; Analyzed data: ZL, YZ; Interpretation of results of experiments: ZL, XL; Prepared figures: ZL, JP; Drafted manuscript: ZL, YZ.

Conflict of interest

The authors declare that there are no conflicts of interest.

References (62)

  • T.T. Zhao et al.

    Effects of (−)-sesamin on motor and memory deficits in an MPTP-lesioned mouse model of Parkinson's disease treated with l-DOPA

    Neuroscience

    (2016)
  • L.R. Chioca et al.

    Anxiolytic-like effect of lavender essential oil inhalation in mice: participation of serotonergic but not GABAA/benzodiazepine neurotransmission

    J Ethnopharmacol

    (2013)
  • S. Pellow et al.

    Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat

    J Neurosci Methods

    (1985)
  • L. Prut et al.

    The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review

    Eur J Pharmacol

    (2003)
  • D.H. Kim et al.

    Gomisin a improves scopolamine-induced memory impairment in mice

    Eur J Pharmacol

    (2006)
  • S. Ahmad et al.

    Anti-inflammatory role of sesamin in STZ induced mice model of diabetic retinopathy

    J Neuroimmunol

    (2016)
  • S. Ahmad et al.

    Sesamin attenuates neurotoxicity in mouse model of ischemic brain stroke

    Neurotoxicology

    (2014)
  • Z. Xu et al.

    Sesamin protects SH-SY5Y cells against mechanical stretch injury and promoting cell survival

    BMC Neurosci

    (2017)
  • T. Baluchnejadmojarad et al.

    Sesamin imparts neuroprotection against intrastriatal 6-hydroxydopamine toxicity by inhibition of astroglial activation, apoptosis, and oxidative stress

    Biomed Pharmacother

    (2017)
  • M.M. Khan et al.

    Sesamin attenuates behavioral, biochemical and histological alterations induced by reversible middle cerebral artery occlusion in the rats

    Chem Biol Interact

    (2010)
  • V.K. Dubey et al.

    Possible involvement of corticosterone and serotonin in antidepressant and antianxiety effects of chromium picolinate in chronic unpredictable mild stress induced depression and anxiety in rats

    J Trace Elem Med Biol

    (2015)
  • I. Mahar et al.

    Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects

    Neurosci Biobehav Rev

    (2014)
  • A. Sheldrick et al.

    Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) levels in post-mortem brain tissue from patients with depression compared to healthy individuals - a proof of concept study

    Eur Psychiatry

    (2017)
  • R. Yirmiya et al.

    Depression as a microglial disease

    Trends Neurosci

    (2015)
  • M. Ohnishi et al.

    Sesamin suppresses activation of microglia and p44/42 MAPK pathway, which confers neuroprotection in rat intracerebral hemorrhage

    Neuroscience

    (2013)
  • S. Zheng et al.

    Sesamin suppresses STZ induced INS-1 cell apoptosis through inhibition of NF-kappaB activation and regulation of Bcl-2 family protein expression

    Eur J Pharmacol

    (2015)
  • G. Masi et al.

    The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression

    CNS Drugs

    (2011)
  • M. Woelfer et al.

    The role of depressive subtypes within the neuroinflammation hypothesis of major depressive disorder

    Neuroscience

    (2018)
  • T.T. Zhao et al.

    Effects of (−)-Sesamin on chronic stress-induced anxiety disorders in mice

    Neurochem Res

    (2017)
  • D.H. Root et al.

    Norepinephrine activates dopamine D4 receptors in the rat lateral habenula

    J Neurosci

    (2015)
  • K. Kelly et al.

    Toward achieving optimal response: understanding and managing antidepressant side effects

    Dialogues Clin Neurosci

    (2008)
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