Abstract

BackgroundMenopause predisposes individuals to affective disorders, such as depression, which is tightly related to neuroinflammation. While the neuroinflammatory condition has been demonstrated in ovariectomized (OVX) rodents, there is limited evidence concerning microglial polarization, a key process in brain immune activation, in menopause-related brain.MethodsTherefore, the present study aims to evaluate the polarized microglia in long-term OVX rats and we further explored whether supplementation of ω-3 polyunsaturated fatty acids (PUFA), the pleiotropic bioactive nutrient, is effective in the neurobehavioral changes caused by OVX.ResultsOur data showed that OVX-induced anxiety and depression-like behaviors in rats, accompanied with increased neural apoptosis and microglial activation in the hippocampus. Additionally, OVX enhanced proinflammatory cytokines expression and suppressed the expression of anti-inflammatory cytokine, IL-10. Correspondingly, OVX reinforced NFκB signaling and shifted the microglia from immunoregulatory M2 phenotype to proinflammatory M1 phenotype. Meanwhile, daily supplementation with PUFA suppressed microglial M1 polarization and potentiated M2 polarization in OVX rats. In parallel, PUFA also exerted antidepressant and neuroprotective activities, accompanied with neuroimmune-modulating actions.ConclusionCollectively, the present study firstly demonstrated the disturbed microglial polarization in the OVX brain and provide novel evidence showing the association between the antidepressant actions of PUFA and the restraint neuroinflammatory progression.

Highlights

  • Menopause predisposes individuals to affective disorders, such as depression, which is tightly related to neuroinflammation

  • polyunsaturated fatty acids (PUFA) exerted robust anti-anxiety properties in Elevated plus maze (EPM) test of OVX rats and there was a significant interaction between PUFA and OVX on anxietylike behaviors in time spent in open arms (F = 16.09, p < 0.01) (Fig. 1a) and open arm entries (F = 24.73, p < 0.01) (Fig. 1b)

  • Neuroprotective effects of PUFA in OVX rats As shown in Fig. 2., chronic OVX induced the abundance of transferase-mediated FITC-dUTP nick end labeling (Tunel)-positive cells compared with Sham-operated control group (Sham) group, indicating that the apoptotic cell rate in the hippocampus was significantly increased after OVX, whereas the rate of apoptotic cells in the OVX + PUFA group was markedly reduced compared with OVX group (PUFA×OVX interactions, F = 27.84, p < 0.01)

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Summary

Introduction

Menopause predisposes individuals to affective disorders, such as depression, which is tightly related to neuroinflammation. While the neuroinflammatory condition has been demonstrated in ovariectomized (OVX) rodents, there is limited evidence concerning microglial polarization, a key process in brain immune activation, in menopause-related brain. The occurrence menopausal disorders in both brain and periphery is related to the loss of ovarian function and estrogen deficiency. In this scenario, ovariectomized (OVX) rodents become a widely used animal model of menopause, which is generally referred to as surgical menopause [2]. Treatment with the endotoxin, lipopolysaccharide (LPS), induces immune activation in both periphery and brain, resulting in depression-like behaviors [6]. Microglia can polarize into proinflammatory M1 phenotype and immunoregulatory M2 phenotype, which is responsible for the production of proinflammatory or antiinflammatory cytokines, respectively [8]

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