Antidepressant activity of ω-3 polyunsaturated fatty acids in ovariectomized rats: role of neuroinflammation and microglial polarization

Abstract

Background: 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. Methods: Therefore, 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. Results: Our 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. Conclusion: Collectively, 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.

The relevance of the endocrine condition in microglia morphology and dendrite complexity of doublecortin‐associated neurons in young adult and middle‐aged female rats exposed to acute stress

“…Further, the OVX per se appears to be working as a factor that promotes morphological microglial retraction associated with the activation state. In line with these results, reports indicate that long-term OVX in young adult rats promotes microglial activation and polarization in the hippocampus and frontal cortex in rodents (Ge et al, 2020;Wu et al, 2020).…”

The Causal Role of Magnesium Deficiency in the Neuroinflammation, Pain Hypersensitivity and Memory/Emotional Deficits in Ovariectomized and Aged Female Mice

“…Previous works from different groups have shown that OVX induces neuroinflammation (overproduction of inflammatory cytokines and glial activation in CNS) and/or memory decline, depression-like behaviors in mice, [45][46][47][48][49][50][51][52][53] and in rats. [54][55][56][57][58] Consistently, in the present work we found that chronic pain and memory/emotional deficits were associated with neuroinflammation in OVX and aged female mice. This is in line with clinical data showing that chronic pain is present in 35.0% of the surveyed population of 1207 subjects, the incidence of chronic pain is much higher in old women.…”

Indole-3-Carbinol Selectively Prevents Chronic Stress-Induced Depression-but not Anxiety-Like Behaviors via Suppressing Pro-Inflammatory Cytokine Production and Oxido-Nitrosative Stress in the Brain

“…In recent years, the over-accumulation of pro-inflammatory cytokines in the blood and brain tissues has been widely-reported to be associated with the pathogenesis of depression. For example, the over-activation of microglia has been repeatedly reported to mediate the progression of depression in rodent animals ( Zhao et al, 2016 ; Duan et al, 2020 ; Jing Li et al, 2020 ; Wu et al, 2020 ; Kumar et al, 2021 ), and suppression of neuroinflammation by minocycline treatment could can ameliorate depressive symptoms ( Wang et al, 2020 ; Bassett et al, 2021 ). Individuals suffering from depression have increased levels of pro-inflammatory cytokines in the blood ( Petralia et al, 2020 ; Primo de Carvalho Alves and Sica da Rocha, 2020 ).…”

“…It is known that the development of neuroinflammatory responses at stress conditions is usually accompanied with significant reductions in anti-inflammatory mediators ( Zhao et al, 2016 ; Duan et al, 2020 ; Jing Li et al, 2020 ; Wu et al, 2020 ; Kumar et al, 2021 ). Thus, enhancing the production of anti-inflammatory mediators in the brain may mediate the antidepressant effect of I3C.…”

“…In rodent models of depression and anxiety, high levels of pro-inflammatory cytokines and low levels of anti-inflammatory mediators such as IL-10 and IL-4 in the brain are also correlated with the progression of abnormal behaviors ( Wang et al, 2018 ; Walker et al, 2019 ; Zhang et al, 2019 ; Guha et al, 2020 ; Wu et al, 2021 ). Skewing the neuroinflammatory responses in the brain towards an anti-inflammatory state can prevent the progression of abnormal behaviors in animals stimulated with detrimental stress ( Zhao et al, 2016 ; Duan et al, 2020 ; Jing Li et al, 2020 ; Wu et al, 2020 ; Kumar et al, 2021 ). Moreover, direct infusion of pro-inflammatory cytokines such as IL-1β and interferon-α (INF-α) into the brain in animals can also induce behavioral abnormalities ( Park et al, 2015 ; Zhifei Li et al, 2020 ), and clinically-available antidepressants such as fluoxetine can improve behaviors in depressed animals ( Du et al, 2016 ) and patients suffering from generalized anxiety disorders ( Hou et al, 2019 ) partially through suppression of inflammation.…”