Endogenous Omega (n)-3 Fatty Acids in Fat-1 Mice Attenuated Depression-Like Behavior, Imbalance between Microglial M1 and M2 Phenotypes, and Dysfunction of Neurotrophins Induced by Lipopolysaccharide Administration.

Minqing Gu,Cai Song,Wende Li,Cai Zhang,Yuntao Zhao,Yuyu Li,Yajuan Li,Yongping Zhang,Haiting Tang

doi:10.3390/nu10101351

Abstract

n-3 polyunsaturated fatty acids (PUFAs) have been reported to improve depression. However, PUFA purities, caloric content, and ratios in different diets may affect the results. By using Fat-1 mice which convert n-6 to n-3 PUFAs in the brain, this study further evaluated anti-depressant mechanisms of n-3 PUFAs in a lipopolysaccharide (LPS)-induced model. Adult male Fat-1 and wild-type (WT) mice were fed soybean oil diet for 8 weeks. Depression-like behaviors were measured 24 h after saline or LPS central administration. In WT littermates, LPS reduced sucrose intake, but increased immobility in forced-swimming and tail suspension tests. Microglial M1 phenotype CD11b expression and concentrations of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17 were elevated, while M2 phenotype-related IL-4, IL-10, and transforming growth factor (TGF)-β1 were decreased. LPS also reduced the expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (Trk B), while increasing glial fibrillary acidic protein expression and pro-BDNF, p75, NO, and iNOS levels. In Fat-1 mice, LPS-induced behavioral changes were attenuated, which were associated with decreased pro-inflammatory cytokines and reversed changes in p75, NO, iNOS, and BDNF. Gas chromatography assay confirmed increased n-3 PUFA levels and n-3/n-6 ratios in the brains of Fat-1 mice. In conclusion, endogenous n-3 PUFAs may improve LPS-induced depression-like behavior through balancing M1 and M2-phenotypes and normalizing BDNF function.

Highlights

Inflammatory factors can stimulate the hypothalamic-pituitary-adrenal (HPA) axis to secrete glucocorticoids and activate glial cells to release proinflammatory mediators in the brain [1].Nutrients 2018, 10, 1351; doi:10.3390/nu10101351 www.mdpi.com/journal/nutrientsBoth excessive production of glucocorticoids and proinflammatory cytokines can contribute to neuron apoptosis and dysfunction of neurotransmission and neurotrophins, thereby triggering depression [2].There are two phenotypes of microglia, M1 and M2 [3]
The later can release a variety of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and fibroblast growth factor
Our data showed that arachidonic acid (AA) concentration was unchanged in Fat-1 mice when compared to WT mice, even though subtotal n-3 polyunsaturated fatty acids (PUFAs) concentrations and n-3/n-6 ratio were increased

Summary

Introduction

Inflammatory factors can stimulate the hypothalamic-pituitary-adrenal (HPA) axis to secrete glucocorticoids and activate glial cells to release proinflammatory mediators in the brain [1].Nutrients 2018, 10, 1351; doi:10.3390/nu10101351 www.mdpi.com/journal/nutrientsBoth excessive production of glucocorticoids and proinflammatory cytokines can contribute to neuron apoptosis and dysfunction of neurotransmission and neurotrophins, thereby triggering depression [2].There are two phenotypes of microglia, M1 and M2 [3]. Both excessive production of glucocorticoids and proinflammatory cytokines can contribute to neuron apoptosis and dysfunction of neurotransmission and neurotrophins, thereby triggering depression [2]. The activated M2 phenotype may up-regulate arginase (Arg)-1 and anti-inflammatory cytokines IL-10, IL-4, and transforming growth factor (TGF)-β1, which can reduce inflammation and protect neurons. The later can release a variety of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and fibroblast growth factor. These neurotrophic factors can nourish neurons, promote nerve growth, and maintain synaptic plasticity and transmission [4]. Studies from clinical investigation and animal experiments reported that increased depressive-like behavior was associated with a decrease in the total number of astrocytes in the anterior cortex of mice [5] and deficient BDNF in the hippocampus [6]

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Discussion

Conclusion