EPA is More Effective than DHA to Improve Depression-Like Behavior, Glia Cell Dysfunction and Hippcampal Apoptosis Signaling in a Chronic Stress-Induced Rat Model of Depression.

Ling Yan,Cai Song,Cai Zhang,Zhilan Peng,Jiajia Wang,Yongping Zhang,Zhiyou Yang

doi:10.3390/ijms21051769

Ling Yan, Cai Song + Show 5 more

Open Access

https://doi.org/10.3390/ijms21051769

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Abstract

Clinical evidence indicated that eicosapentaenoic acid (EPA) was more effective than docosahexaenoic acid (DHA) in depression treatment. However, possible mechanisms remain unclear. Here, a chronic unpredictable mild stress (CUMS)-induced model of depression was used to compare EPA and DHA anti-depressant effects. After EPA or DHA feeding, depression-like behavior, brain n-3/n-6 PUFAs profile, serum corticosterone and cholesterol concentration, hippocampal neurotransmitters, microglial and astrocyte related function, as well as neuronal apoptosis and survival signaling pathways were studied. EPA was more effective than DHA to ameliorate CUMS-induced body weight loss, and depression-like behaviors, such as increasing sucrose preference, shortening immobility time and increasing locomotor activity. CUMS-induced corticosterone elevation was reversed by bother fatty acids, while increased cholesterol was only reduced by EPA supplement. Lower hippocampal noradrenaline and 5-hydroxytryptamine concentrations in CUMS rats were also reversed by both EPA and DHA supplement. However, even though CUMS-induced microglial activation and associated increased IL-1β were inhibited by both EPA and DHA supplement, increased IL-6 and TNF-α levels were only reduced by EPA. Compared to DHA, EPA could improve CUMS-induced suppressive astrocyte biomarkers and associated BDNF-TrkB signaling. Moreover, EPA was more effective than DHA to attenuate CUMS-induced higher hippocampal NGF, GDNF, NF-κB, p38, p75, and bax expressions, but reversed bcl-2 reduction. This study for the first time revealed the mechanisms by which EPA was more powerful than DHA in anti-inflammation, normalizing astrocyte and neurotrophin function and regulating NF-κB, p38 and apoptosis signaling. These findings reveal the different mechanisms of EPA and DHA in clinical depression treatment.

Highlights

Neuroinflammation and neurotrophin dysfunction play crucial roles in the etiology of depression [1]
In the open field test (OFT), compared to control group, numbers of crossing and rearing in the open field arena were significantly decreased in rats subjected to chronic unpredictable mild stress (CUMS) (p < 0.01) (Figure 1C,D), which could only be improved by eicosapentaenoic acid (EPA), and no effect shown by docosahexaenoic acid (DHA) supplementation (Figure 1C,D)
Reduced nerve growth factor (NGF) expression was observed in rats exposed to CUMS (p < 0.01), which could be rescued by the consumption of either EPA or DHA (p < 0.01, p < 0.05 respectively)

Summary

Introduction

Neuroinflammation and neurotrophin dysfunction play crucial roles in the etiology of depression [1]. Brain n3/n6 PUFAs profile, serum corticosterone and cholesterol concentration, hippocampal monoamine neurotransmitter levels, hippocampal inflammatory cytokine concentrations, and expressions of glial marker CD11b, astrocyte marker glial fibrillary acidic protein (GFAP), neurotrophins, including glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and BDNF, BDNF receptors TrkB and p75, NF-κB and p38 MAPK pathways, as well as neuron apoptosis (bax) and anti-apoptosis (bcl-2) signaling in the hippocampus were studied. 1H769owever, EPA exerted better effects than DHA to improve CUMS-ind3uocf e17d depression-like behaviors changes. In the OFT, compared to control group, numbers of crossing and rearing in the open field arena were significantly decreased in rats subjected to CUMS (p < 0.01) (Figure 1C,D), which could only be improved by EPA, and no effect shown by DHA supplementation (Figure 1C,D). DA: 268.7.8279D3±o±p1a3.3m.3197in1e, DOPAC:3,4dihydroxyphenylacetic acid, HVA: homovanillic acid, 5-HT: serotonin, 5-HIAA: MH5-VHhAyPd:Ghr:oo3m-xmyoeivntahdnooixlllyeic--43a--hcaiydcde, rt5oi-cpHahTcei:ndsye. lrD,oNtaotEna:iannr,oe5r-aeHdxIrpAernAeas:lsi5ne-edh,yaDdsArom:xDeyaionnpda±omlSeiE-n3eM-,acD. e*OtipcPa

Cytokine Concentrations in the Hippocampus

Changes in Glial Activation

Materials and Methods

Sucrose Preference Test

Forced Swimming Test

Open Field Test

Measurement of Serum Total Cholesterol and Corticosterone Levels

Western Blotting

Statistical Analysis

Findings

Conclusions