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. 2020 May;28(5):621-629.
doi: 10.1016/j.jsps.2020.04.001. Epub 2020 Apr 9.

Systemic TNF-α blockade attenuates anxiety and depressive-like behaviors in db/db mice through downregulation of inflammatory signaling in peripheral immune cells

Musaad A Alshammari  1 , Mohammad R Khan  1 , Hafiz Majid Mahmood  1 , Abdulaziz O Alshehri  1 , Fawaz F Alasmari  1 , Faleh M Alqahtani  1 , Abdullah F Alasmari  1 , Shakir D Alsharari  1 , Abdulaziz Alhossan  2 , Sheikh F Ahmad  1 , Ahmed Nadeem  1 , Tahani K Alshammari  1
Affiliations

Systemic TNF-α blockade attenuates anxiety and depressive-like behaviors in db/db mice through downregulation of inflammatory signaling in peripheral immune cells

Musaad A Alshammari et al. Saudi Pharm J. 2020 May.

Abstract

Research studies have indicated that the comorbidity burden of mood disorders and obesity is reasonably high. Insulin signaling has been shown to modulate multiple physiological functions in the brain, indicating its association with neuropsychiatric diseases, including mood disorders. Leptin is a hormone responsible for regulating body weight and insulin homeostasis. Previous studies on db/db mice (a mouse model that carries a spontaneous genetic mutation in leptin receptor Leprdb ) have shown that they exhibit inflammation as well as neurobehavioral traits associated with mood. Therefore, targeting inflammatory pathways such as TNF-α may be an effective strategy in the treatment of obesity-linked mood disorders. The objective of this study was to investigate the effect of long-term administration of etanercept (a TNF-α blocker) on anxiety and depressive-like behaviors in db/db mice. This was performed using light/dark box, forced swim, and open field tests with lean littermate wild type (WT) mice serving as a control group. Using flow cytometry in peripheral blood, we further examined the molecular effects of etanercept on NF-κB p65, TNF-α, IL-17A, and TLR-4 expressing CD4+, CD8+, and CD14+ cells in the peripheral blood. Our data show that peripheral administration of etanercept decreased these cells in db/db mice. Furthermore, our results indicated that peripheral administration of etanercept reduced anxiety and depressive-like behaviors. Therefore, targeting TNF-α signaling might be an effective strategy for modulating obesity-associated depression and anxiety.

Keywords: Anxiety-like behavior; Depression; Depressive-like behavior; Etanercept; Inflammation; Obesity; TNF-α; db/db mice.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Anxiety-related behavioral tests in db/db, littermate WT mice, and Etanercept-treated mice. (A) Locomotor activity test, (B) Open field test, and (C) Light/dark box test. The four groups of mice were: littermate WT + saline, db/db + saline, littermate WT + 5 mg/kg ETN, and db/db mice + 5 mg/kg ETN; i.p. an injection every other day for 21 days. *P < 0.05 compared with db/db saline-treated mice. Data are shown as mean ± SEM (n = 6). Littermate WT = lean control mice, ETN = etanercept treated mice.
Fig. 2
Fig. 2
Results of a forced swim-test to examine depressive-like behavior in four groups of mice: littermate WT + saline, db/db + saline, littermate WT + 5 mg/kg ETN, and db/db mice + 5 mg/kg ETN; i.p. an injection every other day for 21 days. *P < 0.05 compared with littermate WT saline-treated mice. Data are shown as mean ± SEM (n = 6). Littermate WT = lean control mice, ETN = etanercept treated mice.
Fig. 3
Fig. 3
Etanercept reversed the increase in IL-17A + and IL-17A-producing CD4 + and CD8 + T cells peripherally in db/db mice. A and B. The effects of ETN on IL-17A+ and IL-17A- expressing CD4+ and CD8+ T cells in the peripheral blood (analyzed using flow cytometry). C. Representative dot plots for one mouse from each group. *P < 0.05 compared with db/db saline-treated mice. Data are shown as mean ± SEM (n = 4).
Fig. 4
Fig. 4
Etanercept reduced NF-κBp65 expressing CD4 + and CD8 + T cells peripherally in db/db mice. A and B. The effects of ETN on NF-κBp65+ and NF-κBp65+-expressing CD4+ and CD8+ T cells in the peripheral blood (analyzed using flow cytometry). C. Representative dot plots for one mouse from each group using flow-cytometric studies. *P < 0.05 compared with db/db saline-treated mice. Data are shown as mean ± SEM (n = 4).
Fig. 5
Fig. 5
Etanercept reduced TNF-α+ and TNF-α- expressing CD4 + and CD8 + T cells peripherally in db/db mice. A and B. The effects of ETN on TNF-α+ and TNF-α- expressing CD4+ and CD8+ T cells in the peripheral blood (analyzed using flow cytometry). 6C. Representative dot plots for one mouse from each group. *P < 0.05 compared with db/db saline-treated mice. Data are shown as mean ± SEM (n = 4).
Fig. 6
Fig. 6
The effects of ETN on TLR-4-producing CD14+ cells in the peripheral blood (analyzed using flow cytometry). *P < 0.05 compared with db/db saline-treated mice. Data are shown as mean ± SEM (n = 4).
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