Intranasal Administration of Brain-Derived Neurotrophic Factor Rescues Depressive-Like Phenotypes in Chronic Unpredictable Mild Stress Mice

Abstract

Introduction: Major depression disorder is the most common diagnosed mental illnesses, and it bring a high social and economic burden. However, the current treatment for depression has limitations with side effects. Hence, there is an urgent need to search more effective treatment for major depressive disorder. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons.

Methods: We administered BDNF into chronic unpredictable mild stress (CUMS)-induced depression mice and assessed the effects of intranasal delivery of BDNF in depression by the tail suspension test, forced swimming test, novelty suppressed feeding test, and open-field test.

Results: We find that the intranasal administration of BDNF reversed the depressive-like behaviors in CUMS mice as measured Further analyses suggested that BDNF treatment reduced pro-inflammatory cytokine (IL-6, TNF-α, iNOS and IL-1β) expressions in the hippocampus of CUMS mice. In addition, our results showed that BDNF markedly reduced oxidative stress in the hippocampus and blood of CUMS mice. Moreover, our data suggested that BDNF treatment increased neurogenesis in the hippocampus of CUMS mice.

Discussion: Taken together, our results for the first time demonstrated that intranasal delivery of BDNF protein exhibited anti-depressant-like effects in mice, and therefore may represent a new therapeutic strategy for major depressive disorder.

Keywords: BDNF; depression; inflammatory cytokine; neurogenesis; oxidative stress.

Figure 1

Intranasal BDNF treatment ameliorated CUMS-induced depressive-like behaviors. (A) Schematic representation of experimental design for the CUMS-induced depression model. (B) BDNF restored the depressive-like behaviors in OFT. (C)BDNF restored the depressive-like behaviors in NSFT. (D)BDNF treated mice exhibited less depression-like behavior in TST. (E) BDNF treated mice showed less depressive-like behavior in FST. Data are presented as mean ± S.E.M, n = 10 for control group, n = 10 for CUMS group, n = 9 for CUMS+BDNF group. *p < 0.05, **p < 0.01 and ***p < 0.001. One way ANOVA statistics: F _a =47.90, F _b = 14.77, F _c =4.991, F _d =4.723.

Figure 2

Intranasal BDNF treatment reduced oxidative stress in CUMS model mic. The serum MDA levels (A) and SOD activities (B) in mice under various treatments. The hippocampal MDA levels (C) and SOD (D) activities in mice under various treatments. Values are expressed as the mean ± SEM, n = 8 for control group, n = 8 for CUMS group, n = 7 for CUMS+BDNF group. *p < 0.05, **p < 0.01 and ***p < 0.001. One way ANOVA statistics: F _a =6.943, F _b = 2.401, F _c =13.36, F _d =54.60.

Figure 3

Intranasal BDNF treatment reduced inflammatory-associated gene expressions in the hippocampus of CUMS model mice. The hippocampal mRNA expression levels of IL-1β (A), TNF-α (B), iNOS (C) and IL-6 (D) in mice under various treatments. Data are presented as mean ± S.E.M, n = 3, *p < 0.05 and **p < 0.01. One way ANOVA statistics: F _a =25.20, F _b = 25.93, F _c =5.338, F _d =12.56.

Figure 4

Intranasal BDNF treatment reduced inflammatory-associated protein levels in the hippocampus of CUMS model mice. (A) Representative images showing BDNF reduced NLRP3, IL-1β and TNF-α protein levels in the hippocampus of CUMS mice as measured by Western blot.Quantifications of the relative band densities of IL-1β (B), NLRP3 (C), and TNF-α (D) in the hippocampus of mice under various treatments. Data are presented as mean ± S.E.M, n = 3. *p < 0.05 and **p < 0.01. One way ANOVA statistics: F_b =16.74, F _c = 18.12, F _d = 6.832.

Figure 5

Effect of BDNF treatment on neurogenesis in the hippocampus. (A) Confocal photomicrographs of doublecortin-immunostained immature neurons in the dentate gyrus of mice under various treatments. (B) Quantification of doublecortin-positive cells in the dentate gyrus of mice under various treatments. Data are presented as mean ± S.E.M, n = 4. ***p < 0.001. One way ANOVA statistics: F _a = 42.39.