Red Raspberry Extract Decreases Depression-Like Behavior in Rats by Modulating Neuroinflammation and Oxidative Stress

Abstract

Objective: Red raspberry serves as a proven natural product to produce anti-inflammatory, antioxidant, and anticancer functions, but limited findings are available on its effects on depression. This study, by using a chronic unpredictable mild stress- (CUMS-) induced depression model, thus investigated the effects and underlying mechanism of red raspberry extract (RRE) on depressive behavior, inflammation, and oxidative stress.

Methods: Different treatments were given after random grouping of Sprague-Dawley rats, including no intervention (control), CUMS induction, and CUMS+different concentrations of RRE, and subsequently, depression-like behavior tests were performed. HE staining was designed to observe the pathological damage of the hippocampal tissue in rats. The levels of oxidative stress, endocrine hormones, and inflammatory factors were determined by biochemical assay and ELISA, and gene expression (mRNA and protein) in the hippocampal tissue by qRT-PCR and Western blot.

Results: On completion of CUMS treatment, the rats showed severe depression-like behavior, with obvious hippocampal tissue damage, oxidative inflammatory response, and endocrine imbalance. Importantly, RRE treatment significantly improved such depression-like behavior and attenuated histopathological damage in CUMS rats when reducing inflammation and oxidative stress and endocrine imbalance with upregulation of glutathione (GSH), superoxide dismutase (SOD), and interleukin- (IL-) 10 and downregulation of adrenocorticotropic hormone (ACTH), corticosterone (CORT), malondialdehyde (MDA), IL-1β, cyclooxygenase- (COX-) 2, and human macrophage chemoattractant protein- (MCP-) 1. In addition, for CUMS rats, RRE was a contributor to increasingly expressed brain-derived neurotrophic factor (BDNF), neurotrophic tyrosine receptor kinase 2 (TrkB), and p-mTOR but inhibited p-GSK-3β expression in the hippocampal tissue. All the above antidepressant effects of RRE were concentration-dependent.

Conclusion: By regulating neuroinflammation, oxidative stress response, endocrine level, and BDNF/TrkB level, RRE showed potential efficacy in alleviating depression-like behavior and histopathological damage of hippocampal tissue in CUMS rats by regulating the GSK3β and mTOR signaling pathways.

Figure 1

Grouping treatment of Sprague-Dawley rats and the behavioral experimental process. W0-W4 represent the rat's body weight on the 0th to 4th week, respectively. OFT: open field test; FST: forced swim test; EPM: elevated maze test; SPT: sucrose preference test.

Figure 2

Effect of RRE on depression-like behavior and histopathological damage in the hippocampal tissues of rats in each group: (a, b) body weight of rats during weeks 0-4; (c) sucrose preference test before and after CUMS; (d, e) total distance moved; (d) time spent in the central area of rats (e) in open field test; (f, g) open arm entries (f) and time spent in open arms (g) in elevated plus maze test; (h, i) immobility (h) and swimming (i) time in force swim test; (j) HE staining showing the pathological damage of the hippocampal tissue. ^∗∗P < 0.01vs. control group, ^##P < 0.01vs. CUMS group.

Figure 3

Effects of RRE on ACTH and CORT levels in the serum of CUMS rats. (a, b) ELISA detecting the levels of CORT (a) and ACTH (b) in the serum: ^∗∗P < 0.01vs. control group, ^##P < 0.01vs. CUMS group.

Figure 4

Effects of RRE on neuroinflammation in CUMS rats. (a–d) The secretion levels of IL-1β (a), IL-10 (b), COX-2 (c), and MCP-1 (d) in hippocampal tissue measured by ELISA, ^∗∗P < 0.01vs. control group, ^##P < 0.01vs. CUMS group.

Figure 5

Effects of RRE on oxidative stress response in CUMS rats: (a–c) the contents of GSH (a), SOD (b), and MDA (c) in the hippocampal tissue determined by biochemical tests, ^∗∗P < 0.01vs. control group, ^##P < 0.01vs. CUMS group.

Figure 6

Effects of RRE on BDNF and TrkB expression levels in the hippocampal tissue of CUMS rats: (a) qRT-PCR was used to detect BDNF (a) and TrkB (b) expression in the hippocampal tissues; (c) Western blot to measure protein expression of BDNF and TrkB in the rats' hippocampal tissue. ^∗∗P < 0.01 vs. control group, ^#P < 0.05 and ^##P < 0.01vs. CUMS group.

Figure 7

Effects of RRE on GSK-3β and mTOR signaling pathways in CUMS rats: (a) mTOR, p-mTOR, GSK-3β, and p-GSK-3β in the hippocampal tissue measured by Western blot; (b) grayscale analysis of p-mTOR/mTOR and p-GSK-3β/GSK-3β ratios. ^∗∗P < 0.01 vs. control group, ^##P < 0.01 vs. CUMS group.