Morinda officinalis oligosaccharides alleviate chronic unpredictable mild stress-induced depression through the BDNF/TrkB/CREB pathway and symptoms of sexual dysfunction in mice

Abstract

Background: In recent years, depression has become a global public health concern, and one of the common concomitant symptoms are diminished sexual motivation and impaired sexual performance. The aim of this study was to investigate the potential effects of Morinda officinalis oligosaccharides (MOO) on depression and its concomitant symptom, sexual dysfunction.

Methods: Chronic unpredictable mild stress (CUMS)-induced depression model was constructed, and the effects of MOO on depression and sexual abilities were evaluated.

Results: The results revealed that MOO was able to alleviate CUMS-induced depression-like behavior in mice, to inhibit hippocampal neuron apoptosis, to reverse monoamine neurotransmitter imbalance, increase Brain-derived neurotrophic factor (BDNF) expression levels in the hippocampus, to modulate the composition and distribution of gut microbiota, and to increase the abundance of probiotics after continuous gavage of MOO for 28 days. MOO further confirmed that sexual dysfunction is closely related to the development of depression by improving the lack of sexual motivation and low sexual performance in CUMS-induced depressed mice, modulating the disruption of sex hormone secretion in serum, and alleviating sperm morphology and functional defects in the epididymis.

Conclusion: These findings on MOO provide a basis for exploring its antidepressant mechanism, its use to improve hypogonadotropic symptoms, and for future development of new antidepressant drug to improves hypogonadotropic symptoms.

Keywords: BDNF/TrkB/CREB pathway; CUMS; Morinda officinalis oligosaccharides; depression; gut microbiota; sexual dysfunction.

Figure 1

MOO improved depression-like behavior in CUMS-Induced mice. (A) Timeline of CUMS procedure, drug administration, behavioral tests, mouse sacrifice, tissue and blood collection. (B) The general formula of the structure of MOO; (C) 28-day mouse body weight; (D–H) Behavioral experiments include SPT (D), TST (E), FST (F), and OFT (G–H) to assess depressive-like behavior in CUMS mice. Results were expressed as mean ± SD (n = 10). ^##p < 0.01 vs. control group; ^*p < 0.05 and ^**p < 0.01 vs. CUMS group.

Figure 2

Neuroprotective effect of MOO on hippocampal neurons in CUMS-induced mice. (A) Nissl-stained neurons in the hippocampal CA1 region, scale bar: 50 μm and 20 μm; (B) Number of Nissl bodies in the hippocampal CA1 region. Blue arrows indicate changes in Nissl bodies in the CA1 region of the hippocampus. Results are expressed as mean ± SD (n = 3). ^##p < 0.01 vs. control group; ^**p < 0.01 vs. CUMS group.

Figure 3

Effect of MOO on monoamine neurotransmission in CUMS-induced mice. (A–D) ELISA detection of the expression levels of monoamine neurotransmitters 5-HT (A), NE (B), DA (C), and 5-HIAA (D) in hippocampal tissue. Results are expressed as mean ± SD (n = 3). ^##p < 0.01 vs. control group; ^*p < 0.05; and ^**p < 0.01 vs. CUMS group.

Figure 4

Effect of MOO on the BDNF/TrkB/CREB signaling pathway in the hippocampus of mice with CUMS-induced depression. (A–C) RT-qPCR analysis of BDNF (A), TrkB (B), and CREB (C) expression in the hippocampus. (D–F) Western blot analysis of BDNF (D), p-TrkB (E), and p-CREB (F) expression in the hippocampus. Data are expressed as mean ± SD (n = 3). ^##p < 0.01 vs. control group; ^*p < 0.05; and ^**p < 0.01 vs. CUMS group.

Figure 5

Effect of MOO on the diversity of gut microbiota in CUMS-induced mice. (A,B) Wayne’s diagram of OTU core discs and their quantitative values. (C–E) Effect of MOO on α-diversity of gut microbiota in mice, Chao’s index (C), Shannon’s index (D), and Simpson’s index (E). (F,G) Effect of MOO on β-diversity of gut microbiota in mice. Results are expressed as mean ± SD (n = 6). ^#p < 0.05, ^##p < 0.01, vs. control group; ^*p < 0.05, ^**p < 0.01 vs. CUMS group.

Figure 6

Effect of MOO on the composition of gut microbiota in CUMS-induced mice. (A) Image of abundance at the phylum level. (C–E) Species abundance at the phylum level. (B) Image of abundance at the genus level. (F–K) Species abundance at the genus level. Results are expressed as mean ± SD (n = 6). ^#p < 0.05, ^##p < 0.01 vs. control group; ^*p < 0.05, ^**p < 0.01 vs. CUMS group.

Figure 7

Effect of MOO on histopathological changed in the sex organs of CUMS-induced depressed mice. (A) H&E staining evaluation of testis tissue, scale bar: 50 μm, and 20 μm. (B) H&E staining evaluation of epididymis tissue, scale bar: 50 μm, and 20 μm (n = 3). Blue arrows indicate the number of layers and arrangement of spermatogenic cells within the seminiferous tubules of testicular tissue; black arrows indicate the lumen of epididymal tissue containing spermatozoa and secretions.

Figure 8

Effect of MOO on sex hormone secretion and sperm morphology in CUMS-induced depressed mice. (A–D) ELISA assay detection of the expression levels of sex hormone T (A), FSH (B), LH (C), and E₂ (D) in mice serum. (E) Sperm deformities in the epididymis. Results are expressed as mean ± SD (n = 3). ^#p < 0.05, ^##p < 0.01 vs. control group; ^*p < 0.05, ^**p < 0.01 vs. CUMS group.