sapogenins and Depressive-Disorder

Chronic social defeat stress (CSDS) is a widely used behavioural paradigm of psychosocial stress that can be used to research the pathogenesis of depression and seek antidepressant drugs. Dammarane sapogenins (DS), the deglycosylated product of ginsenosides, has a wide range of biological activities, including immunomodulatory, antifatigue, antitumour and antidepressant activities. However, whether DS has antidepressant-like effects in a CSDS mouse model remains unknown. Therefore, the present study was conducted to evaluate the antidepressant properties of DS in CSDS mice and its underlying mechanisms. The results showed that the oral administration of DS (40 and 80 mg/kg) increased the time spent in the interaction zone in the social interaction test and the sucrose intake in the sucrose preference test, decreased the latency in the novelty-suppressed feeding test, and reduced the immobility time in both the tail suspension test and forced swimming test. Biochemical analyses of brain tissue and serum showed that DS treatment significantly decreased serum corticosterone levels and enhanced brain monoamine neurotransmitter levels in CSDS mice. In addition, an impairment in hippocampal neurogenesis that paralleled a reduced BDNF level in the hippocampus was observed in the mice that were subjected with CSDS for 3 weeks, while treatment with DS reversed these changes. Moreover, DS treatment significantly upregulated BDNF, pTrkB/TrkB, pAkt/Akt, pPI3K/PI3K, pCREB/CREB, pERK1/2/ERK1/2 and pmTOR/mTOR protein expression in the hippocampus. In conclusion, our results showed that DS exerts antidepressant-like effects in mice with CSDS-induced depression, that the effects may be mediated by the normalization of monoamine neurotransmitter levels, the prevention of HPA axis dysfunction and the impairment of hippocampal neurogenesis, and that this occurs partly through the ability of DS to enhance BDNF expression by increasing the TrkB/CREB/ERK pathway and the PI3K/AKT/mTOR pathway.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Corticosterone; Dammaranes; Depression; Depressive Disorder; Disease Models, Animal; Ginsenosides; Hippocampus; Hypothalamo-Hypophyseal System; Male; Mice; Mice, Inbred C57BL; Neurogenesis; Phosphatidylinositol 3-Kinases; Pituitary-Adrenal System; Sapogenins; Signal Transduction; Stress, Psychological; Triterpenes

Ginsenoside Rb3 has been proved to have antidepressant-like effects, which possesses 1 xylose and 3 glucose moieties with 20(S)-protopanaxadiol (PPD) as the aglycone. However, it is commonly accepted that orally ingested ginsenosides can be deglycosylated or partially deglycosylated into active derivatives by the intestinal bacteria. To identify potential antidepressant drug candidates, we compared the antidepressant-like activities between ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K (C-K), and PPD. Effects of acute (1-day), short chronic (7-days), and longer chronic treatments (14-days) with these ginsenosides (50 and 100mg/kg, p.o.) on the behavioral changes in the forced swim test (FST), tail suspension test (TST) and open field test were investigated. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels and mouse brain monoamine neurotransmitters 5-HT, NA and DA levels were measured using commercially available competitive enzyme-linked immunosorbent assay (ELISA) kits. Interestingly, C-K showed antidepressant-like activities similar to that of Rb3, and Rg3 displayed antidepressant-like effects at lower dosage and faster time, indicating it has better effects than Rb3, whereas Rh2 and PPD failed to show any effect. Our results also showed, unlike the positive control fluoxetine, Rb3, Rg3 and C-K significantly increased the NA levels in the brain regions of mice exposed to FST but did not affect the 5-HT and DA levels. Moreover, treatment with Rg3 could reverse swim stress-induced increased levels of serum ACTH and corticosterone. These results suggest that C-K and Rg3 are the active deglycosylated derivatives, especially the latter compound, which is more potent than Rb3 and exerts antidepressant-like effects by regulating NA, ACTH and corticosterone levels.

Topics: Adrenocorticotropic Hormone; Animals; Antidepressive Agents; Brain Chemistry; Corticosterone; Depressive Disorder; Ginsenosides; Hindlimb Suspension; Male; Mice; Motor Activity; Neurotransmitter Agents; Sapogenins; Swimming