Insight into the metabolic mechanism of Diterpene Ginkgolides on antidepressant effects for attenuating behavioural deficits compared with venlafaxine

Abstract

Depression is a severe and chronic mental disorder, affecting about 322 million individuals worldwide. A recent study showed that diterpene ginkgolides (DG) have antidepressant-like effects on baseline behaviours in mice. Here, we examined the effects of DG and venlafaxine (VLX) in a chronic social defeat stress model of depression. Both DG and VLX attenuated stress-induced social deficits, despair behaviour and exploratory behaviour. To elucidate the metabolic changes underlying the antidepressive effects of DG and VLX, we investigated candidate functional pathways in the prefrontal cortex using a GC-MS-based metabolomics approach. Metabolic functions and pathways analysis revealed that DG and VLX affect protein biosynthesis and nucleotide metabolism to enhance cell proliferation, with DG having a weaker impact than VLX. Glutamate and aspartate metabolism played important roles in the antidepressant effects of DG and VLX. Tyrosine degradation and cell-to-cell signaling and interaction helped discriminate the two antidepressants. L-glutamic acid was negatively correlated, while hypoxanthine was positively correlated, with the social interaction ratio. Understanding the metabolic changes produced by DG and VLX should provide insight into the mechanisms of action of these drugs and aid in the development of novel therapies for depression.

WITHDRAWN: Ginkgolide B reduces hepatic lipid accumulation and ameliorates nonalcoholic fatty liver disease in high-fat diet–induced obese mice

“…Ginkgolides A, B, C were primarily terpenoids and were found that more pharmacological effects improved depression, ischemic stroke and lung injury [18,[49][50][51]. Our earlier experiments demonstrated that ginkgolide C could suppress lipogenesis in 3T3-L1 adipocytes [20].…”

<p>Diterpene Ginkgolides Exert an Antidepressant Effect Through the NT3-TrkA and Ras-MAPK Pathways</p>

“…Our previous studies showed that DG ameliorated brain neurotransmitter perturbation and metabolic dysfunction in mice. [8][9][10] However, the underlying molecular mechanisms, including gene-protein-metabolite interactions, remained unclear. Here, we used metabolomics combined with molecular biology methods to explore the antidepressant mechanisms of DG in the HP and PFC.…”

“…DG Meglumine Injection was a commercial drug of diterpene ginkgolides, 9,10 which was provided by Jiangsu Kanion Pharmaceutical Co., Ltd (Shanghai, China). It is a mixture of different diterpene ginkgolides (mainly contains ginkgolide A, B and K), which are responsible for the main pharmacological neuroprotective in ginkgo biloba extract.…”

“…[4][5][6][7] Our recent studies demonstrated that diterpene ginkgolides (DG), the main components of ginkgo biloba extract, have antidepressant effects. [8][9][10] DG is natural platelet activating factor receptor antagonists that effectively inhibit thrombosis and protect against cerebral ischemia and brain inflammation. Studies show that DG has antioxidant, anti-inflammatory and anti-apoptotic effects, which protects brain neurons and improves brain functions, including cognition.…”

“…[11][12][13] Our previous studies demonstrated that DG significantly improved the depression-like behavioral phenotypes associated with anhedonia, behavioral despair and social disorders in mice. [8][9][10] Furthermore, initial studies suggest that DG exerts antidepressant effects by ameliorating brain neurotransmitter levels and metabolic disorders. However, the underlying molecular mechanisms are still unclear, and long-term changes in liver and kidney function, blood sugar and blood lipids have not been reported.…”