The emerging possibility of the use of geniposide in the treatment of cerebral diseases: a review

Abstract

With the advanced discoveries in the field of pathogenesis, a series of cerebral diseases, such as cerebral ischaemia, Alzheimer's disease, and depression, have been found to have multiple signalling targets in the microenvironment. Only a few existing agents have been shown to have curative effects due to this specific circumstance. In recent decades, active ingredients isolated from natural plants have been shown to be crucial for original drug development. Geniposide, mainly extracted from Gardenia jasminoides Ellis, is representative of these natural products. Geniposide demonstrates various biological activities in the treatment of cerebral, cardiovascular, hepatic, tumorous, and other diseases. The multiple protective effects of geniposide on the brain have especially drawn increasing attention. Thus, this article specifically reviews the characteristics of current models of cerebral ischaemia and illustrates the possible effects of geniposide and its pathogenetic mechanisms on these models. Geniposide has been shown to significantly reduce the area of cerebral infarction and alleviate neuronal damage and necrosis mainly by inhibiting inflammatory signals, including NLRP3, TNF-α, IL-6, and IL-1β. Neuronal protection was also involved in activating the PI3K/Akt and Wnt/catenin pathways. Geniposide was able to increase autophagy and inhibit apoptosis by regulating the function of mTOR in treating Alzheimer's disease. Geniposide has also been shown to act as a glucagon-like peptide-1 receptor (GLP-1R) agonist to reduce amyloid plaques and inhibit oxidative stress to alleviate memory impairment as well as synaptic loss. Moreover, geniposide has been shown to exert antidepressant effects primarily by regulating the hypothalamic-pituitary-adrenal (HPA) axis. Detailed explorations have shown that the biological activities of inhibiting inflammatory cytokine secretion, alleviating oxidative stress, and suppressing mitochondrial damage are also involved in the mechanism of action of geniposide. Therefore, geniposide is a promising agent awaiting further exploration for the treatment of cerebral diseases via various phenotypes or signalling pathways.

Keywords: Alzheimer’s disease; Cerebral ischaemia; Depression; Geniposide; Mechanism.

Fig. 1

A The plant Gardenia jasminoides Ellis. B Molecular structure of geniposide

Fig. 2

The therapeutic effect of geniposide on cerebral ischaemic disease. Geniposide enhances GluN2A-dependent survival signals, including pAKT, pERK and PSD-95, and works by reducing the expression of iNOS and NF-κB and inhibiting the release of the inflammatory factors tumour necrosis factor-α (TNF-α) and IL-6. In addition, geniposide activates the PI3K/AKT and Wnt/catenin pathways by upregulating the expression of H19 in PC-12 cells

Fig. 3

The therapeutic effect of geniposide on Alzheimer's disease. Geniposide increases the expression level of p-4E-BP1 and reduces the expression of p-mTOR and p-Akt to improve cognitive impairment. It can treat AD by directly upregulating the phosphorylation level of Akt and downregulating the phosphorylation level of tau protein

Fig. 4

The therapeutic effect of geniposide on depression and other brain diseases. Geniposide downregulates the expression level of proinflammatory cytokines and upregulates the expression of GLP-1R/protein kinase B (AKT) signal-related proteins. It can also further upregulate the mRNA expression of BDNF and TrkB in diabetic mice to treat depressive behaviour

Fig. 5

Multitarget function of geniposide in cerebral diseases. Geniposide treats cerebral diseases by exerting antiapoptotic and anti-inflammatory effects, inhibiting the phosphorylation of related factors, and inhibiting cell damage