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. 2022 Aug 25:13:980449.
doi: 10.3389/fphar.2022.980449. eCollection 2022.

Combination of panax ginseng and ginkgo biloba extracts attenuate cerebral ischemia injury with modulation of NLRP3 inflammasome and CAMK4/CREB pathway

Aimei Zhao  1   2 , Nan Liu  3 , Guozhi Jiang  4 , Li Xu  2 , Mingjiang Yao  2 , Yehao Zhang  2 , Bingjie Xue  2 , Bo Ma  2 , Dennis Chang  5 , Yujing Feng  6 , Yunyao Jiang  7 , Jianxun Liu  2 , Guoping Zhou  1
Affiliations

Combination of panax ginseng and ginkgo biloba extracts attenuate cerebral ischemia injury with modulation of NLRP3 inflammasome and CAMK4/CREB pathway

Aimei Zhao et al. Front Pharmacol. .

Abstract

Stroke is a major cause of death and disability throughout the world. A combination of Panax Ginseng and Ginkgo biloba extracts (CGGE) is an effective treatment for nervous system diseases, but the neuroprotective mechanism underlying CGGE remains unclear. Both network analysis and experimental research were employed to explore the potential mechanism of CGGE in treating ischemic stroke (IS). Network analysis identified a total number of 133 potential targets for 34 active ingredients and 239 IS-related targets. What's more, several processes that might involve the regulation of CGGE against IS were identified, including long-term potentiation, cAMP signaling pathway, neurotrophin signaling pathway, and Nod-like receptor signaling pathway. Our studies in animal models suggested that CGGE could reduce inflammatory response by inhibiting the activity of Nod-like receptor, pyrin containing 3 (NLRP3) inflammasome, and maintain the balance of glutamate (Glu)/gamma-aminobutyric acid (GABA) via activating calmodulin-dependent protein kinase type Ⅳ (CAMK4)/cyclic AMP-responsive element-binding protein (CREB) pathway. These findings indicated the neuroprotective effects of CGGE, possibly improving neuroinflammation and excitotoxicity by regulating the NLRP3 inflammasome and CAMK4/CREB pathway.

Keywords: CAMK4/CREB; NLRP3 inflammasome; ginkgo biloba extract; ginseng extract; ischemic stroke; network analysis.

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Conflict of interest statement

NL was employed by the company Beijing Increasepharm Safety and Efficacy Co., Ltd. GJ was employed by Shineway Pharmaceutical Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The workflow of the study.
FIGURE 2
FIGURE 2
CGGE ameliorated MCE-induced neurological deficits. (A,B) TTC staining. The positive side (A) and the negative side (B) of the brain slices. White color indicates “infarcted area.” (C,D) Neurological deficit scores after 2 h (C) and 24 h (D). All data were expressed as mean ± SD, n = 10, ### p < 0.001 vs. Control group, **p < 0.01, *p < 0.05 vs. Model group. (E) HE staining of the hippocampus, scale bar, 200 μm (CA3 × 100).
FIGURE 3
FIGURE 3
The compound-target network of CGGE.
FIGURE 4
FIGURE 4
PPI network of candidate targets of CGGE against IS.
FIGURE 5
FIGURE 5
GO (A) and KEGG (B) pathway enrichment analysis of CGGE against IS.
FIGURE 6
FIGURE 6
CGGE modulated the glutamate and GABA concentration level. (A) The changes in Glu level. (B) The changes in GABA level. (C) Changes in the Glu/GABA ratio. ## p < 0.01 vs. sham group; **p < 0.01, *p < 0.05 vs. MCE group (n = 6).
FIGURE 7
FIGURE 7
CGGE activated CaMKⅣ/CREB in the ipsilateral cortex. (A) Protein expression levels of CAMK4, p-CREB, CREB1. (B,C) The analysis of protein expression of CAMK4, p-CREB/CREB1. (D,E) The mRNA expression of Camk4 and Creb1. (## p < 0.01, vs. sham group; **p < 0.01, *p < 0.05, vs. MCE group) (n = 3).
FIGURE 8
FIGURE 8
CGGE inhibited NLRP3 Inflammasome in ipsilateral cortex. (A) Protein expression of NLRP3, CASP1, and ASC. (B,C,D) The analysis of protein expression of NLRP3, CASP1, and ASC. (## p < 0.01, vs. sham group; **p < 0.01, *p < 0.05, vs. MCE group) (n = 3).
FIGURE 9
FIGURE 9
Venn diagram depicts the overlap of CaM, CAMK4, and CGGE-involved signaling pathways. Long-term potentiation, cAMP signaling pathway, and neurotrophin signaling pathway are related to the activation of CREB.
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