Role of Ginkgolides in the Inflammatory Immune Response of Neurological Diseases: A Review of Current Literatures

Abstract

The inflammatory immune response (IIR) is a physiological or excessive systemic response, induced by inflammatory immune cells according to changes in the internal and external environments. An excessive IIR is the pathological basis for the generation and development of neurological diseases. Ginkgolides are one of the important medicinal ingredients in Ginkgo biloba. Many studies have verified that ginkgolides have anti-platelet-activating, anti-apoptotic, anti-oxidative, neurotrophic, and neuroimmunomodulatory effects. Inflammatory immunomodulation is mediated by inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. They also inhibit the platelet-activating factor (PAF)-mediated signal transduction to attenuate the inflammatory response. Herein, we reviewed the studies on the roles of ginkgolides in inflammatory immunomodulation and suggested its potential role in novel treatments for neurological diseases.

Keywords: Guillain–Barré syndrome; ginkgolides; inflammatory immune response; multiple sclerosis; neurological diseases.

Figure 1

Composition and pharmacological properties of ginkgolides. Ginkgolides are isolated and purified from the leaves of Ginkgo biloba. The ginkgo leaf extracts commonly contain flavonoids such as quercetin, kaempferol, myricetin, and terpene trilactone. The extracted terpene trilactone include ginkgolide A (GA), B, C, M, J, and K and bilobalide (BB). Ginkgolides have anti-PAF, anti-apoptotic, anti-oxidative, neurotrophic, and neuroimmunomodulatory effects. GA, ginkgolides A; BB, bilobalide; PAF, platelet-activating factor; PAFR, platelet-activating factor receptor; p-SAPK/JNK, phospho-stress-activated protein kinase/c-Jun N-terminal kinase; PARP, poly (ADP-ribose) polymerase; BDNF, brain-derived neurotrophic factor; TLR4, toll-like receptor-4; NF-κB, nuclear factor-kappa B.

Figure 2

PAF-mediated signal transduction of ginkgolides in the regulation of IIR. PAF binds to PAF receptor in vivo, and coupled with G protein, phospholipase C is activated and has an effect on phosphatidylinositol 4,5-bisphosphate. Phosphatidylinositol bisphosphate breakdown produces inositol triphosphate and diglyceride. Inositol triphosphate can induce intracellular calcium concentration increases and diglyceride can activate PKC. Finally, it exerts a biological effect by secreting cytokines and proteins. GB competitively inhibits PAF binding to PAFR in order to reduce the above series of reactions and play an anti-inflammatory role. PAF, platelet-activating factor; IIR, inflammatory immune response; PKC, protein kinase C; GB, ginkgolide B.PAF, platelet-activating factor; PAFR, platelet-activating factor receptor; GB, ginkgolide B; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-triphosphate; DAG, diacylglycerol; PKC, protein kinase C; IIR, inflammatory immune response.

Figure 3

MAPK and NF-κB signaling pathway of ginkgolides in the regulation of IIR. Lipopolysaccharide stimulates the dimerization of TLR4 and activates the conserved MAPK tertiary kinase cascade through MyD88, interleukin-1 receptor-associated kinase, which leads to the activation of transcription factors. Finally, it promotes the expression of inflammatory factors in target cells, thus participating in the inflammatory reaction process induced by lipopolysaccharide. As shown in the figure, ginkgolides have effects on MAPK and TLRs/MyD88/NF-κB signaling transduction pathway. It can down-regulate MyD88, transforming growth factor-β-activated kinase-1, IκB kinases, IκBα, extracellular signal-regulated protein kinase 1/2, extracellular signal-regulated JNK, and p38, ultimately reducing inflammation. MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; IIR, inflammatory immune response; MyD88, myeloid differentiation primary response 88; TLR, toll-like receptor.TLR, toll-like receptor; MyD88, myeloid differentiation primary response 88; IRAK, interleukin-1 receptor-associated kinase; TAK1, transforming growth factor-β-activated kinase-1; IKK, IκB kinases; MAP3K, mitogen-activated protein kinase kinase kinase; ERK, extracellular signal-regulated protein-1; JNK, c-Jun amino-terminal kinase; NF-κB, nuclear factor-κB; AP1, activator protein-1; TBK1, TANK-binding kinase 1; IRF, interferon regulatory factor; IIR, inflammatory immune response.