An Overview of Recent Advances in the Neuroprotective Potentials of Fisetin against Diverse Insults in Neurological Diseases and the Underlying Signaling Pathways

Abstract

The nervous system plays a leading role in the regulation of physiological functions and activities in the body. However, a variety of diseases related to the nervous system have a serious impact on human health. It is increasingly clear that neurological diseases are multifactorial pathological processes involving multiple cellular systems, and the onset of these diseases usually involves a diverse array of molecular mechanisms. Unfortunately, no effective therapy exists to slow down the progression or prevent the development of diseases only through the regulation of a single factor. To this end, it is pivotal to seek an ideal therapeutic approach for challenging the complicated pathological process to achieve effective treatment. In recent years, fisetin, a kind of flavonoid widely existing in fruits, vegetables and other plants, has shown numerous interesting biological activities with clinical potentials including anti-inflammatory, antioxidant and neurotrophic effects. In addition, fisetin has been reported to have diverse pharmacological properties and neuroprotective potentials against various neurological diseases. The neuroprotective effects were ascribed to its unique biological properties and multiple clinical pharmacological activities associated with the treatment of different neurological disorders. In this review, we summarize recent research progress regarding the neuroprotective potential of fisetin and the underlying signaling pathways of the treatment of several neurological diseases.

Keywords: fisetin; flavonoid; nerve injury; neurological diseases; neuroprotection.

Figure 1

Overview of the natural sources of fisetin and its therapeutic potential in treating neurological disorders and health complications.

Figure 2

Schematic representation of multifaceted neuroprotective potentials of fisetin against diverse insults in neurological diseases. Fisetin is used to treat neurological diseases through a variety of mechanisms including anti-inflammatory, antioxidant stress, antiapoptosis, autophagy regulation, synaptic function improvement, enhancement of proteasome activity, improvement of mitochondrial function and neurotrophic effect. Uparrows (↑) and Downarrows (↓) represent upregulation and downregulation, respectively. Abbreviations: TXB1, thromboxane B1; TXB2, thromboxane B2; 5-HETE, 5-hydroxyeicosatetraenoic acid; 12-HETE, 12-hydroxyeicosatetraenoic acid; PGD2, prostaglandin D2; PGJ2, prostaglandin J2; 15d PGD2, 15-deoxy-PGD2; NO, nitric oxide; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; TNF-α, tumor necrosis factor α; IL-1 β, interleukin 1 β; IL-1R: interleukin-1 receptor; IL-6, Interleukin 6; IL-8, Interleukin 8; Emr-1, EGF-Like module-containing mucin-like hormone receptor 1; MIP-1α, microphage inflammatory protein-1α; CXCR4, chemokine (C-X-C motif) receptor 4; MCP-1, monocyte chemotactic protein-1; SOD, superoxide dismutase; HO-1, heme oxygenase-1; ROS, radical oxygen species; LPO, lipid peroxidation; LHP, lipid hydroperoxidation; PC, protein carbonyl; MDA, malondialdehyde; GSH, glutathione glutathione; CAT, Catalase; GST, Glutathione-S-transferase; GPx, glutathione peroxide; AOPP, Advanced oxidation protein products; AV, autophagic vesicles; SYN, Synaptophysin; SNAP-25, synaptosomal-associated protein 25; SNAP-23, synaptosomal-associated protein 23; PSD-95, postsynaptic density protein 95; CaMKII, Calcium–calmodulin (CaM)-dependent protein kinase II; CREB, cAMP response element-binding protein; NEP, neprilysin; MMP, mitochondrial membrane potential; BDNF, brain-derived neurotrophic factor; GDNF, glial-cell-derived neurotrophic factor.

Figure 3

Schematic diagram of the potential signaling pathways underlying the neuroprotective effects of fisetin against neurological disease. The potential of fisetin has been highlighted in the modulation of different neuroprotection-related signaling pathways, mainly including NF-κB, Keap1/Nrf2/ARE, PI3K-Akt, MAPK and TFEB, which are associated with the initiation and progression of neurological diseases. Abbreviations:TLR4: Toll-like receptor 4; NF-κB: nuclear factor kappa B; IKK: IκB kinases; ROS: radical oxygen species; iNOS: inducible nitric oxide synthase; COX-2: cyclooxygenase-2; TNF-α: tumor necrosis factor α; IL-1β: interleukin 1β; IL-6: Interleukin 6; IL-8: Interleukin 8; GPx: glutathione peroxide; HO-1: heme oxygenase-1; NQO1: NAD(P)H: quinine oxidoreductase 1; Nrf2: NF-E2-related factor 2; Keap1: Kelch-like ECH-associated protein 1; ARE: antioxidant-response element; HIF-1α: hypoxia-inducible factor 1α; HRE: hypoxia-response element; PI3K: Phosphoinositide 3-kinase; PIP3: Phosphatidylinositol Triphosphate; GSK3β: Glycogen synthase kinase-3 beta; CREB: cAMP response element-binding protein; mTOR: mechanistic target of rapamycin; CDK5: Cyclin-dependent kinase; TFEB: Transcription factor EB; RAS: Reliability, availability and serviceability; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase.