Isoliquiritigenin Confers Neuroprotection and Alleviates Amyloid-β42-Induced Neuroinflammation in Microglia by Regulating the Nrf2/NF-κB Signaling

Abstract

BackgroundNeuroinflammation and oxidative stress are two major pathological characteristics of Alzheimer’s disease (AD). Amyloid-β oligomers (AβO), a toxic form of Aβ, promote the neuroinflammation and oxidative stress in the development of AD. Isoliquiritigenin (ISL), a natural flavonoid isolated from the root of liquorice, has been shown to exert inhibitory effects on inflammatory response and oxidative stress.ObjectivesThe main purpose of this study is to assess the influence of ISL on inflammatory response and oxidative stress in BV2 cells stimulated with AβO, and to explore the underlying molecular mechanisms.Methods3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H- tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) cytotoxicity assays were used to assess the toxic or protective effects of ISL. The expression levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays. Morphological changes in BV2 cells were assessed by immunofluorescence method. Nitric oxide (NO) assay kit was used to determinate the NO production. Western blot, qRT-PCR and immunofluorescence were used to explore the underlying molecular mechanisms.ResultsISL treatment reduced the production of inflammatory cytokines and NO, and alleviated the morphological changes in BV2 cells induced by AβO. ISL treatment further protected N2a cells from the toxic medium of AβO-stimulated BV2 cells. ISL activated nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and suppressed nuclear factor-κB (NF-κB) signaling in BV2 cells.ConclusionISL suppresses AβO-induced inflammation and oxidative stress in BV2 cells via the regulation of Nrf2/NF-κB signaling. Therefore, ISL indirectly protects neurons from the damage of toxic conditioned media.

Natural Products as Modulators of Nrf2 Signaling Pathway in Neuroprotection

“…This compound at 10 and 20 μM concentrations demonstrated anti-inflammatory and antioxidant activity in microglia BV2 cells stimulated by AβO, as it increased the activation of the Nrf2/HO-1 pathway and inhibited NF-κB. Consequently, nitric oxide production and proinflammatory cytokines that generate neuronal damage in AD were reduced [ 50 ].…”

Pharmacological Modulations of Nrf2 and Therapeutic Implications in Aneurysmal Subarachnoid Hemorrhage

“…It has been proved that Isoliquiritigenin (ISL) has a strong antioxidant effect and prevents oxidative stress-related diseases [ 97 , 98 ]. In central nervous system (CNS) diseases, ISL has also been found to play a brain-protective role and it improves cognitive impairment in various acute brain injuries and neurodegenerative diseases [ 99 , 100 , 101 ]. In addition, ISL can penetrate the BBB and directly influence the central nervous system [ 100 ].…”

Beneficial effects of natural flavonoids on neuroinflammation

“…Isoliquiritigenin ( Figure 4 ), with a chalcone structure, is derived from licorice root. Isoliquiritigenin alleviates morphological changes and reduces the levels of COX-2, iNOS, NO, IL-1β, IL-6, and TNF-α via the up-regulation of Nrf2, HO-1 and NQO1, and the inhibition of p65 nuclear translocation in BV2 cells induced by Aβ oligomers, and increases the cell viability in co-culture of BV2 cells and N2a cells ( 135 ). In vivo study, isoliquiritigenin reverses LPS-induced cognitive deficits, promotes the expression of PSD-95, BDNF, and synaptophysin, and restrains the secretion of CCL3, TNF-α, IL-1β, and IL-6 in hippocampus from LPS-stimulated rats via increasing GSK-3β phosphorylation and Nrf2, HO-1, NQO1 expression, as well as suppressing the protein expression of NF-κB ( 136 ).…”