Neuroprotective Effects of Hesperetin in Regulating Microglia Polarization after Ischemic Stroke by Inhibiting TLR4/NF-κB Pathway

Abstract

This study aimed to explore the influence of hesperidin on the polarization of microglia to clarify the key mechanism of regulating the polarization of M2 microglia. C57BL/6 mice were randomly divided into middle cerebral artery occlusion model group (MCAO group), MCAO + hesperidin treatment group (MCAO + hesperidin group), and sham group (sham operation group). The mice were assessed with neurological scores for their functional status. 2,3,5-Triphenyltetrazole chloride (TTC) was used to determine the volume of cerebral infarction. Hematoxylin and eosin (H&E) staining was performed to detect brain loss. The system with 1% O2, 5% CO2, and 92% N2 was applied to establish BV2 in vitro model induced by MCAO. TNF-α, IL-1β, TGF-β, and IL-10 levels of cytokines in the supernatant were detected by ELISA. RT-qPCR was used to detect mRNA levels of M1 iNOS, CD11b, CD32, and CD86, and mRNA levels of M2 CD206, Arg-1, and TGF-β. The Iba-1, iNOS, and Arg-1 of microglia and protein levels of TLR4 and p-NF-κB related to the pathway were detected by Western blot. After treatment with hesperidin, BV2 cells induced by MCAO in vitro can reduce the proinflammatory cytokines of TNF-α and IL-1β significantly, further upregulating anti-inflammatory cytokines of TGF-β, IL-10 while inhibiting TLR4 and p-NF-κB expression. The MCAO-induced BV2 cells treated by TLR-4 inhibitor TAK-242 and NF-κB inhibitor BAY 11-7082 had similar polarization effects to those treated with hesperidin. This study found that hesperetin gavage treatment can improve the neurological deficit and regulate the polarization of microglia in MCAO mice. In vitro experiments further verified that hesperidin plays a neuroprotective role by inhibiting the TLR4-NF-κB pathway, thus providing new targets and strategies for neuroprotection and nerve repair after ischemic stroke.

Eriodictyol: a review of its pharmacological activities and molecular mechanisms related to ischemic stroke

“…24 It is worth noting that hesperidin, which has been extensively studied, can improve the neurological deficit and regulate the polarization of microglia cells in MCAO mice after administration, which may play a neuroprotective role by inhibiting the TLR4-NF-κB pathway. 39,40 Additionally, the glycosylated forms are captured in the colon, hydrolyzed by the colonic microbiota to their individual aglycones and then assimilated into the enterocytes, and metabolized by glucuronidation, sulfation, and/or methylation. 41,42 Recent studies have displayed that the disaccharide structure of the primary compositions of flavanones in citrus hinders their ingestion by passive transportation in the small intestine and then decreases their bioavailability and post-pones their absorption.…”

“…24 It is worth noting that hesperidin, which has been extensively studied, can improve the neurological deficit and regulate the polarization of microglia cells in MCAO mice after administration, which may play a neuroprotective role by inhibiting the TLR4-NF-κB pathway. 39,40 Additionally, the glycosylated forms are captured in the colon, hydrolyzed by the colonic microbiota to their individual aglycones and then assimilated into the enterocytes, and metabolized by glucuronidation, sulfation, and/or methylation. 41,42…”

Brain microvascular endothelial cell‐derived exosomes transmitting circ_0000495 promote microglial M1‐polarization and endothelial cell injury under hypoxia condition

“…For example, oxymatrine suppressed neuroinflammation through modulating microglial M1/M2 polarization via TLR4/NF‐κB pathway 46 . Hesperetin exerted neuroprotective effects on modulating microglial polarization after ischemic stroke through suppressing TLR4/NF‐κB pathway 47 . Herein, our earlier research found that circ_0000495 was highly expressed in exosomes secreted from HBMVECs under hypoxia condition.…”

Antioxidant, Antiapoptotic, and Anti-Inflammatory Effects of Hesperetin in a Mouse Model of Lipopolysaccharide-Induced Acute Kidney Injury

“…Wang et al reported that hesperetin alleviates LPS-induced acute lung injury in mice via the inhibition of the TLR4-MyD88-NF-κB pathway [ 20 ]. Zhang et al also reported that hesperetin inhibited the polarization of microglia and exerted a protective effect in a mouse model of ischemic stroke by suppressing the TLR4-NF-κB pathway [ 58 ]. Overall, these results suggest that the beneficial action of hesperetin on LPS-induced cytokine production and macrophage infiltration may be mainly due to the suppression of the TLR4-MyD88-NF-κB cascade.…”