Glycyrrhizin Protects Mice Against Experimental Autoimmune Encephalomyelitis by Inhibiting High-Mobility Group Box 1 (HMGB1) Expression and Neuronal HMGB1 Release

Abstract

The inflammatory mediator high-mobility group box 1 (HMGB1) plays a critical role in the pathogenesis of human multiple sclerosis (MS) and mouse experimental autoimmune encephalomyelitis (EAE). Glycyrrhizin (GL), a glycoconjugated triterpene extracted from licorice root, has the ability to inhibit the functions of HMGB1; however, GL’s function against EAE has not been thoroughly characterized to date. To determine the benefit of GL as a modulator of neuroinflammation, we used an in vivo study to examine GL’s effect on EAE along with primary cultured cortical neurons to study the GL effect on HMGB1 release. Treatment of EAE mice with GL from onset to the peak stage of disease resulted in marked attenuation of EAE severity, reduced inflammatory cell infiltration and demyelination, decreased tumor necrosis factor-alpha (TNF-α), IFN-γ, IL-17A, IL-6, and transforming growth factor-beta 1, and increased IL-4 both in serum and spinal cord homogenate. Moreover, HMGB1 levels in different body fluids were reduced, accompanied by a decrease in neuronal damage, activated astrocytes and microglia, as well as HMGB1-positive astrocytes and microglia. GL significantly reversed HMGB1 release into the medium induced by TNF-α stimulation in primary cultured cortical neurons. Taken together, the results indicate that GL has a strong neuroprotective effect on EAE mice by reducing HMGB1 expression and release and thus can be used to treat central nervous system inflammatory diseases, such as MS.

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

“…; Sun et al . ). The nuclear to cytosol translocation of HMGB1 and its release from neural cells is associated with post‐translational modifications and is implicated in the epileptic seizure generation (Fig.…”

“…GL is reported as a natural anti‐inflammatory compound compared to an anti‐HMGB1 mAb (Sun et al . ). Earlier studies have documented that GK has the potential to bind directly to both HMG boxes in HMGB1, thereby demonstrating its neuroprotective effects in a wide variety of neurological diseases (Gong et al .…”

“…), experimental autoimmune encephalomyelitis via inhibiting HMGB1 expression and neuronal HMGB1 release (Sun et al . ), and focal cerebral ischemia (Gong et al . ).…”

“…Understanding the dynamics of HMGB1 translocation and activity is an important factor that will be helpful in assessing the disease pathology. Arrays of studies have repeatedly reported the release of HMGB1 from nuclei in a range of neurological disorders including epilepsy (Fu et al 2017;Zhao et al 2017;Angelopoulou et al 2018;Sun et al 2018). The nuclear to cytosol translocation of HMGB1 and its release from neural cells is associated with posttranslational modifications and is implicated in the epileptic seizure generation (Fig.…”

The “Treatise on the spleen and stomach” (Pí Wèi Lùn) as the first record of multiple sclerosis in the medical literature – A hypothesis based on the analysis of clinical presentation and herbal medicine

“…We also found seven articles on Glycyrrhizae radix (甘草 gān cǎo ), and its isolates which affected EAE. 62 , 63 , 64 , 65 , 66 , 67 , 68 These isolates are Glycyrrhizin (GL) or glycyrrhizic acid (GA), 18-β-glycyrrhetinic acid (GRA), and Licochalcone A (LicoA). GL or GA is a triterpenoid saponin extracted from Glycyrrhiza glabra .…”