Alarmin HMGB1 Plays a Detrimental Role in Hippocampal Dysfunction Caused by Hypoxia-Ischemia Insult in Neonatal Mice: Evidence from the Application of the HMGB1 Inhibitor Glycyrrhizin

Abstract

Hippocampal dysfunction related to cognitive impairment and emotional disorders in young children and adolescents caused by neonatal hypoxic-ischemic brain injury (HIBI) has attracted increasing attention in recent years. Crosstalk between the nervous and immune systems organized by hypoxiaischemia (HI) insult may contribute to hippocampal dysfunction after HIBI. Extracellular HMGB1 functions as a damage-associated molecular pattern to instigate and amplify inflammatory responses, but whether this molecule is correlated with hippocampal dysfunction after HIBI is largely unknown. Therefore, this study examined hippocampal function after HMGB1 inhibition in an experimental HIBI model to verify the hypothesis that HMGB1 is a key mediator of hippocampal neuropathology in neonatal HIBI. By administering different doses of the HMGB1-specific inhibitor glycyrrhizin (GLY), we first found that GLY reversed the HI insult-induced loss of neurons and myelin in the hippocampal region and neurobehavioral impairments, partially in a dose-dependent manner, and based on this, we determined the optimal drug concentration to be 50 mg/kg. Subsequent analysis found that this neuroprotective effect was achieved through the inhibition of HMGB1 expression and nucleocytoplasmic translocation, a reduction in the abnormal expression of proteins associated with the downstream signaling pathway of HMGB1, a decrease in the inflammatory response, the suppression of increases in microglia/ astrocytes, and the inhibition of hippocampal cell apoptosis. Collectively, our discoveries contribute to the rising appreciation of the role of HMGB1 in the neuropathology of hippocampal dysfunction and related behavioral outcomes following HIBI.

N-Acetyl Cysteine Restores Sirtuin-6 and Decreases HMGB1 Release Following Lipopolysaccharide-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Mice

“…HMGB1 can be passively released during various forms of cell death, such as pyroptosis, apoptosis, autophagy, necroptosis, and necrosis ( Scaffidi et al, 2002 ). Increased extracellular HMGB1 was recently linked to HI-induced brain damage in the hippocampus of neonatal mice, and it was shown that treatment with an HMGB1 inhibitor reversed the HI-induced loss of gray and white matter in the hippocampus and reduced neurobehavioral impairments ( Le et al, 2020 ).…”

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

“…Direct binding of glycyrrhizin to both box A and box B of HMGB1 (Kd =~150 µM) has been demonstrated by nuclear magnetic resonance (NMR) and fluorescence studies (Table 1), and the IC 50 of glycyrrhizin is 50 µM in inhibiting cell migration of 3T3 fibroblasts stimulated with HMGB1 at 1 nM [104]. It has yet to be tested whether glycyrrhizin can prevent CIPN, although it inhibits diabetic neuropathy and retinopathy [92,105], dermatitis [106], chemotherapy and radiation resistance [107,108], brain injury by ischemic stroke [109,110], etc.…”

High Mobility Group Box 1/Toll-like Receptor 4 Signaling Increases GABRB3 Expression in Alcohol Exposure

“…We used 0.9% saline to dissolve all drugs. Mice were treated with saline (control group), alcohol (20% v/v, 2 g/kg) or alcohol+glycyrrhizin (50 mg/kg) 10,11 by intraperitoneal (ip) injection once per day for seven days. [12][13][14] Glycyrrhizin was administered on days six and seven after alcohol injection.…”