Effect of HMGB1 and RAGE on brain injury and the protective mechanism of glycyrrhizin in intracranial‑sinus occlusion followed by mechanical thrombectomy recanalization

Abstract

The key to successful treatment of cerebral venous-sinus occlusion (CVO) is the rapid recanalization of the sinus following venous-sinus occlusion; however, rapid recanalization of the sinus may also cause secondary cerebral injury. The present study examined mechanical thrombectomy-related brain injury and the possible molecular mechanisms following CVO recanalization, and investigated the protective effect of glycyrrhizin (GL) in CVO recanalization. The cerebral venous sinus thrombosis (CVST) model was induced in rats using 40% FeCl 3 . Mechanical thrombectomy was performed at 6 h post-thrombosis. GL was administered to rats following thromboembolism. Neurological function and brain water content were measured prior to sacrifice of the rats. Serum malondialdehyde, superoxide dismutase and nitric-oxide synthase concentrations were measured. The expression levels of high-mobility group box 1 (HMGB1) and receptor of advanced glycation end products (RAGE) and its downstream inflammatory mediators were measured in serum and brain tissues. Rapid CVO recanalization caused brain injury, and the brain parenchymal damage and neurological deficits caused by CVO were not completely restored following recanalization. Similarly, following rapid recanalization in the venous sinus, the expression levels of HMGB1 and RAGE were lower than those in the CVST group, but remained significantly higher than those of the sham group. The combination of mechanical thrombectomy and GL improved cerebral infarction and cerebral edema in rats, and inhibited the extracellular transport of HMGB1, and the expression of downstream inflammatory factors and oxidative-stress products. The administration of exogenous recombinant HMGB1 reversed the neural protective effects of GL. In conclusion, mechanical thrombectomy subsequent to CVO in rats can cause brain injury following recanalization. HMGB1 and RAGE promote inflammation in the process of brain injury following recanalization. GL has a relatively reliable neuroprotective effect on brain injury by inhibiting HMGB1 and its downstream inflammatory factors, and decreasing oxidative stress.

Glycyrrhizin Attenuates Hypoxic-Ischemic Brain Damage by Inhibiting Ferroptosis and Neuroinflammation in Neonatal Rats via the HMGB1/GPX4 Pathway

“…Owing to the difficulty of delivering these two ferroptosis inhibitors across the blood–brain barrier, their clinical applications to CNS diseases are limited [ 18 , 21 ]. GL, a major constituent of licorice root, has been demonstrated to pass through the blood–brain barrier and exert a neuroprotective effect when administered by intraperitoneal injection [ 22 ]. The protective effect of GL against mitochondrial injury and oxidative stress has also been confirmed in pathological conditions [ 36 ].…”

“…Glycyrrhizin (GL) is a natural glycosyl triterpenoid product and is recognized as an inhibitor of high-mobility group box 1 (HMGB1) [ 22 ]. HMGB1 is a ubiquitous transcription factor that is involved in the maintenance of nucleosome structure, chromatin remodeling, and the regulation of DNA recombination and repair [ 23 – 25 ].…”

A novel rat model for cerebral venous sinus thrombosis: verification of similarity to human disease via clinical analysis and experimental validation

“…Several previous studies have reported a relationship between inflammation and venous thrombosis. [ 46 – 48 ]. One in vivo noted that neutrophils contribute to the initiation of thrombosis [ 49 ].…”

Inflammation in Cerebral Venous Thrombosis

“…High mobility group box 1 (HMGB1), a member of the damage-associated molecular pattern molecular family, is recently reported to be implicated in the inflammatory cascade-amplification reaction in the pathophysiology of CVT ( 67 ). Under normal physical conditions, HMGB1 exists in the nucleus and maintains the chromosomal structure and physiological activities of the DNA ( 99 ).…”

“…On suffering inflammatory stimuli, HMGB1 is released into the extracellular space and immediately activates the innate immune response ( 99 ). Independently, HMBG1 can activate its downstream mediator, the receptor for advanced glycated end products (RAGE), to induce endocytosis and generate proinflammatory factors such as TNF-α, IL-1β, and IL-6 ( 67 ). The inhibition of HMGB1 and RAGE can reduce the expression of downstream inflammatory factors and attenuate CVT-mediated further damage ( 67 ).…”