Glycyrrhizin, an HMGB1 inhibitor, exhibits neuroprotective effects in rats after lithium-pilocarpine-induced status epilepticus

Li, Yajun; Wang, Lin; Zhang, Bei; Gao, Fei; Yang, Chunmei

doi:10.1111/jphp.13040

Cited by 47 publications

(37 citation statements)

References 57 publications

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“…Recently, GL attenuated neuronal damage and altered disease progression post‐SE by inhibiting HMGB1 activity and its translocation, and protected BBB integrity in an experimental SE model induced by lithium‐pilocarpine (Li et al . ).…”

Section: Hmgb1‐targeting Therapeutic Agents In Epilepsy: An Updatementioning

confidence: 97%

“…In addition, GL protects rat hippocampus and olfactory bulb from oxidative and inflammatory damage induced by pilocarpine via inhibiting IL-1b and TNF-a in an experimental model of SE, although no antiepileptic properties were reported in this study (Gonz alez-Reyes et al 2016). Recently, GL attenuated neuronal damage and altered disease progression post-SE by inhibiting HMGB1 activity and its translocation, and protected BBB integrity in an experimental SE model induced by lithium-pilocarpine (Li et al 2018).…”

Section: Hmgb1 Inhibitorsmentioning

confidence: 99%

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

Paudel

Semple

Jones

et al. 2019

Journal of Neurochemistry

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Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti‐epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1‐targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.

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Section: Hmgb1‐targeting Therapeutic Agents In Epilepsy: An Updatementioning

confidence: 97%

Section: Hmgb1 Inhibitorsmentioning

confidence: 99%

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

Paudel

Semple

Jones

et al. 2019

Journal of Neurochemistry

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“…Glycyrrhizin is a small-molecule inhibitor of extracellular HMGB1 cytokine activity [103] with the potential to penetrate BBB [104]. The neuroprotective effect of glycyrrhizin has been demonstrated in an array of neurological disorders, including epilepsy [105], TBI [106], and PD [107]. Although the therapeutic effect of glycyrrhizin has not been demonstrated in AD mice with developed Aβ pathology, its effects have been extensively evaluated against several AD-like pathologies such as LPS-induced neuroinflammation and cognitive deficits, as well as in surgery-induced cognitive decline.…”

Section: Effects Of Hmgb1 Neutralization In Admentioning

confidence: 99%

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Paudel

Angelopoulou

Piperi

et al. 2020

Cells

170

128

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

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“…Glycyrrhizin, which is an extract of licorice root, is a triterpenoid saponin glycoside used as a natural sweetener and it has been described with potential immunomodulating, anti-inflammatory, hepato-and neuro-protective, and antineoplastic activities [23][24][25][26]. Previous studies have shown that glycyrrhizin suppresses HMGB1 expressions and mitogenic activities, and impedes its DNA-binding function.…”

Section: Introductionmentioning

confidence: 99%

High-Mobility Group Box 1 Protein Signaling in Painful Diabetic Neuropathy

Thakur¹,

Sadanandan²,

Chattopadhyay³

2020

IJMS

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Diabetes is a global epidemic and more than 50% diabetic patients are also diagnosed with neuropathy, which greatly affects the quality of life of the patients. Available treatments are not always successful due to the limited efficacy and complications, such as addiction and dependency. Studies have implicated that high mobility group box1 (HMGB1) protein plays a crucial role in neuroinflammation and the development of neuropathic conditions. HMGB1 is a proinflammatory cytokine that can be released from necrotic cells in passive form or in response to inflammatory signals as an active form. HMGB1 is the ligand for the receptor for advanced glycation end products (RAGE), and toll-like receptors, (TLR)-2 and TLR4, which also indirectly activates C-X-C chemokine receptor type 4 (CXCR4). We investigated whether blocking of HMGB1 can reduce pain and inflammation in diabetic neuropathic animals to further understand the role of HMGB1 in diabetic neuropathy. Type 2 diabetic rats and mice were treated with natural inhibitor of HMGB1, glycyrrhizin (GLC) for five days/week for four weeks at a dose of 50 mg/kg per day by intraperitoneal injection. The animals were divided into three categories: naïve control, diabetic alone, diabetic with GLC treatment. All of the behavioral analyses were conducted before and after the treatment. The expression of inflammatory markers and changes in histone acetylation in the peripheral nervous system were measured by immunohistochemistry and Western blot analysis after the completion of the treatment. Our study revealed that TLR4, HMGB1, CXCR4, and Nod-like receptor protein 3 (NLRP3) levels were increased in the spinal and dorsal root ganglia (DRG) neurons of Type 2 diabetic mice and rats with painful neuropathy. GLC treatment inhibited the increases in TLR4, NLRP3, and CXCR4 expressions and improved the mechanical and thermal pain threshold in these animals. Immunohistochemical studies revealed that hyperglycemia mediated inflammation influenced HMGB1 acetylation and its release from the neurons. It also altered histone 3 acetylation in the microglial cells. The inhibition of HMGB1 by GLC prevented the release of HMGB1 as well as H3K9 acetylation. These findings indicate that the interruption of HMGB1 mediated inflammation could ameliorate diabetic neuropathy and might exhibit a unique target for the treatment.

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Glycyrrhizin, an HMGB1 inhibitor, exhibits neuroprotective effects in rats after lithium-pilocarpine-induced status epilepticus

Cited by 47 publications

References 57 publications

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

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

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

High-Mobility Group Box 1 Protein Signaling in Painful Diabetic Neuropathy

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