High‐mobility group box 1 in Parkinson's disease: from pathogenesis to therapeutic approaches

Angelopoulou, Efthalia; Piperi, Christina; Papavassiliou, Athanasios G.

doi:10.1111/jnc.14450

Cited by 45 publications

(37 citation statements)

References 51 publications

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“…HMGB1 has been found to be closely related to the inflammatory diseases (Lu et al, 2012). It can be actively secreted by inflammatory cells and released by necrotic cells (Angelopoulou et al, 2018). After that HMGB1 can bind to various transmembrane receptors including TLR2, TLR4, and TLR9, and increase DNA-binding capacity of several transcription factors, such as p53 as well as NF-kB (Martinotti et al, 2015), ultimately leading to inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease

et al. 2020

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Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root of Sophora flavescens, presents amounts of pharmacological properties including immunomodulation, anti-inflammation, anti-oxidation, and anti-virus. Recent studies tend to focus on its effects on neuroinflammation and neuroprotection in Parkinson's disease (PD) due to its profound anti-inflammatory effect. In this study, the neuroprotective and anti-neuroinflammatory effects of OMT were investigated in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-stimulated mice and 1-methyl-4-phenylpyridinium (MPP +)-induced mice primary microglia. Additionally, mice primary neuron-microglia cocultures and primary microglia infected with Cathepsin D (CathD)-overexpressed lentivirus were used to clarify whether the neuroprotective effect of OMT was through a CathDdependent pathway. Results showed that OMT dose-dependently alleviated MPTPinduced motor deficits and conferred significant dopamine (DA) neuroprotection against MPTP/MPP +-induced neurotoxicity. In addition, OMT inhibited MPTP/MPP +-induced microglia activation and the pro-inflammatory cytokines release. Further, OMT downregulated the expression of CathD, and inhibited the activation of the HMGB1/TLR4 signaling pathway as well as the nuclear translocation of NF-kB both in vivo and in vitro. It is worth noting that overexpression of CathD reversed OMT-targeted inhibition of HMGB1/TLR4/NF-kB signaling and OMT-produced neuroprotection in reconstituted neuron-microglia co-cultures. Our findings indicated that OMT conferred DA neuroprotection and attenuated microglial-mediated neuroinflammation through CathDdependent inhibition of HMGB1/TLR4/NF-kB signaling pathway. Our study supports a potential role for OMT in ameliorating PD, and proposes that OMT may be useful in the treatment of PD.

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Section: Discussionmentioning

confidence: 99%

Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease

et al. 2020

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“…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.…”

Section: Hmgb1 Dynamics During Epilepsymentioning

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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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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“…Neuroinflammation due to an overactivated and/or chronically activated state of microglia is another source of excessive and uncontrolled release of free radicals. Molecular mechanisms underlying these pathophysiological processes are still under evaluation, but recent evidence comes from studies on high-mobility group box 1 (HMGB1) [11], mammalian target of rapamycin (mTOR) signaling [12], and the nuclear factor, erythroid 2 like 2 (Nrf2) [13], among others. Recent breakthroughs from genetic studies revealed that lysosomal system dysfunction is one of the earliest pathogenetic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Effect of Alpha-Lipoic Acid in 6-Hydroxydopamine Unilateral Intrastriatal Injected Rats

et al. 2020

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The toxin 6-hydroxydopamine (6-OHDA) is a highly oxidizable dopamine (DA) analog that is widely used for reproducing several cell processes identified in Parkinson’s disease (PD). Due to the close similarity of its neurotoxic mechanism to those of DA, it is suitable as a model for testing the effects of potentially neuroprotective drugs. This study aimed to evaluate the effect of alpha-lipoic acid (LA) on brain oxidative stress (OS) in unilateral intrastriatal (6-OHDA) injected rats. Forty male Wistar rats, four months old (220–260 g), were evaluated. Half of them received LA (35 mg/kg i.p.) from the start to the end of the experiment. On day 2 of the trial, ten LA-supplemented rats and ten non-LA-supplemented rats were subjected to the apomorphine test. Brain homogenates were evaluated for thiobarbituric acid-reactive substances (TBARS) and glutathione peroxidase (GPx) activity. The same evaluation procedures were repeated on day 14 with the remaining animals. An increased TBARS level and decreased GPx activity, suggestive for OS, were recorded in homogenates on day 14 vs. day 2 of the experiment in the 6-OHDA treated rats. The simultaneous application of LA mitigated these changes. Our study demonstrates that the low dose of LA could be of value for decreasing the OS of the neurotoxic 6-OHDA, supporting the need for further studies of the benefit of LA treatment in PD.

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High‐mobility group box 1 in Parkinson's disease: from pathogenesis to therapeutic approaches

Cited by 45 publications

References 51 publications

Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease

Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease

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

Antioxidant Effect of Alpha-Lipoic Acid in 6-Hydroxydopamine Unilateral Intrastriatal Injected Rats

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