Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy

Walker, Lauren; Frigerio, Federica; Ravizza, Teresa; Ricci, Emanuele; Tse, Karen; Jenkins, Rosalind E.; Sills, Graeme J.; Jorgensen, Andrea; Porcu, Luca; Thippeswamy, Thimmasettappa; Alapirtti, Tiina; Peltola, Jukka; Brodie, Martin J.; Park, Brian Kevin; Marson, Anthony G; Antoine, Daniel J.; Vezzani, Annamaria; Pirmohamed, Munir

doi:10.1172/jci92001

Cited by 84 publications

(72 citation statements)

References 57 publications

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“…Immunohistochemistry for IL-1β (1:200; Santa Cruz Biotechnology, Heidelberg, Germany), HMGB1 (1:1000; ABCAM, Cambridge, UK) and TLR4 (1:150; Santa Cruz Biotechnology, Heidelberg, Germany) was done as previously described in detail [30, 32, 33]. The IL-1β-immunostained area was measured in the whole temporal slice of the hippocampus (20X magnification).…”

Section: Methodsmentioning

confidence: 99%

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

et al. 2018

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Neuroinflammation is consistently found in many neurological disorders, but whether or not the inflammatory response independently affects neuronal network properties is poorly understood. Here, we report that intracerebroventricular injection of the prototypical inflammatory molecule lipopolysaccharide (LPS) in rats triggered a strong and long lasting inflammatory response in hippocampal microglia associated with a concomitant up-regulation of Toll-like receptor (TLR4) in pyramidal and hilar neurons. This, in turn, was associated with a significant reduction of the dendritic hyperpolarization-activated cyclic-AMP gated channel type 1 (HCN1) protein level while Kv4.2 channels were unaltered as assessed by western blot. Immunohistochemistry confirmed the HCN1 decrease in CA1 pyramidal neurons and showed that these changes were associated with a reduction of TRIP8b, an auxiliary subunit for HCN channels implicated in channel subcellular localization and trafficking. At the physiological level, this effect translated into a 50% decrease in HCN1-mediated currents (Ih) measured in the distal dendrites of hippocampal CA1 pyramidal cells. At the functional level, the band-pass filtering properties of dendrites in the theta frequency range (4-12 Hz) and their temporal summation properties were compromised. We conclude that neuroinflammation can independently trigger an acquired channelopathy in CA1 pyramidal cell dendrites that alters their integrative properties. By directly changing cellular function, this phenomenon may participate in the phenotypic expression of various brain diseases.

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Section: Methodsmentioning

confidence: 99%

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

et al. 2018

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“…HMGB1 also activates RAGE but the binding potency of each isoform for RAGE is yet to be known (Walker et al . ).…”

Section: Hmgb1 Post‐translational Modification and Receptor Systemmentioning

confidence: 97%

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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“…A paradigmatic example in this respect is High‐Mobility Group Box 1 (HMGB1) (Walker et al . ), which behaves as a ‘mechanistic’ biomarker, since it is directly involved in the pathogenesis of diseases for which it acts as a biomarker. This appears to be also the case of S100B.…”

Section: S100b As An Active Factor In Neural Injurymentioning

confidence: 99%

The S100B story: from biomarker to active factor in neural injury

Michetti

D’Ambrosi

Toesca

et al. 2018

Journal of Neurochemistry

273

238

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S100B is a Ca -binding protein mainly concentrated in astrocytes. Its levels in biological fluids (cerebrospinal fluid, peripheral and cord blood, urine, saliva, amniotic fluid) are recognized as a reliable biomarker of active neural distress. Although the wide spectrum of diseases in which the protein is involved (acute brain injury, neurodegenerative diseases, congenital/perinatal disorders, psychiatric disorders) reduces its specificity, its levels remain an important aid in monitoring the trend of the disorder. Mounting evidence now points to S100B as a Damage-Associated Molecular Pattern molecule which, when released at high concentration, through its Receptor for Advanced Glycation Endproducts, triggers tissue reaction to damage in a series of different neural disorders. This review addresses this novel scenario, presenting data indicating that S100B levels and/or distribution in the nervous tissue of patients and/or experimental models of different neural disorders, for which the protein is used as a biomarker, are directly related to the progress of the disease: acute brain injury (ischemic/hemorrhagic stroke, traumatic injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis), congenital/perinatal disorders (Down syndrome, spinocerebellar ataxia-1), psychiatric disorders (schizophrenia, mood disorders), inflammatory bowel disease. In many cases, over-expression/administration of the protein induces worsening of the disease, whereas its deletion/inactivation produces amelioration. This review points out that the pivotal role of the protein resulting from these data, opens the perspective that S100B may be regarded as a therapeutic target for these different diseases, which appear to share some common features reasonably attributable to neuroinflammation, regardless their origin.

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Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy

Cited by 84 publications

References 57 publications

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

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

The S100B story: from biomarker to active factor in neural injury

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