Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures

Iori, Valentina; Maroso, Mattia; Rizzi, Massimo; Iyer, Anand M.; Vertemara, Roberta; Carli, Mirjana; Agresti, A; Antonelli, Antonella; Bianchi, Marco E.; Aronica, Eleonora; Ravizza, Teresa; Vezzani, Annamaria

doi:10.1016/j.nbd.2013.03.006

Cited by 137 publications

(160 citation statements)

References 80 publications

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“…Previous studies have shown that KA treatment induces neuroinflammation and microglial activation through high mobility group box-1 (HMGB1) and its receptors for advanced glycation end products (RAGE). 21,22 We confirmed that hippocampal HMGB1 and RAGE expressions were increased at 2 h after KA treatment, and Iba-1 expression, which is upregulated upon microglial activation, was increased at 6 h after KA treatment ( Supplementary Figures S4a and b). The Iba-1 immunoreactivity was intense in dentate gyrus and CA3 regions of KAtreated mice (Supplementary Figure S4c) and was dramatically decreased in TonEBP ( þ / À ) mice (Figure 4).…”

Section: Resultssupporting

confidence: 63%

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

et al. 2014

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Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood-brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote ( þ / À ) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP ( þ / À ) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP ( þ / À ) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-jB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target.

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Section: Resultssupporting

confidence: 63%

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

et al. 2014

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“…Similarly, increased immunostaining for HMGB1 and its receptors, TLR4 and Receptor for Advanced Glycation Endproducts (RAGE), has been demonstrated in the brain tissue of mice following induction of both kainate-and bicuculline-induced acute seizures and kainate-induced chronic epilepsy [24,32]. Increased staining for HMGB1, TLR4 and RAGE, is detectable in an analogous pattern to that observed in mouse models of epilepsy in human hippocampal tissue obtained at surgery from patients with (2).…”

Section: Il-1β and Hmgb1 Expression In Seizuresmentioning

confidence: 65%

“…Similarly, selective inhibition of HMGB1 or TLR4 delays seizure onset and decreases seizure number and duration in both kainate-and bicuculline-induced acute seizure models and reduces the number of spontaneous epileptic seizures in the kainate model of chronic epilepsy [33]. Knock-out of TLR4 or RAGE is also anticonvulsant in kainate models of acute and chronic seizures [32]. Increased expression of IL-1β and HMGB1 in a variety of experimental models and clinical seizure disorders, in addition to their established pro-convulsant effects, provides evidence that targeting IL-1β and HMGB1 may prove successful in the treatment of epilepsy.…”

Section: Il-1β and Hmgb1 Exacerbate Seizuresmentioning

confidence: 99%

Epilepsy and the inflammasome: Targeting inflammation as a novel therapeutic strategy for seizure disorders

Edye¹,

Walker²,

Sills³

et al. 2014

Inflammasome

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Epilepsy is the most common serious brain disorder worldwide. Recent evidence from experimental models of epilepsy and clinical brain tissue from epilepsy surgery suggests inflammation may play a pathological role in this disorder. Activation of a multimolecular protein complex termed the ‘inflammasome’ occurs during inflammation to drive the innate immune response. Inflammasome activation, with release of inflammatory mediators including interleukin-1β and high-mobility group box-1, may play a crucial role in the development of epilepsy (epileptogenesis) after brain insult. Immunomodulatory drugs targeting the inflammasome pathway may represent a novel antiepileptogenic treatment strategy for epilepsy. This review summarises the current literature surrounding inflammasome activation and epilepsy.

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“…Pharmacologic antagonism of specific proinflammatory pathways activated in glia and neurons has been attempted in animals with acute or chronic seizures: the data showed a reduction of 50% -70% of seizure recurrence by targeting IL-1R1/TLR4 signaling or TNF-a/p55 receptors demonstrating a significant anti-ictogenic effect of such treatments (Vezzani et al 2011c;Balosso et al 2013;Iori et al 2013;Weinberg et al 2013). Pharmacological blockade of individual proinflammatory pathways after an epileptogenic injury and before epilepsy develops induced disease-modifying effects (e.g., neuroprotection, decreased frequency and severity of chronic seizures, reduced comorbidities) in animal models, although not preventing the onset of the disease (Vezzani et al 2013a,b;Rojas et al 2014).…”

Section: Immunity and Inflammation In Epilepsymentioning

confidence: 99%

Immunity and Inflammation in Epilepsy

Vezzani

Lang

Aronica

2015

Cold Spring Harb Perspect Med

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This review reports the available evidence on the activation of the innate and adaptive branches of the immune system and the related inflammatory processes in epileptic disorders and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities. Major challenges in this field remain: a better understanding of the key inflammatory pathogenic pathways activated in chronic epilepsy and during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. The relevance of this information for developing novel therapies will be highlighted.

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Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures

Cited by 137 publications

References 80 publications

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

Epilepsy and the inflammasome: Targeting inflammation as a novel therapeutic strategy for seizure disorders

Immunity and Inflammation in Epilepsy

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