Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures
Toll-like receptor 4 (TLR4) activation in neuron and astrocytes by High Mobility Group Box 1 (HMGB1) protein is a key mechanism of seizure generation. HMGB1 also activates the Receptor for Advanced Glycation Endproducts (RAGE), but it was unknown whether RAGE activation contributes to seizures or to...
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| Format: | Article |
| Language: | English |
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Elsevier
2013-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996113000946 |
| _version_ | 1828911032612945920 |
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| author | Valentina Iori Mattia Maroso Massimo Rizzi Anand M. Iyer Roberta Vertemara Mirjana Carli Alessandra Agresti Antonella Antonelli Marco E. Bianchi Eleonora Aronica Teresa Ravizza Annamaria Vezzani |
| author_facet | Valentina Iori Mattia Maroso Massimo Rizzi Anand M. Iyer Roberta Vertemara Mirjana Carli Alessandra Agresti Antonella Antonelli Marco E. Bianchi Eleonora Aronica Teresa Ravizza Annamaria Vezzani |
| author_sort | Valentina Iori |
| collection | DOAJ |
| description | Toll-like receptor 4 (TLR4) activation in neuron and astrocytes by High Mobility Group Box 1 (HMGB1) protein is a key mechanism of seizure generation. HMGB1 also activates the Receptor for Advanced Glycation Endproducts (RAGE), but it was unknown whether RAGE activation contributes to seizures or to HMGB1 proictogenic effects.We found that acute EEG seizures induced by 7 ng intrahippocampal kainic acid (KA) were significantly reduced in Rage−/− mice relative to wild type (Wt) mice. The proictogenic effect of HMGB1 was decreased in Rage−/− mice, but less so, than in Tlr4−/− mice.In a mouse mesial temporal lobe epilepsy (mTLE) model, status epilepticus induced by 200 ng intrahippocampal KA and the onset of the spontaneous epileptic activity were similar in Rage−/−, Tlr4−/− and Wt mice. However, the number of hippocampal paroxysmal episodes and their duration were both decreased in epileptic Rage−/− and Tlr4−/− mice vs Wt mice.All strains of epileptic mice displayed similar cognitive deficits in the novel object recognition test vs the corresponding control mice.CA1 neuronal cell loss was increased in epileptic Rage−/− vs epileptic Wt mice, while granule cell dispersion and doublecortin (DCX)-positive neurons were similarly affected. Notably, DCX neurons were preserved in epileptic Tlr4−/− mice.We did not find compensatory changes in HMGB1-related inflammatory signaling nor in glutamate receptor subunits in Rage−/− and Tlr4−/− naïve mice, except for ~20% NR2B subunit reduction in Rage−/− mice.RAGE was induced in neurons, astrocytes and microvessels in human and experimental mTLE hippocampi.We conclude that RAGE contributes to hyperexcitability underlying acute and chronic seizures, as well as to the proictogenic effects of HMGB1. RAGE and TLR4 play different roles in the neuropathologic sequelae developing after status epilepticus.These findings reveal new molecular mechanisms underlying seizures, cell loss and neurogenesis which involve inflammatory pathways upregulated in human epilepsy. |
| first_indexed | 2024-12-13T18:55:42Z |
| format | Article |
| id | doaj.art-d2976583e6974629ab7dd018e75dec79 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:55:42Z |
| publishDate | 2013-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-d2976583e6974629ab7dd018e75dec792022-12-21T23:34:49ZengElsevierNeurobiology of Disease1095-953X2013-10-0158102114Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizuresValentina Iori0Mattia Maroso1Massimo Rizzi2Anand M. Iyer3Roberta Vertemara4Mirjana Carli5Alessandra Agresti6Antonella Antonelli7Marco E. Bianchi8Eleonora Aronica9Teresa Ravizza10Annamaria Vezzani11Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, ItalyDepartment of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, ItalyDepartment of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, ItalyDepartment of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, The Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN)-Epilepsy Institute in the Netherlands Foundation, Heemstede, The NetherlandsDepartment of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, ItalyDepartment of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, ItalyDivision of Genetics and Cell Biology, San Raffaele Scientific Institute and University, Milan, ItalyDivision of Genetics and Cell Biology, San Raffaele Scientific Institute and University, Milan, ItalyDivision of Genetics and Cell Biology, San Raffaele Scientific Institute and University, Milan, ItalyDepartment of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, The Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN)-Epilepsy Institute in the Netherlands Foundation, Heemstede, The NetherlandsDepartment of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, ItalyDepartment of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy; Corresponding author at: Laboratory of Experimental Neurology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Via G. La Masa 19, 20123 Milano, Italy. Fax: +39 02 3546277.Toll-like receptor 4 (TLR4) activation in neuron and astrocytes by High Mobility Group Box 1 (HMGB1) protein is a key mechanism of seizure generation. HMGB1 also activates the Receptor for Advanced Glycation Endproducts (RAGE), but it was unknown whether RAGE activation contributes to seizures or to HMGB1 proictogenic effects.We found that acute EEG seizures induced by 7 ng intrahippocampal kainic acid (KA) were significantly reduced in Rage−/− mice relative to wild type (Wt) mice. The proictogenic effect of HMGB1 was decreased in Rage−/− mice, but less so, than in Tlr4−/− mice.In a mouse mesial temporal lobe epilepsy (mTLE) model, status epilepticus induced by 200 ng intrahippocampal KA and the onset of the spontaneous epileptic activity were similar in Rage−/−, Tlr4−/− and Wt mice. However, the number of hippocampal paroxysmal episodes and their duration were both decreased in epileptic Rage−/− and Tlr4−/− mice vs Wt mice.All strains of epileptic mice displayed similar cognitive deficits in the novel object recognition test vs the corresponding control mice.CA1 neuronal cell loss was increased in epileptic Rage−/− vs epileptic Wt mice, while granule cell dispersion and doublecortin (DCX)-positive neurons were similarly affected. Notably, DCX neurons were preserved in epileptic Tlr4−/− mice.We did not find compensatory changes in HMGB1-related inflammatory signaling nor in glutamate receptor subunits in Rage−/− and Tlr4−/− naïve mice, except for ~20% NR2B subunit reduction in Rage−/− mice.RAGE was induced in neurons, astrocytes and microvessels in human and experimental mTLE hippocampi.We conclude that RAGE contributes to hyperexcitability underlying acute and chronic seizures, as well as to the proictogenic effects of HMGB1. RAGE and TLR4 play different roles in the neuropathologic sequelae developing after status epilepticus.These findings reveal new molecular mechanisms underlying seizures, cell loss and neurogenesis which involve inflammatory pathways upregulated in human epilepsy.http://www.sciencedirect.com/science/article/pii/S0969996113000946AlarminCell lossDamage associated molecular patternDAMPGliaInflammation |
| spellingShingle | Valentina Iori Mattia Maroso Massimo Rizzi Anand M. Iyer Roberta Vertemara Mirjana Carli Alessandra Agresti Antonella Antonelli Marco E. Bianchi Eleonora Aronica Teresa Ravizza Annamaria Vezzani Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures Neurobiology of Disease Alarmin Cell loss Damage associated molecular pattern DAMP Glia Inflammation |
| title | Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures |
| title_full | Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures |
| title_fullStr | Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures |
| title_full_unstemmed | Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures |
| title_short | Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures |
| title_sort | receptor for advanced glycation endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures |
| topic | Alarmin Cell loss Damage associated molecular pattern DAMP Glia Inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996113000946 |
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