title: Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures.
abstract: 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 7ng 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 200ng 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.
authors.affiliation: Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iori
authors.forename: Mattia
authors.initials: M
authors.lastname: Maroso
authors.forename: Massimo
authors.initials: M
authors.lastname: Rizzi
authors.forename: Anand M
authors.initials: AM
authors.lastname: Iyer
authors.forename: Roberta
authors.initials: R
authors.lastname: Vertemara
authors.forename: Mirjana
authors.initials: M
authors.lastname: Carli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Agresti
authors.forename: Antonella
authors.initials: A
authors.lastname: Antonelli
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Teresa
authors.initials: T
authors.lastname: Ravizza
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004558:Electric Stimulation / Q000009:adverse effects; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D024243:HMGB1 Protein / Q000008:administration & dosage / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000172:deficiency; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
chemical_list: C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018690:Excitatory Amino Acid Agonists; D024243:HMGB1 Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007608:Kainic Acid
keywords: Alarmin; Cell loss; DAMP; Damage associated molecular pattern; Glia; Inflammation; Neurogenesis; Seizures; Toll-like receptor