title: Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells.
abstract: OBJECTIVE
  Neuroinflammatory processes have been implicated in the pathophysiology of seizure/epilepsy. High mobility group box 1 (HMGB1), a non-histone DNA binding protein, behaves like an inflammatory cytokine in response to epileptogenic insults. Kainic acid (KA) is an excitotoxic reagent commonly used to induce epilepsy in rodents. However, the molecular mechanism by which KA-induced HMGB1 affords the initiation of epilepsy, especially the role of extracellular HMGB1 in neurotransmitter expression, remains to be elucidated.
  
  
  METHODS
  Experimental early stage of epilepsy-related hyperexcitability was induced in primary rat neural cells (PRNCs) by KA administration. We measured the localization of HMGB1, cell viability, mitochondrial activity, and expression level of glutamate metabolism-associated enzymes.
  
  
  RESULTS
  KA induced the translocation of HMGB1 from nucleus to cytosol, and its release from the neural cells. The translocation is associated with post-translational modifications. An increase in extracellular HMGB1 decreased PRNC cell viability and mitochondrial activity, downregulated expression of glutamate decarboxylase67 (GAD67) and glutamate dehydrogenase (GLUD1/2), and increased intracellular glutamate concentration and major histocompatibility complex II (MHC II) level.
  
  
  CONCLUSIONS
  That a surge in extracellular HMGB1 approximated seizure initiation suggests a key pathophysiological contribution of HMGB1 to the onset of epilepsy-related hyperexcitability.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Colleen
authors.initials: C
authors.lastname: Pappas
authors.forename: Teresita
authors.initials: T
authors.lastname: Malapira
authors.forename: Fernando Ĺ
authors.initials: FĹ
authors.lastname: Vale
authors.forename: Naoki
authors.initials: N
authors.lastname: Tajiri
authors.forename: Cesar V
authors.initials: CV
authors.lastname: Borlongan
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D000949:Histocompatibility Antigens Class II; D007527:Isoenzymes; D018698:Glutamic Acid; D005969:Glutamate Dehydrogenase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D007608:Kainic Acid
keywords: Epilepsy; GABA; Glutamate; HMGB1; Kainic acid; Primary rat neural cells