Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells

Yuji Kaneko, Colleen Pappas, Teresita Malapira, Fernando L. Vale, Naoki Tajiri, Cesar V. Borlongan

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Background/Aims: 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.

Original languageEnglish (US)
Pages (from-to)947-959
Number of pages13
JournalCellular Physiology and Biochemistry
Volume41
Issue number3
DOIs
StatePublished - May 1 2017
Externally publishedYes

Keywords

  • Epilepsy
  • GABA
  • Glutamate
  • HMGB1
  • Kainic acid
  • Primary rat neural cells

ASJC Scopus subject areas

  • Physiology

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