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

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.

HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes

“…The neuronal translocation of HMGB1 has been examined by several groups after ischemic [1,2], traumatic [3], and epileptic injuries [16,17]. All these works clearly showed the translocation of HMGB1 from nuclei to the extracellular space through the cytosolic compartment.…”

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

“…Moreover, HMGB1 modulates the expression level of glutamate metabolism‐associated enzymes in epilepsy‐related hyperexcitability, postulating that HMGB1 signaling contributes in the generation of epileptic seizures (Kaneko et al . ). A similar line of evidence was reported which documented the expression level of HMGB1 in epileptic and control group at an interval of 24 and 72 h. In a KA‐induced epilepsy model, the HMGB1 expression level in the epileptic group was lower as compared to control group ( p < 0.05) at 24 h and increased compared to the control group at 72 h ( p < 0.05).…”

“…Immunoprecipitation (IP) of neurons exposed to KA excitotoxicity revealed that HMGB1 was acetylated, phosphorylated and ubiquitinated, implicating that post-translational modifications after KA administration caused HMGB1 to dissociate from chromatin DNA and promoted its release into the extracellular setting. Moreover, HMGB1 modulates the expression level of glutamate metabolism-associated enzymes in epilepsy-related hyperexcitability, postulating that HMGB1 signaling contributes in the generation of epileptic seizures (Kaneko et al 2017). A similar line of evidence was reported which documented the expression level of HMGB1 in epileptic and control group at an interval of 24 and 72 h. In a KA-induced epilepsy model, the HMGB1 expression level in the epileptic group was lower as compared to control group (p < 0.05) at 24 h and increased compared to the control group at 72 h (p < 0.05).…”

HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction

“…High mobility group box 1 proteins are a family of DAMPs ( Lotze and Tracey, 2005 ), which are highly conserved non-histone nuclear proteins and contributes to the architecture of chromatin DNA ( Baxevanis and Landsman, 1995 ). HMGB1 acts as an inflammatory cytokine in response to epileptogenic insults ( Kaneko et al, 2017 ). HMGB1 acts as a pathogenic inflammatory response to mediate ranges of conditions such as epilepsy ( Maroso et al, 2010 ), septic shock ( Wang et al, 1999 ), ischemia ( Kim et al, 2006 ; Wang et al, 2015 ), TBI ( Okuma et al, 2012 ), PD ( Sasaki et al, 2016 ), AD ( Fujita et al, 2016 ), and MS ( Andersson et al, 2008 ).…”