Kainic Acid-Induced Excitotoxicity Leads to the Activation of Heat Shock Response.

Abstract

Heat shock response (HSR) which is regulated by heat shock factor 1 (HSF1) is the most important mechanism and the major regulator that prevents protein aggregation in neurodegenerative diseases. Excitotoxicity, which is the accumulation of excess glutamate in synaptic cleft, is observed in age-dependent neurodegenerative diseases and also in stroke, epilepsy, and brain trauma. Only a few studies in the literature show the link between excitotoxicity and HSR. In this study, we aimed to show the molecular mechanism underlying this link. We applied heat shock (HS) treatment and induced excitotoxicity with kainic acid (KA) in neuroblastoma (SHSY-5Y) and glia (immortalized human astrocytes (IHA)) cells. We observed that, only in SHSY-5Y cells, heat shock preconditioning increases cell survival after KA treatment. GLT-1 mRNA expression is increased as a result of KA treatment and HS due to the elevation of HSF1 binding to GLT-1 promoter which was induced by HSF1 phosphorylation and sumolation in SHSY-5Y cells. Additionally, glutamine synthetase and glutaminase expressions are increased after HS preconditioning in SHSY-5Y cells indicating that HS activates glutamate metabolism modulators and accelerates the glutamate cycle. In glia cells, we did not observe the effect of HS preconditioning. In summary, heat shock preconditioning might be protective against excitotoxicity-related cell death and degeneration.