Genetic and pharmacological targeting of heat shock protein 70 in the mouse amygdala-kindling model

Eva-Lotta von Rüden, Fabio Wolf, Fabio Gualtieri, Michael Keck, Clayton R Hunt, Tej K Pandita, Heidrun Potschka

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Inflammatory responses involving Toll-like receptor signaling represent a key factor contributing to epileptogenesis. Thus, it is of particular interest to explore the relevance of Toll-like receptor ligands and modulators, like heat shock protein 70 (HSP70). Motivated by recent findings demonstrating an up-regulation of HSP70 in a model of epileptogenesis, we analyzed the consequences of genetic and pharmacological targeting of HSP70 expression in a mouse kindling paradigm. Lack of inducible HSP70 resulted in increased pre-kindling seizure thresholds. However, at threshold stimulation the deficiency promoted seizure spread as indicated by an increased seizure severity. Subsequent kindling stimulations elicited more severe seizures in knockout mice, whereas endogenous termination of seizure activity remained unaffected with duration of behavioral and electrographic seizure activity comparable to wildtype mice. Interestingly, HSP70 deficiency resulted in enhanced microglia activation in the CA1 region. Next, we assessed a pharmacological targeting approach aiming to promote HSP70 expression. Celastrol treatment had no impact on kindling progression, but reduced post-kindling seizure thresholds and enhanced microglia activation in CA1 and CA3. In conclusion, the findings from HSP70-knockout mice support a protective role of HSP70 with an impact on microglia activation and spread of seizure activity. Unexpectedly, Celastrol administration resulted in detrimental consequences. These findings should be considered as a warning about the general safety of Celastrol as a drug candidate. The impact of pathophysiological mechanisms on the quality of Celastrol effects requires comprehensive future studies exploring influencing factors. Moreover, alternate strategies to increase HSP70 expression should be further developed and validated.

Original languageEnglish (US)
JournalACS Chemical Neuroscience
DOIs
StateE-pub ahead of print - Nov 5 2018

Keywords

  • Celastrol
  • Hspa1a/ b
  • Toll-like receptor
  • epileptogenesis
  • microglia
  • seizure

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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