Geldanamycin induces heat shock proteins in brain and protects against focal cerebral ischemia

Aigang Lu, Ruiqiong Ran, Sophie Parmentier-Batteur, Alex Nee, Frank R Sharp

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

Geldanamycin (GA), a benzoquinone ansamycin, binds Hsp90 in vitro, releases heat shock factor (HSF1) and induces heat shock proteins (Hsps). Because viral and transgenic overexpression of Hsps protects cells against ischemia in vitro, we hypothesized that GA would protect brain from focal ischemia by inducing Hsps in vivo. Adult male Sprague-Dawley rats were subjected to 2-hour middle cerebral artery occlusions (MCAO) using the suture technique followed by 22-h reperfusions. GA or vehicle was injected into the lateral cerebral ventricles (i.c.v) 24 h before ischemia. Geldanamycin at 1 μg/kg decreased infarct volumes by 55.7% (p < 0.01) and TUNEL-positive cells by 30% in cerebral cortex. GA also improved behavioral outcomes (p < 0.01) and reduced brain edema (p < 0.05). Western blots showed that the 1 μg/kg GA dose induced Hsp70 and Hsp25 protein 8.2-fold and 2.7-fold, respectively, by 48 h following administration. Immunocytochemistry showed that GA induced Hsp70 in neurons and Hsp25 in glia and arteries in cortex, hippocampus, hypothalamus, and other brain regions. GA reduced co-immunoprecipitation of HSF1 with Hsp90 in brain tissue homogenates, promoted HSE-binding of HSF in brain nuclear extracts using gel shift assays, and increased luciferase reporter gene transcription for the Hsp70 promoter in PC12 cells. The data show that geldanamycin protects brain from focal ischemia and that this may be due, at least in part, to geldanamycin stimulation of heat shock gene transcription.

Original languageEnglish (US)
Pages (from-to)355-364
Number of pages10
JournalJournal of Neurochemistry
Volume81
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • Cerebral ischemia
  • Heat shock elements
  • Heat shock factors
  • Heat shock proteins
  • Stroke

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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