Geldanamycin protects rat brain through overexpression of HSP70 and reducing brain edema after cerebral focal ischemia

Kwon, Hyung‐Min; Kim, Yun-Hee; Yang, Seung-In; Kim, Yong-Ju; Lee, Seung‐Hoon; Yoon, Byung‐Woo

doi:10.1179/174313208x289615

Cited by 30 publications

(33 citation statements)

References 27 publications

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“…In contrast to these findings, several groups including ours have found that 17AAG favors cell survival when treated transiently or with lower doses (Koga et al 2006, Kwon et al 2008, Wang et al 2011, Wen et al 2008, Yano et al 2008. Nonetheless, 17AAG's function in stroke has not been studied although its toxic precursor, geldanamycin, exerts beneficial effects in animal stroke models (Kwon et al 2008, Wen, Li, Zong, Yu et al 2013.…”

Section: Introductionmentioning

confidence: 80%

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Bradley

Zhao

Wang

et al. 2014

J. Cell Commun. Signal.

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Stress adaptation effect provides cell protection against ischemia induced apoptosis. Whether this mechanism prevents other types of cell death in stroke is not well studied. This is an important question for regenerative medicine to treat stroke since other types of cell death such as necrosis are also prominent in the stroke brain apart from apoptosis. We report here that treatment with 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, protected neural progenitor cells (NPCs) against oxygen glucose deprivation (OGD) induced cell death in a dose dependent fashion. Cell death assays indicated that 17AAG not only ameliorated apoptosis, but also necrosis mediated by OGD. This NPC protection was confirmed by exposing cells to oxidative stress, a major stress signal prevalent in the stroke brain. Mechanistic studies demonstrated that 17AAG activated PI3K/Akt and MAPK cell protective pathways. More interestingly, these two pathways were activated in vivo by 17AAG and 17AAG treatment reduced infarct volume in a middle cerebral artery occlusion (MCAO) stroke model. These data suggest that 17AAG protects cells against major cell death pathways and thus might be used as a pharmacological conditioning agent for regenerative medicine for stroke.

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Section: Introductionmentioning

confidence: 80%

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Bradley

Zhao

Wang

et al. 2014

J. Cell Commun. Signal.

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“…The existing research focuses on the application of GA in cerebral ischemia and brain hemorrhage (Kwon et al 2008;Lu et al 2002;Manaenko et al 2010). These studies collectively determined that Hsp70 induction by GA represses expression of pro-inflammatory markers, reduces infarct size, and downregulates apoptotic pathways in stroke and hemorrhage.…”

Section: Role For Hsps In Therapy and Hsp70-inducing Pharmaceuticalsmentioning

confidence: 99%

Anti-inflammatory properties and pharmacological induction of Hsp70 after brain injury

Kim

Yenari

2012

Inflammopharmacol

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The 70-kDa heat shock protein (Hsp70) is thought to protect the brain from a variety of insults. Although the mechanism has been largely limited to its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory pathways. Brain injury and ischemia are associated with an immune response that is largely innate. Hsp70 appears to suppress this response and lead to improved neurological outcome. However, most of this work has relied on the use of genetic mutant models or Hsp70 overexpression using gene transfer or heat stress, thus limiting its translational utility. A few compounds have been studied by various disciplines which, through their ability to inhibit Hsp90, can cause induction of Hsp70. The investigation of Hsp70-inducing pharmacological compounds has obvious clinical implications in terms of potential therapies to mitigate neuroinflammation and lead to neuroprotection from stroke or traumatic brain injury. This review will focus on the inflammation modulating properties of Hsp70, and the current literature surrounding the pharmacological induction in acute neurological injury models with comments on potential applications at the clinical level.

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“…Geldanamycin has been shown to induce apoptosis [1,5,6,8,9,10,15,20,21,22,23], an effect paralleled by altered gene expression, downregulation of Akt, p38 MAPK activation, mitochondrial depolarization, reactive oxygen species formation, decline of reduced glutathion, lipid peroxidation and caspase activation [5,9,15,20,21]. On the other hand, geldanamycin may counteract neuronal injury, an effect attributed to destabilization of RIP1 protein [4,7,24]. …”

Section: Introductionmentioning

confidence: 99%

“…The benzoquinone ansamycin antibiotic geldanamycin has been shown to inhibit heat shock protein Hsp90 [1,2,3,4,5,6,7,8,9,10,11,12], which prevents stress-induced cellular damage [2], stabilizes various oncogenic kinases [1,7,9,10,12] and influences gene expression e.g. by up-regulating NF-κB [13,14].…”

Section: Introductionmentioning

confidence: 99%

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

Jilani

Qadri

Läng

2013

Cell Physiol Biochem

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Background/aims: Geldanamycin, a benzoquinone ansamycin antibiotic, and its analogues induce apoptosis of tumor cells and are thus considered for the treatment of cancer. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca²⁺-concentration ([Ca²⁺]_i) and formation of ceramide. The present study explored, whether geldanamycin modifies [Ca²⁺]_i, ceramide formation, cell volume and phosphatidylserine abundance at the erythrocyte surface. Methods: Erythrocyte volume was estimated from forward scatter, phosphatidylserine-abundance from annexin V binding, hemolysis from hemoglobin release, ceramide formation from binding of fluorescent antibodies and [Ca²⁺]_i from Fluo3-fluorescence. Results: A 48 hours exposure to geldanamycin significantly decreased forward scatter (≥ 5 µM), significantly increased annexin-V-binding (≥ 25 µM), but did not significantly modify Fluo3-fluorescence (up to 50 µM). The annexin-V-binding following geldanamycin treatment was not significantly modified by removal of extracellular Ca²⁺ but was paralleled by significantly increased ceramide formation (50 µM). Conclusions: Geldanamycin stinulated eryptosis, an effect at least partially due to ceramide formation.

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Geldanamycin protects rat brain through overexpression of HSP70 and reducing brain edema after cerebral focal ischemia

Abstract: GA protects brain from focal ischemia and reduces edema. This may be due, at least in part, to GA overexpression of HSP70.

Cited by 30 publications

References 27 publications

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Anti-inflammatory properties and pharmacological induction of Hsp70 after brain injury

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

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