Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1

Hargitai, Judit; Lewis, Hannah C.; Boros, Imre; Rácz, Tı́mea; Fiser, András; Kurucz, István; Benjamin, Ivor J.; Vı́gh, László; Pénzes, Zoltán; Csermely, Péter; Latchman, David S.

doi:10.1016/s0006-291x(03)01254-3

Cited by 144 publications

(108 citation statements)

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“…Indeed, we have previously shown that pharmacological activation of the heat shock response and consequent elevation in levels of hsp70 and hsp90 by treatment with a hsp co-inducer, arimoclomol, can protect motoneurons in vivo in models of both acute injury-induced motoneuron degeneration as well as progressive motoneuron degeneration in the SOD1 mouse model of ALS [16][17]. Arimoclomol is also a potent hsp co-inducer under in vitro conditions and has been shown to act via activation of heat shock factor 1 (HSF-1), the main hsp transcription factor [18][19]. Similar hsp-inducing properties have been attributed to the active ingredient in a herbal medicine called celastrol.…”

Section: Introductionmentioning

confidence: 99%

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Kalmár¹,

Greensmith²

2009

Cellular and Molecular Biology Letters

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Abbreviations used: ALS -Amyotrophic Lateral Sclerosis; HSF-1 -heat shock factor-1; hsp -heat shock protein; HSR -heat shock response Research article ACTIVATION OF THE HEAT SHOCK RESPONSE IN A PRIMARY CELLULAR MODEL OF MOTONEURON NEURODEGENERATION -EVIDENCE FOR NEUROPROTECTIVE AND NEUROTOXIC EFFECTSBERNADETT KALMAR* and LINDA GREENSMITH Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United KingdomAbstract: Pharmacological up-regulation of heat shock proteins (hsps) rescues motoneurons from cell death in a mouse model of amyotrophic lateral sclerosis. However, the relationship between increased hsp expression and neuronal survival is not straightforward. Here we examined the effects of two pharmacological agents that induce the heat shock response via activation of HSF-1, on stressed primary motoneurons in culture. Although both arimoclomol and celastrol induced the expression of Hsp70, their effects on primary motoneurons in culture were significantly different. Whereas arimoclomol had survival-promoting effects, rescuing motoneurons from staurosporin and H 2 O 2 induced apoptosis, celastrol not only failed to protect stressed motoneurons from apoptosis under same experimental conditions, but was neurotoxic and induced neuronal death. Immunostaining of celastrol-treated cultures for hsp70 and activated caspase-3 revealed that celastrol treatment activates both the heat shock response and the apoptotic cell death cascade. These results indicate that not all agents that activate the heat shock response will necessarily be neuroprotective.

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Section: Introductionmentioning

confidence: 99%

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Kalmár¹,

Greensmith²

2009

Cellular and Molecular Biology Letters

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“…Arimoclomol is a co-inducer that acts by prolonging the binding of heat shock transcription factor HSF1, the master regulator of the heat shock response, to HSE elements in the promoter regions of stress-inducible genes resulting in prolonged transcription of Hsp genes (Hargitai et al 2003). In a mouse model of ALS, arimoclomol was found to improve motor performance and extend lifespan of SOD1 G93A transgenic mice (Kieran et al 2004;Kalmar et al 2008Kalmar et al , 2014McGoldrick et al 2013;Poppe et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Celastrol has shown therapeutic potential in a number of animal models of neurodegenerative diseases including ALS (Kiaei et al 2005), Parkinson's disease (Cleren et al 2005), polyglutamine disease (Zhang and Sarge 2007), and Alzheimer's disease (Paris et al 2010) and has the added benefit of being a potent anti-inflammatory and anti-oxidant (Allison et al 2001;Jung et al 2007;Faust et al 2009;Kim et al 2009;Venkatesha et al 2012;Wong et al 2012;Yang et al 2014;Sharma et al 2015). Arimoclomol is a co-inducer that amplifies the induction of Hsps, prolongs life and motor performance in an animal model of ALS (Hargitai et al 2003;Kieran et al 2004;Kalmar et al 2008Kalmar et al , 2014, and is currently in clinical trials on human patients (ClinicalTrials.gov identifier: NCT00706147). Coapplication of celastrol and arimoclomol represents a potential multitarget therapeutic strategy for the treatment of neurodegenerative diseases that could impact disease mechanisms, such as synaptic dysfunction, at early stages of disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Arimoclomol is a co-inducer of Hsps that prolongs the binding of activated HSF1 to heat shock elements (HSEs) in the promoter regions of heat shock genes (Hargitai et al 2003;Kieran et al 2004;Kalmar et al 2014). Interestingly, arimoclomol is currently in human clinical trials for ALS (ClinicalTrials.gov identifier: NCT00706147) and is well tolerated in ALS patients up to 300 mg/day (Genc and Ozdinler 2013).…”

Section: Introductionmentioning

confidence: 99%

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Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol

Deane

Brown

2016

Cell Stress and Chaperones

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“…Geranylgeranylacetone, an anti-ulcer agent, activates HSF1 in the cochlea and prevents acoustic injury in guinea pigs (Mikuriya et al 2005). Bimoclomol acts as a HSP co-inducer by prolonging the activation of HSF1 (Hargitai et al 2003). Recently, additional classes of synthetic small molecule modulators of HSF1 activity have been identified through a genetic screen in yeast (Neef et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Induction of Heat Shock Proteins by Hyperthermia and Noise Overstimulation in Hsf1 −/− Mice

Gong

Fairfield

Fullarton

et al. 2011

JARO

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Diverse cellular and environmental stresses can activate the heat shock response, an evolutionarily conserved mechanism to protect proteins from denaturation. Stressors activate heat shock transcription factor 1 (HSF1), which binds to heat shock elements in the genes for heat shock proteins, leading to rapid induction of these important molecular chaperones. Both heat and noise stress are known to activate the heat shock response in the cochlea and protect it from subsequent noise trauma. However, the contribution of HSF1 to induction of heat shock proteins following noise trauma has not been investigated at the molecular level. We evaluated the role of HSF1 in the cochlea following noise stress by examining induction of heat shock proteins in Hsf1 +/− control and Hsf1 −/− mice. Heat stress rapidly induced expression of Hsp25, Hsp47, Hsp70.1, Hsp70.3, Hsp84, Hsp86, and Hsp110 in the cochleae of wild-type and Hsf1 +/− mice, but not in Hsf1 −/− mice, confirming the essential role of HSF1 in mediating the heat shock response. Exposure to broadband noise (2-20 kHz) at 106 dB SPL for 2 h produced partial hearing loss. Maximal induction of heat shock proteins occurred 4 h after the noise. In comparison to heat stress, noise stress resulted in lower induced levels of Hsp25, Hsp70.1, Hsp70.3, Hsp86, and Hsp110 in Hsf1 +/− mice. Induction of these heat shock proteins was attenuated, but not completely eliminated, in Hsf1 −/− mice. These same noise exposure conditions induced genes for several immediate early transcription factors and maximum induction occurred earlier than for heat shock proteins. Thus, additional signaling pathways and transcriptional regulators that are activated by noise probably contribute to induction of heat shock proteins in the cochlea.

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Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1

Cited by 144 publications

References 23 publications

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol

Induction of Heat Shock Proteins by Hyperthermia and Noise Overstimulation in Hsf1 −/− Mice

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