Celastrol Blocks Neuronal Cell Death and Extends Life in Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

There is substantial evidence that both inflammation and oxidative damage contribute to the pathogenesis of motor neuron degeneration in the G93A SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS). Celastrol is a natural product from Southern China, which exerts potent anti-inflammatory and antioxidative effects. It also acts potently to increase expression of heat shock proteins including HSP70. We administered it in the diet to G93A SOD1 mice starting at 30 days of age. Celastrol treatment significantly improved weight loss, motor performance and delayed the onset of ALS. Survival of celastrol-treated G93A mice increased by 9.4% and 13% for 2 mg/kg/day and 8 mg/kg/day doses, respectively. Cell counts of lumbar spinal cord neurons confirmed a protective effect, i.e. 30% increase in neuronal number in the lumbar spinal cords of celastrol-treated animals. Celastrol treatment reduced TNF-α, iNOS, CD40, and GFAP immunoreactivity in the lumbar spinal cord sections of celastrol-treated G93A mice compared to untreated G93A mice. TNF-α immunoreactivity co-localized with SMI-32 (neuronal marker) and GFAP (astrocyte marker). HSP70 immunoreactivity was increased in lumbar spinal cord neurons of celastrol-treated G93A mice. Celastrol has been widely used in treating inflammatory diseases in man, and is well tolerated; therefore, it may be a promising therapeutic candidate for the treatment of human ALS.

Firefly luciferase mutants as sensors of proteome stress

“…Indeed, results from compound screens have identified several PR that induce or prevent the heat shock response (Calamini et al, 2012;Westerheide and Morimoto, 2005). For instance, celastrol has been identified as an activator of heat shock response (Trott et al, 2008;Westerheide et al, 2004) and has been shown to protect neuronal cells against toxic effects of mutant Htt (Wang et al, 2005;Zhang and Sarge, 2007) or mutant SOD1 (Kiaei et al, 2005). Similarly, triptolide has been identified as an inhibitor of HSF1 and hence of heat shock response (Westerheide et al, 2006) and has been demonstrated to induce apoptosis in pancreatic cancer cells by reducing Hsp70 levels (Phillips et al, 2007).…”

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

“…Celastrol was identified in an NIH-sponsored drug screen aimed at identifying potential therapeutic compounds that could suppress a hallmark of neurodegenerative diseases, namely protein misfolding resulting in aggregation (Abbott 2002;Heemskerk et al 2002). Subsequently, celastrol was shown to be beneficial 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). Celastrol also exhibits potent anti-inflammatory and anti-oxidant properties in several animal models of inflammation and apoptosis to combat other aspects of neurodegenerative disease pathology (Allison et al 2001;Faust et al 2009;Kim et al 2009;Sharma et al 2015).…”

“…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).…”

“…Celastrol induces Hsps in neuronal cells (Chow and Brown 2007) and is neuroprotective in a number of animal models of neurodegenerative disease including ALS (Kiaei et al 2005), Parkinson's disease (Cleren et al 2005), polyglutamine expansion disease (Zhang and Sarge 2007), and Alzheimer's disease (Paris et al 2010). Celastrol also exhibits potent anti-inflammatory and antioxidant properties (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).…”

Celastrol Synergistically Enhances Temozolomide Cytotoxicity in Melanoma Cells

“…In the past decade, CEL has become the focus of numerous preclinical studies that have shown its potential for use in a wide range of conditions, from inflammatory diseases such as arthritis and Crohn's disease to neurologic diseases such as Alzheimer's and amyotrophic lateral sclerosis (14)(15)(16)(17). More recently, both in vitro and in vivo studies have yielded results suggesting that CEL may also be effective in the treatment of chemoresistant neoplasms including pancreatic cancer, glioma, and melanoma (18)(19)(20).…”