Cystamine Inhibits Caspase Activity

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormally expended polyglutamine domain. There is no effective treatment for HD; however, inhibition of caspase activity or prevention of mitochondria dysfunction delays disease progression in HD mouse models. Similarly administration of cystamine, which can inhibit transglutaminase, prolonged survival of HD mice, suggesting that inhibition of transglutaminase might provide a new treatment strategy. However, it has been suggested that cystamine may inhibit other thiol-dependent enzymes in addition to transglutaminase. In this study we show that cystamine inhibits recombinant active caspase-3 in a concentration-dependent manner. At low concentrations cystamine is an uncompetitive inhibitor of caspase-3 activity, becoming a non-competitive inhibitor at higher concentrations. The IC 50 for cystaminemediated inhibition of caspase-3 activity in vitro was 23.6 M. In situ cystamine inhibited in a concentrationdependent manner the activation of caspase-3 by different pro-apoptotic agents. Additionally, cystamine inhibited caspase-3 activity to the same extent in cell lines stably overexpressing wild type tissue transglutaminase (tTG), a mutant inactive tTG, or an antisense for tTG, demonstrating that cystamine inhibits caspase activity independently of any effects it may have on the transamidating activity of tTG. Finally, treatment with cystamine resulted in a robust increase in the levels of glutathione. These findings demonstrate that cystamine may prolong neuronal survival and delay the onset of HD by inhibiting caspases and increasing the level of antioxidants such as glutathione.

Tissue transglutaminase-induced aggregation of α-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies

“…In our cellular model, the formation of ␣-synuclein aggregates was significantly reduced by CTM. Interestingly, in addition to its role as a tTGase inhibitor, CTM blocks caspase 3 activity and increases cellular glutathionine levels, suggesting that it may prolong neuronal survival (62). Based on these observations, CTM or a related compound with a similar mechanism of action would be a promising pharmacological tool to be tested in PD models.…”

Chronic Cystamine Treatment Inhibits Small Artery Remodelling in Rats

“…In animal models, cystamine has a neuroprotective effect [41], and β-mercaptoethanolamine is a registered drug used in the treatment of cystinosis and currently in trial for treatment of Huntington chorea [42]. Other actions of cystamine have also been reported, including interaction with matrix metalloproteinases, which are known to inhibit tTG activity [43], as well as inhibition of caspase 3 and antioxidant activity [44]. Cystamine has thus, in addition to its ability to inhibit tTG, multiple other actions in vivo, and cautious interpretation of the present results is needed.…”

“…The purpose of the present study was to test whether infusion of the tTG inhibitor cystamine is able to prevent inward remodelling in vivo. Cystamine is a substrate of transglutaminases that instead of enhancing the formation of cross-links binds covalently to the active site to act as a competitive inhibitor of tTG [22], although it also has other actions [23, 24]. Furthermore, we investigated whether cystamine would be able to inhibit outward remodelling, where the experiments with tTG knockout mice had indicated that this would not be inhibited [15].…”

Advanced Glycation End Products (AGEs) Induce Apoptosis via a Novel Pathway

“…TG is a therapeutic target for several neurodegenerative disorders. Cystamine, which inactivates TG, inhibits other thiol-dependent enzymes such as caspases (43) and thus plays an important role in AGE-mediated IL-8 release and cell death, which means that it might be an important therapeutic molecule in neuroprotection. Secretion of several proteolytic enzymes might also trigger AGE-mediated inflammatory responses.…”