The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms

Abstract

The benzothiazepine CGP37157 has shown neuroprotective effects in several in vitro models of excitotoxicity involving dysregulation of intracellular Ca2+ homeostasis. Although its mechanism of neuroprotection is unclear, it is probably related with some of its effects on Ca2+ homeostasis. CGP37157 is a well-known inhibitor of the mitochondrial Na+/Ca2+ exchanger (mNCX). However, it is not very specific and also blocks several other Ca2+ channels and transporters, including voltage-gated Ca2+ channels, plasma membrane Na+/Ca2+ exchanger and the Ca2+ homeostasis modulator 1 channel (CALHM1). In the present work, we have studied if CGP37157 could also induce changes in life expectancy. We now report that CGP37157 extends C. elegans lifespan by 10%–15% with a bell-shaped concentration-response, with high concentrations producing no effect. The effect was even larger (25% increase in life expectancy) in worms fed with heat-inactivated bacteria. The worm CGP37157 concentration producing maximum effect was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and was close to the IC50 for inhibition of the Na+/Ca2+ exchanger. CGP37157 also extended the lifespan in eat-2 mutants (a model for caloric restriction), suggesting that caloric restriction is not involved in the mechanism of lifespan extension. Actually, CGP37157 produced no effect in mutants of the TOR pathway (daf15/unc24) or the insulin/insulin-like growth factor-1 (IGF-1) pathway (daf-2), indicating that the effect involves these pathways. Moreover, CGP37157 was also ineffective in nuo-6 mutants, which have a defect in the mitochondrial respiratory chain complex I. Since it has been described that neuroprotection by this compound in cell cultures is abolished by mitochondrial inhibitors, this suggests that life extension in C. elegans and neuroprotection in cell cultures may share a similar mechanism involving mitochondria.

The Mitochondrial Targets of Neuroprotective Drug Vinpocetine on Primary Neuron Cultures, Brain Capillary Endothelial Cells, Synaptosomes, and Brain Mitochondria

“…This effect of vinpocetine is similar to that found with CGP-37157, a dedicated inhibitor of the mitochondrial Na + -dependent Ca 2+ release [25]. CGP-37157 has neuroprotective effects [45]. Inhibition of ion channels is also in the spectrum of vinpocetine, e.g.…”

The Mitochondrial Na+/Ca2+ Exchanger Inhibitor CGP37157 Preserves Muscle Structure and Function to Increase Lifespan and Healthspan in Caenorhabditis elegans

“…We have reported previously that CGP37157 increased lifespan in eat-2(ad1113) mutants (caloric restriction mimetic), but it produced no effect in daf-2(e1370) mutants (insulin/IGF-1 receptor), nuo-6(qm200) mutants (mitochondrial respiratory chain complex I mutant) and daf-15(m81)/unc-24(e138) mutants (mTOR regulatory protein Raptor mutant) ( García-Casas et al, 2019 ). Therefore, its effects on longevity are somehow mediated by the insulin/IGF-1 and mTOR pathways, and require functional mitochondrial respiratory chain.…”

“…We have reported recently that CGP37157 extends lifespan on C. elegans worms with a bell-shaped concentration–response, so that the effect was obtained at submaximal concentrations, with higher doses producing no effect ( García-Casas et al, 2019 ). The actual target responsible for the lifespan effect in C. elegans is unknown, in part because the diversity of Na + /Ca 2+ exchanger isoforms is much greater in C. elegans .…”

“…Finally, as for the mechanism underlying the effects of CGP37157 on C. elegans lifespan, we have described that the effect disappeared in mutants of the mitochondrial respiratory chain ( nuo-6 ), the TOR pathway ( daf-15 ) and the insulin/IGF1 pathway ( daf-2 ) ( García-Casas et al, 2019 ), but further work was required to clarify the pathways involved. We have extended here this study by using mutants of aak-1;aak-2 /AMP-activated kinase, sir-2.1 /sirtuin, rsks-1 /S6 kinase and daf-16 /FOXO.…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…CGP37157, an inhibitor of the mitochondrial Na + /Ca 2+ exchanger that has shown neuroprotective activity in several experimental models of neurotoxicity [109,110], was recently reported to be able to increase C. elegans lifespan by a mechanism that required functional mitochondria, because the effect disappeared in the nuo-6 mitochondrial complex I mutant strain [111].…”