RT info:eu-repo/semantics/article
T1 The neuroprotector benzothiazepine CGP37157 extends lifespan in C. elegans worms
A1 García Casas, Paloma
A1 Arias del Val, Jessica
A1 Álvarez Illera, María Pilar
A1 Wojnicz, Aneta
A1 Ríos, Cristobal de los
A1 Fonteriz García, Rosalba Inés
A1 Montero Zoccola, María Teresa
A1 Álvarez Martín, Javier
K1 C. elegans
K1 CGP37157
K1 lifespan
K1 aging
K1 neuroprotection
K1 Ca2+ signaling
K1 mitochondria
K1 Na+/Ca2+ exchanger
K1 2415 Biología Molecular
AB 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 isabolished by mitochondrial inhibitors, this suggests that life extension in C. elegans and neuroprotection in cell cultures may share a similar mechanism involving mitochondria.
PB Frontiers
SN 1663-4365
YR 2019
FD 2019
LK https://uvadoc.uva.es/handle/10324/66090
UL https://uvadoc.uva.es/handle/10324/66090
LA eng
NO Frontiers in Aging Neuroscience, 2018, vol. 10, 440
NO Producción Científica
DS UVaDOC
RD 27-dic-2024