Neuroprotective profile of pyridothiazepines with blocking activity of the mitochondrial Na+/Ca2+ exchanger

Martínez-Sanz, Francisco J.; Lajarín-Cuesta, Rocío; González‐Lafuente, Laura; Moreno-Ortega, Ana J.; Punzón, Eva; Cano‐Abad, María F.; Rı́os, Cristóbal de los

doi:10.1016/j.ejmech.2015.12.043

Cited by 15 publications

(21 citation statements)

References 36 publications

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“…Therefore, we carry out a more physiological model of biological evaluation, defined by the use of rat hippocampal slices subjected to toxic stimuli related to AD, recording the ability of selected compounds to counteract the tissue damage. 17,50,63,80 In this preparation, neurons are surrounded by their natural environment, e.g. glia cells, extracellular matrix, etc.…”

Section: Resultsmentioning

confidence: 99%

Gramine Derivatives Targeting Ca²⁺ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

et al. 2016

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Section: Resultsmentioning

confidence: 99%

Gramine Derivatives Targeting Ca²⁺ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

et al. 2016

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“…) was synthesised at our laboratories as previously described (Martínez‐Sanz et al . ). All other chemicals used were of reagent grade from Merck and Panreac Química (Madrid, Spain).…”

Section: Methodsmentioning

confidence: 97%

The quantal catecholamine release from mouse chromaffin cells challenged with repeated ACh pulses is regulated by the mitochondrial Na⁺/Ca²⁺ exchanger

López-Gil

Nanclares

Méndez-López

et al. 2017

The Journal of Physiology

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Using caged-Ca photorelease or paired depolarising pulses in voltage-clamped chromaffin cells (CCs), various pools of secretory vesicles with different readiness to undergo exocytosis have been identified. Whether these pools are present in unclamped CCs challenged with ACh, the physiological neurotransmitter at the splanchnic nerve-CC synapse, is unknown. We have explored here whether an ACh-sensitive ready-release vesicle pool (ASP) is present in C57BL6J mouse chromaffin cells (MCCs). Single cells were fast perfused with a Tyrode solution at 37°C, and challenged with 12 sequential ACh pulses (100 μm, 2 s, every 30 s) plus a K pulse given at the end (75 mm K ). After the first 2-3 ACh pulses the amperometrically monitored secretory responses promptly decayed to a steady-state level of around 25% of the initial response. The last K pulse, however, overcame such decay. Repeated ACh pulses to voltage-clamped cells elicited non-desensitising nicotinic currents. Also, the [Ca ] transients elicited by repeated ACh pulses that were superimposed on a stable baseline elevation did not undergo decay. The novel blocker of the mitochondrial Na /Ca exchanger (mNCX) ITH12662 prevented the decay of secretion elicited by ACh pulses and delayed the rate of [Ca ] clearance. The experiments are compatible with the idea that C57BL6J MCCs have an ASP vesicle pool that is selectively recruited by the physiological neurotransmitter ACh and is regulated by the rate of Ca delivery from mitochondria to the cytosol, through the mNCX.

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“…CGP37157 is a very lipophilic drug, showing very poor water solubility (Pei et al, 2003; Martínez-Sanz et al, 2016). This property may difficult the accessibility and distribution of the drug in the worms.…”

Section: Methodsmentioning

confidence: 99%

The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms

García-Casas

Arias-del-Val

Alvarez-Illera

et al. 2019

Front. Aging Neurosci.

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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.

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Neuroprotective profile of pyridothiazepines with blocking activity of the mitochondrial Na+/Ca2+ exchanger

Cited by 15 publications

References 36 publications

Gramine Derivatives Targeting Ca²⁺ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

Gramine Derivatives Targeting Ca²⁺ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

The quantal catecholamine release from mouse chromaffin cells challenged with repeated ACh pulses is regulated by the mitochondrial Na⁺/Ca²⁺ exchanger

The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms

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Neuroprotective profile of pyridothiazepines with blocking activity of the mitochondrial Na+/Ca2+ exchanger

Cited by 15 publications

References 36 publications

Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

The quantal catecholamine release from mouse chromaffin cells challenged with repeated ACh pulses is regulated by the mitochondrial Na+/Ca2+ exchanger

The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms

Contact Info

Product

Resources

About

Gramine Derivatives Targeting Ca²⁺ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

Gramine Derivatives Targeting Ca²⁺ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

The quantal catecholamine release from mouse chromaffin cells challenged with repeated ACh pulses is regulated by the mitochondrial Na⁺/Ca²⁺ exchanger