Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration

Abstract

Mitochondria regulate cellular Ca(2+) oscillations, taking up Ca(2+) through its uniporter and releasing it through the mitochondrial sodium/calcium exchanger. The role of mitochondria in the regulation of Ca(2+) cycle has received much attention recently, as it is a central stage in neuronal survival and death processes. Over the last decades, the 4,1-benzothiazepine CGP37157 has been the only available blocker of the mitochondrial sodium/calcium exchanger, although it targets several other calcium transporters. We report the synthesis of 4,1-benzothiazepine derivatives with the goal of enhancing mitochondrial sodium/calcium exchanger blockade and selectivity, and the evaluation of their cytoprotective effect. The compound 4c presented an interesting neuroprotective profile in addition to an important blockade of the mitochondrial sodium/calcium exchanger. The use of this benzothiazepine could help to understand the physiological functions of the mitochondrial sodium/calcium exchanger. In addition, we hypothesize that a moderate blockade of the mitochondrial sodium/calcium exchanger would provide enhanced neuroprotection in neurons.

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

“…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.…”

“…[12][13][14][15] In this regard, our research group has reported several families of multi-target drugs since 2000, with the control of neuronal Ca 2+ homeostasis as the common target. [16][17][18][19] Many evidences support the idea that pharmacological modulation of Ca 2+ homeostasis within neurons could mitigate the neurotoxicity present in a neurodegeneration scenario, 20 as that neurons having NFT present high activity of Ca 2+ -dependent protease enzymes, 21 or that the presence of Aβ peptides elevates Ca 2+ concentrations in resting neurons, sensitizing them for apoptosis phenomena. [22][23] There is preclinical and clinical evidence that the blockade of voltage-gated Ca 2+ channels (VGCC) may attenuate dementia, since an excessive and prolonged Ca 2+ entry into the cytosol leads to neurodegeneration and neuronal loss.…”

The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms

“…CGP37157 was synthesized as previously described (Martínez-Sanz et al, 2015). γ-cyclodextrin was purchased from PanReac, Barcelona, Spain.…”

“…CGP37157 rescued neuronal death induced by veratridine in both chromaffin cells and rat hippocampal slices, with an EC 50 of 5–10 μM (Nicolau et al, 2009, 2010). It also protected rat hippocampal slices against glutamate or ischemia/reperfusion-elicited stress (González-Lafuente et al, 2012) and SH-SY5Y human neuroblastoma cells subjected to 70 mM K + stimulation (Martínez-Sanz et al, 2015). It has also been shown that CGP37157 protects primary cultures of rat cortical neurons during NMDA insults, probably through inhibition of voltage-dependent Ca 2+ channels (VDCCs; Ruiz et al, 2014).…”

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

“…These results indicate that the expression of CALHM1 seems to be necessary to induce pharmacological neuroprotection with CGP37157 ( Figure 3). As mentioned earlier [21], it has been reported that CGP37157 can block Ca 2+ flux through the mitochondrial sodium/calcium exchanger (mNCX), L-type VDCCs, the plasmalemmal sodium/calcium exchanger (pNCX), and voltage-gated sodium channels, being more selective at mNCX [28]. However, there is currently no experimental evidence in the literature that describes any alteration in the expression or functionality of mNCX, voltage-gated sodium channels, and L-type VDCC when CALHM1 is absent, so it should not affect the expression or function of these channels.…”