Mitochondrial Na+/Ca2+ exchanger, a new target for neuroprotection in rat hippocampal slices.

We tested here the hypothesis that the pharmacological modulation of the mitochondrial Na(+)/Ca(2+) exchanger (mNCX) could be a new neuroprotective strategy to rescue stressed vulnerable neurons from death. We used rat hippocampal slices incubated with veratridine to cause neuronal death through a mechanism involving Na(+) and Ca(2+) overload. CGP37157 (CGP), an inhibitor of the mNCX, rescued veratridine vulnerable neurons from death, showing an EC(50) of 5 µM. This neuroprotection was associated to mitigation of veratridine-elicited overproduction of free radicals and to inhibition of the p38 MAPK-linked apoptotic pathway. These results suggest that the mNCX could become a new target to develop compounds with potential therapeutic neuroprotective actions in neurodegenerative diseases.

Mitochondrial Na+/Ca2+-exchanger blocker CGP37157 protects against chromaffin cell death elicited by veratridine.

Mitochondrial calcium (Ca(2+)) dyshomeostasis constitutes a critical step in the metabolic crossroads leading to cell death. Therefore, we have studied here whether 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP37157; CGP), a blocker of the mitochondrial Na(+)/Ca(2+)-exchanger (mNCX), protects against veratridine-elicited chromaffin cell death, a model suitable to study cell death associated with Ca(2+) overload. Veratridine produced a concentration-dependent cell death, measured as lactate dehydrogenase released into the medium after a 24-h incubation period. CGP rescued cells from veratridine-elicited death in a concentration-dependent manner; its EC(50) was approximately 10 microM, and 20 to 30 microM caused near 100% cytoprotection. If preincubated for 30 min and washed out for 3 min before adding veratridine, CGP still afforded significant cytoprotection. At 30 microM, CGP blocked the veratridine-elicited free radical production, mitochondrial depolarization, and cytochrome c release. At this concentration, CGP also inhibited the Na(+) and Ca(2+) currents by 50 to 60% and the veratridine-elicited oscillations of cytosolic Ca(2+). This drastic cytoprotective effect of CGP could be explained in part through its regulatory actions on the mNCX.