Effects of 1,4-dihydropyridine derivatives (cerebrocrast, gammapyrone, glutapyrone, and diethone) on mitochondrial bioenergetics and oxidative stress: a comparative study

Abstract

The potential protective action of 1,4-dihydropyridine derivatives (cerebrocrast, gammapyrone, glutapyrone, and diethone) against oxidative stress was assessed on mitochondrial bioenergetics, inner membrane anion channel (IMAC), Ca 2þ -induced opening of the permeability transition pore (PTP), and oxidative damage induced by the oxidant pair adenosine diphosphate (ADP)/Fe 2þ (lipid peroxidation) of mitochondria isolated from rat liver. By using succinate as the respiratory substrate, respiratory control ratio (RCR), ADP to oxygen ratio (ADP/O), state 3, state 4, and uncoupled respiration rates were not significantly affected by gammapyrone, glutapyrone, and diethone concentrations up to 100 mM. Cerebrocrast at concentrations higher than 25 mM depressed RCR, ADP/O, state 3, and uncoupled respiration rates, but increased three times state 4 respiration rate. The transmembrane potential (DC) and the phosphate carrier rate were also decreased. At concentrations lower than 25 mM, cerebrocrast inhibited the mitochondrial IMAC and partially prevented Ca 2þ -induced opening of the mitochondrial PTP, whereas gammapyrone, glutapyrone, and diethone were without effect. Cerebrocrast, gammapyrone, and glutapyrone concentrations up to 100 mM did not affect ADP/Fe 2þ -induced lipid peroxidation of rat liver mitochondria, while very low diethone concentrations (up to 5 mM) inhibited it in a dose-dependent manner, as measured by oxygen consumption and thiobarbituric acid reactive substances formation. Diethone also prevented DC dissipation due to lipid peroxidation initiated by ADP/Fe 2þ . It can be concluded that: none of the compounds interfere with mitochondrial bioenergetics at concentrations lower than 25 mM; cerebrocrast was the only compound that affected mitochondrial bioenergetics, but only for concentrations higher than 25 mM; at concentrations that did not affect mitochondrial bioenergetics (#25 mM), only cerebrocrast inhibited the IMAC and partially prevented Ca 2þ -induced opening of the PTP; diethone was the only compound that expressed antioxidant activity at very low concentrations (#5 mM). Cerebrocrast acting as an inhibitor of the IMAC and diethone acting as an antioxidant could provide effective protective roles in preventing mitochondria from oxidative damage, favoring their therapeutic interest in the treatment of several pathological situations known to be associated with cellular oxidative stress.

Comparative effects of three 1,4-dihydropyridine derivatives [OSI-1210, OSI-1211 (etaftoron), and OSI-3802] on rat liver mitochondrial bioenergetics and on the physical properties of membrane lipid bilayers: Relevance to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring

“…This assumption is supported by comparing the results obtained in this study (Figs. 2-4) with the results of identical experiments previously performed with OSI-1212 (cerebrocrast) [16], clearly showing that, at high concentrations (>25 M), like its isomer OSI-3802, has a significant effect on mitochondrial bioenergetics by affecting inner mitochondrial membrane permeability to cations. The influence of 3,5-dialkoxycarbonyl chain length of the 1,4-dihydropyridines on mitochondrial bioenergetics was previously reported for other DHP derivatives.…”

“…Thus, the calcium antagonist foridone (ryodipine, PP-1466), which possesses the same substituent in the position 4 as OSI-1212 (cerebrocrast) and its analogues studied herein, improves mitochondrial bioenergetics in the isolated rat mitochondria from the infarct zone of the heart as well as from relatively undamaged zone [14]. Moreover, we have shown OSI-1212 (cerebrocrast) ability to interact with rat skeletal, neuronal and hepatic mitochondria [15,16], to incorporate into mitochondrial membranes and to induce lipid membrane organization changes [17]. Mitochondria have also been considered as an essential intracellular target for OSI-1212 (cerebrocrast) neuroprotective actions [18,19].…”

Distinct effects of atypical 1,4‐dihydropyridines on 1‐methyl‐4‐phenylpyridinium‐induced toxicity

“…Recent data obtained from studies on isolated liver mitochondria are in good agreement with our results, since they have demonstrated that only lipophilic cerebrocrast but not amino acid-containing DHPs blocks the inner membrane anion channel, K þ /H þ antiporter, and partially prevented Ca 2þ -induced opening of the mitochondrial permeability transition pore. 28 One may suggest that cerebrocrast-induced neuroprotection in vivo experiments can be explained to a great extent by its regulatory properties at the level of mitochondrial processes. Mitochondria probably cannot be considered as the crucial target for glutapyrone and tauropyrone.…”

Protective effect of cerebrocrast on rat brain ischaemia induced by occlusion of both common carotid arteries

“…53 It was shown that cerebrocrast inhibited isolated rat liver mitochondria inner membrane anion channels and partially prevented Ca-induced opening of the mitochondrial PTP, thereby preventing excessive calcium accumulation inside mitochondria as well as inhibiting Cl À transport in the mitochondria. 54 It is As shown in a recent investigation (unpublished data), cerebrocrast at concentrations of 10 and 100 nM significantly inhibited T-type calcium channels. The increase of T-type calcium channel activity evoked a thalamo-cortical dysfunction.…”