1,4-Dihydropyridines as Tools for Mitochondrial Medicine Against Oxidative Stress and Associated Metabolic Disorders

Author(s): Astrida Velena*, Neven Zarkovic, Vija Klusa, Linda Klimaviciusa, Jolanta Pupure, Brigita Vigante, Gunars Duburs

Journal Name: Current Organic Chemistry

Volume 21 , Issue 20 , 2017


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Abstract:

Background & Objective: Various 1,4-dihydropyridines (DHPs) could affect basic and cell-type specific mitochondrial functions in different way and at various extent either as protectors or as harmful compounds, depending on their lipophylicity and chemical modifications of the DHP nucleus. Hence, several DHPs may affect: 1) mitochondrial bioenergetics as well as enzymatic activities including electron transport chain reactions and organic acids consumption rate; 2) mitochondrial lipid peroxidation, production of reactive oxygen species and reactive nitrogen species; 3) antioxidant enzymes: glutathione-S-transferase, superoxide dismutase, catalase; 4) mitochondrial and cellular membranotropic and/or physico-chemical properties: incorporation into mitochondrial membrane, alteration of membrane lipid organization, thermotropic phase transition profile and membrane lateral heterogeneity; 5) chemo-osmotic processes (mitochondrial permeability transition, swelling/contraction/aggregation); 6) mitochondrial viability, protecting mitochondria against toxic effects of doxorubicin, MPP+, mixture of rotenone/oligomycin, etc.); 7) implication of some DHPs in the regulation of mitochondria-mediated heme biosynthetic pathways was checked also in respect to potential differences between their effects on normal and malignant cells. The effects of DHPs on mitochondria of different cellular origin (hepatic, cardiac, neuronal, brain, muscle) were observed.

Methodology: It were reported about several accepted and original methods used in the studies of mitochondrial bioenergetics (respiratory activity, respiratory control ratio – RCR and membrane potential), lipid peroxidation, detection of oxygen and nitrogen radical species, enzyme activity (activities of succinate-, malate-, glutamate-, NADH-dehydrogenases, δ(delta)-aminolevulinic acid synthetase), membrane physico-chemical properties.

Conclusion: DHPs could affect mitochondria solely as well as in combination with other drugs either for the enhancement or for the weakening of their mutual effects, or even being active as one of the essential parts of large complex molecules. Accordingly, bimodal effects on mitochondria (improvement or endangerment of mitochondrial functions) obtained by various DHPs are of high importance for the overall bioactivities of DHPs.

Keywords: 1, 4-Dihydropyridine(s) (DHP(s)), mitochondria, oxidative stress (OS), lipid peroxidation (LP), antioxidant(s) (AO(s)), bioenergetics, chemiosmotic processes, apoptosis.

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Article Details

VOLUME: 21
ISSUE: 20
Year: 2017
Published on: 23 October, 2017
Page: [2030 - 2043]
Pages: 14
DOI: 10.2174/1385272821666170207104206
Price: $58

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