Dimebon attenuates the Aβ-induced mitochondrial permeabilization

• Published in: Current Alzheimer research Vol. 11; no. 5; p. 422
• Main Authors: Shevtsova, Elena F, Vinogradova, Daria V, Kireeva, Elena G, Reddy, V Prakash, Aliev, Gjumrakch, Bachurin, Sergey O
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.01.2014
• Subjects: Amyloid beta-Peptides - pharmacology; Animals; Brain - ultrastructure; Calcium - metabolism; Calcium - pharmacology; Cyclosporine - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Indoles - chemistry; Indoles - pharmacology; Liver - ultrastructure; Male; Mitochondria - drug effects; Mitochondrial ADP, ATP Translocases - drug effects; Mitochondrial Membrane Transport Proteins - drug effects; Permeability - drug effects; Protein Conformation - drug effects; Rats; Rats, Wistar; Time Factors
• ISSN: 1875-5828
• DOI: 10.2174/1567205011666140505094808

The currently available experimental data supports the hypothesis that the neuroprotective effect of dimebon is related to the protection of the brain-mitochondria from neurodegeneration. In this study, the influence of dimebon on mitochondria was investigated to gain a better understanding of the neuroprotective effects of this drug. Here, we demonstrate that dimebon enhances the resistance of the isolated rat brain and liver mitochondria to the induction of mitochondrial permeability transition (MPT) by calcium ions even in the presence of atractyloside, a MPT pore (MPTP) opener, but is ineffective against atractyloside-induced mitochondria swelling. Unlike cyclosporine A (CsA), a MPTP inhibitor, Dimebon does not influence the adenine nucleotide translocase (ANT) conformational changes and is not able to prevent the MPT of de-energized mitochondria. Using three different assays, and using amyloid-β peptide for inducing mitochondrial toxicity, we show that the influence of dimebon on the calcium retention capacity (CRC) of mitochondria depends on the mode of calcium addition. No obvious influence of dimebon on CRC was observed under the conditions of calcium infusion in the pump mode but the increase of CRC of rat brain mitochondria was observed when calcium was added in the bolus mode; the addition of calcium in the single pulse mode led to the increase of the lag period of calcium efflux from mitochondria. From these studies it is shown that dimebon is effective against amyloid-β (Aβ) potentiated mitochondrial swelling and decrease of calcium retention capacity (CRC) of the brain mitochondria.