Dimebon Attenuates the Aβ -Induced Mitochondrial Permeabilization
Elena F. Shevtsova, Daria V. Vinogradova, Elena G. Kireeva, V. Prakash Reddy, Gjumrakch Aliev and Sergey O.BachurinAffiliation:
Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia.
AbstractThe 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.
Alzheimer disease, brain and liver mitochondria, calcium retention capacity, dimebon, mitochondrial permeability transition (MPT).
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