Effect of cognitive drugs on mitochondrial respiration and activity of electron transport chain complexes
Abstract
Drugs like 7-MEOTA (7-methoxytacrine), tacrine, memantine, galanthamine, donepezil, latrepirdine (Dimebon) and piracetam are currently being tested to treat patients suffering from neurodegenerative disorders especially Alzheimer's disease (AD). Most of them show reversible acetylcholinesterase-inhibiting activity, except for memantine, latrepirdine and piracetam.
Defects in mitochondrial metabolism and particularly of electron transport chain (ETC) may play a significant role in pathogenesis of AD; complex IV of ETC plays a major role in controlling of oxidative phosphorylation. We examined in vitro effects of pharmacologically different cognitive (7-MEOTA, memantine, galanthamine, donepezil) and nootropic drugs (latrepirdine, piracetam) on both mitochondrial enzyme activities (citrate synthase and complex IV of ETC) and respiration of isolated brain mitochondria.
High-resolution respirometry was used to determine respiratory rate driven by substrates of complex I or II of ETC. Results demonstrated no significant drug-induced changes in the activity of citrate synthase.
Significantly decreased activity of complex IV was observed for cognitive drugs and increased complex IV activity for nootropic drugs. Slight drug-induced decrease in rate of oxygen consumption was observed for galanthamine, memantine and donepezil, and slight increase for latrepirdine and memantine.
Our results support the view that modulation of mitochondrial functions may participate on therapeutic effects of cognitives and nootropics.