Sváb, Gergely and Dóczi, Judit and Gerencser, Akos A and Ambrus, Attila and Gallyas, Ferenc and Sümegi, Balázs and Tretter, László (2019) The Mitochondrial Targets of Neuroprotective Drug Vinpocetine on Primary Neuron Cultures, Brain Capillary Endothelial Cells, Synaptosomes, and Brain Mitochondria. Neurochemical Research, 44 (10). pp. 2435-2447. ISSN 0364-3190
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Abstract
Vinpocetine is considered as neuroprotectant drug and used for treatment of brain ischemia and cognitive deficiencies for decades. A number of enzymes, channels and receptors can bind vinpocetine, however the mechanisms of many effects' are still not clear. The present study investigated the effects of vinpocetine from the mitochondrial bioenergetic aspects. In primary brain capillary endothelial cells the purinergic receptor-stimulated mitochondrial Ca2+ uptake and efflux were studied. Vinpocetine exerted a partial inhibition on the mitochondrial calcium efflux. In rodent brain synaptosomes vinpocetine (30 μM) inhibited respiration in uncoupler stimulated synaptosomes and decreased H2O2 release from the nerve terminals in resting and in complex I inhibited conditions, respectively. In isolated rat brain mitochondria using either complex I or complex II substrates leak respiration was stimulated, but ADP-induced respiration was inhibited by vinpocetine. The stimulation of oxidation was associated with a small extent of membrane depolarization. Mitochondrial H2O2 production was inhibited by vinpocetine under all conditions investigated. The most pronounced effects were detected with the complex II substrate succinate. Vinpocetine also mitigated both Ca2+-induced mitochondrial Ca2+-release and Ca2+-induced mitochondrial swelling. It lowered the rate of mitochondrial ATP synthesis, while increasing ATPase activity. These results indicate more than a single mitochondrial target of this vinca alkaloid. The relevance of the affected mitochondrial mechanisms in the anti ischemic effect of vinpocetine is discussed.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: Semmelweis University (SE); Hungarian Brain Research Program [KTIA_13_NAP-A-III/6, 2017-1.2.1-NKP-2017-00002]; OTKAOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [K 112230]; Hungarian Higher Education Institution Excellence Program [FIKP 61822 64860 EATV, FIKP 61826 690289 EATV]; Hungarian Academy of SciencesHungarian Academy of Sciences [MTA TKI 02001] Funding text: Open access funding provided by Semmelweis University (SE). Authors are indebted to Christos Chinopoulos (Semmelweis University) for helping us in Ca2+ handling experiments on isolated mitochondria. Authors are also grateful to Katalin Takacs and Andrea Varnagy for the excellent technical assistance. This work was supported by the Hungarian Brain Research Program (KTIA_13_NAP-A-III/6 and 2017-1.2.1-NKP-2017-00002), OTKA (K 112230), Hungarian Higher Education Institution Excellence Program [FIKP 61822 64860 EATV and FIKP 61826 690289 EATV] and the Hungarian Academy of Sciences (MTA TKI 02001), all to Vera Adam-Vizi. Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary Buck Institute for Research on Aging, Novato, CA, United States Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, Pecs, Hungary Szentagothai Research Centre, University of Pecs, Pecs, Hungary Nuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences, Budapest, Hungary Export Date: 4 November 2019 CODEN: NERED Correspondence Address: Tretter, L.; Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, 37-47 Tuzolto Street, Hungary; email: tretter.laszlo@med.semmelweis-univ.hu |
| Uncontrolled Keywords: | Oxygen Consumption; Mitochondria; Reactive oxygen species; neuroprotection; vinpocetine; Atp synthesis; UNCOUPLING; Calcium induced calcium release; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 03 Dec 2019 10:52 |
| Last Modified: | 03 Dec 2019 10:52 |
| URI: | http://real.mtak.hu/id/eprint/104042 |
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