The Mitochondrial Targets of Neuroprotective Drug Vinpocetine on Primary Neuron Cultures, Brain Capillary Endothelial Cells, Synaptosomes, and Brain Mitochondria

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.

Vinpocetine and Ischemic Stroke

“…VPN inhibits voltage gated sodium channels leading to dose dependent reduction of intracellular concentrations of Na and Ca. Thus, the neuroprotective effect of VPN during IS is chiefly mediated by inhibition of neuronal voltage gated sensitive Na-channel [16].…”

“…Therefore, antioxidant mechanisms of VPN are related to direct free radical scavenging effect, potentiating of endogenous antioxidant capacity and inhibition the generation of free radicals. The molecular antioxidant effect of VPN is linked to the suppression of ADP stimulated respiration, mitochondrial Na+/Ca+ exchange, mitochondrial swelling and regulation of mitochondrial membrane potentials [16,27].…”

Role of vinpocetine in ischemic stroke and poststroke outcomes: A critical review

“…Thus, the neuroprotective effect of VPN during IS is chiefly mediated by inhibition of neuronal voltage-gated sensitive Na-channel. [16] Different studies illustrated that oxidative stress, excitotoxicity, and impaired energy metabolism leading to neuronal death by both apoptosis and necrosis during IS. These events lead to reduction of cAMP system which is important in the expression and regulation of brain-derived neurotrophic factor (BDNF), which improves neuronal survival.…”

“…The molecular antioxidant effect of VPN is linked to the suppression of ADP stimulated respiration, mitochondrial Na+/Ca+ exchange, mitochondrial swelling, and regulation of mitochondrial membrane potentials. [29,30] Anti-inflammatory effects of vinpocetine in ischemic stroke I S -i n d u c e d i n f l a m m a t o r y c h a n g e s a n d neuroinflammations lead to secondary brain damage. Toll-like receptors (TLRs) are overexpressed in IS, leading to the induction of the release of pro-inflammatory m e d i a t o r s t h r o u g h m y e l o i d d i f f e r e n t i a t i o n factor-88 (MyD88)-dependent pathway and Toll/IL-IR domain-containing adaptor factor protein inducing interferon-beta (TRIF)-dependent pathway.…”

Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale

“…Discovered in the 1970s by C. Szántay and C. Lörincz et al independently, vinpocetine has been approved in European countries for the treatment of dementia and stroke for over 30 years, and it is available in the United States as a dietary supplement [225]. Preclinical data demonstrate that vinpocetine can rescue cognitive deficits in a rodent AD model [226], increase CREB phosphorylation [227] and BDNF expression [228], downregulate BACE1 [226], upregulate Nrf2 mRNA expression [229], decrease oxidative stress [226,[228][229][230][231][232][233][234][235][236][237][238][239], mitochondrial dysfunction [240,241], and apoptosis [230,239], inhibit GSK3␤ [226,228], NFκB [229,231,232,239,[242][243][244][245][246][247][248][249][250], and the NLPR3 inflammasome [243], decrease levels of pro-inflammatory cytokines IL-1␤ [226,229,231,232,236,…”