Vinpocetine - NutraHacker Journal Club

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An update on vinpocetine: New discoveries and clinical implications

Vinpocetine, a derivative of the alkaloid vincamine, has been clinically used in many countries for treatment of cerebrovascular disorders such as stroke and dementia for more than 30 years. Currently, vinpocetine is also available in the market as a dietary supplement to enhance cognition and memory. Due to its excellent safety profile, increasing efforts have been put into exploring the novel therapeutic effects and mechanism of actions of vinpocetine in various cell types and disease models. Recent studies have revealed a number of novel functions of vinpocetine, including anti-inflammation, antagonizing injury-induced vascular remodeling and high-fat-diet-induced atherosclerosis, as well as attenuating pathological cardiac remodeling. These novel findings may facilitate the repositioning of vinpocetine for preventing or treating relevant disorders in humans.

Role of vinpocetine in cerebrovascular diseases

A cerebrovascular accident, or stroke, is defined as the abrupt onset of a neurological deficit, which can be due to ischemia. Cerebral ischemia is caused by a reduction in blood flow that thereby decreases cerebral metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of certain types of dementia. Vinpocetine, chemically known as ethyl apovincaminate, is a vinca alkaloid that exhibits cerebral blood-flow enhancing and neuroprotective effects. Non-clinical and clinical studies have suggested multiple mechanisms responsible for the beneficial neuroprotective effects of vinpocetine. As no significant side effects related to vinpocetine treatment have been reported, it is considered to be safe for long-term use. This vasoactive alkaloid is widely marketed as a supplement for vasodilation and as a nootropic for the improvement of memory. The present review focuses on studies investigating the role of vinpocetine in cerebrovascular diseases.

[Mechanism of action of vinpocetine]

Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Later studies in various laboratories confirmed the above effects and clearly demonstrated that vinpocetine offers significant and direct neuroprotection both under in vitro and in vivo conditions.

Vinpocetine is the forthcoming adjuvant agent in the management of COVID-19

Vinpocetine (VPN) is an alkaloid derivative of vincamine inhibits phosphodiesterase type 1 that increase cyclic guanosine monophosphate and cyclic adenosine monophosphate. VPN have anti-inflammatory and antioxidant effects with suppression release of pro-inflammatory cytokines. Moreover, VPN mitigates oxidative stress (OS) and inflammatory reactions through inhibition of mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, VPN may decrease hyper-inflammation-induced acute lung injury in COVID-19 through modulation of NF-κB pathway. Taken together, VPN has pulmonary and extra-pulmonary protective effects against COVID-19 through mitigation of OS and hyperinflammation. In conclusion, VPN has noteworthy anti-inflammatory and anti-oxidant effects through inhibition of NF-κB/MAPK signaling pathway so, it may reduce SARS-CoV-2-induced hyper inflammatory and OS.

Personalized medicine: Vinpocetine to reverse effects of GABRB3 mutation

Objective: To screen a library of potential therapeutic compounds for a woman with Lennox-Gastaut syndrome due to a Y302C GABRB3 (c.905A>G) mutation. Methods: We compared the electrophysiological properties of cells with wild-type or the pathogenic GABRB3 mutation. Results: Among 1320 compounds, multiple candidates enhanced GABRB3 channel conductance in cell models. Vinpocetine, an alkaloid derived from the periwinkle plant with anti-inflammatory properties and the ability to modulate sodium and channel channels, was the lead candidate based on efficacy and safety profile. Vinpocetine was administered as a dietary supplement over 6 months, reaching a dosage of 20 mg three times per day, and resulted in a sustained, dose-dependent reduction in spike-wave discharge frequency on electroencephalograms. Improved language and behavior were reported by family, and improvements in global impression of change surveys were observed by therapists blinded to intervention. Significance: Vinpocetine has potential efficacy in treating patients with this mutation and possibly other GABRB3 mutations or other forms of epilepsy. Additional studies on pharmacokinetics, potential drug interactions, and safety are needed.

Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine

Background: Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in the literature. Due to increasing use of dietary supplements in combination with conventional drugs, the risk of adverse effects is on the rise. As a preliminary step to predict a possibility of drug interaction during concomitant use of vinpocetine and conventional drugs, this study was carried out to evaluate the effects of vinpocetine on three main regulators of pharmacokinetic drug interactions namely, cytochromes P450 (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR). Methods: Inhibition of CYPs was evaluated by employing recombinant enzymes. The inhibition of P-gp was determined by calcein-AM uptake method in transfected and wild type MDCKII cells. Modulation of PXR activity was monitored through a reporter gene assay in HepG2 cells. Results: Vinpocetine showed a strong inhibition of P-gp (EC50 8 µM) and a moderate inhibition of recombinant CYP3A4 and CYP2D6 (IC50 2.8 and 6.5 µM) with no activity towards CYP2C9, CYP2C19 and CYP1A2 enzymes. In HLM, competitive inhibition of CYP3A4 (IC50 54 and Ki 19 µM) and non-competitive inhibition of CYP2D6 (IC50 19 and Ki 26 µM) was observed. Activation of PXR was observed only at the highest tested concentration of vinpocetine (30 µM) while lower doses were ineffective. Conclusion: Strong inhibition of P-gp by vinpocetine is indicative of a possibility of drug interactions by altering the pharmacokinetics of drugs, which are the substrates of P-gp. However, the effects on CYPs and PXR indicate that vinpocetine may not affect CYP-mediated metabolism of drugs, as the inhibitory concentrations are much greater than the expected plasma concentrations in humans.

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

Vinpocetine (VPN) is a synthetic ethyl-ester derivative of the alkaloid apovincamine from Vinca minor leaves. VPN is a selective inhibitor of phosphodiesterase type 1 (PDE1) that has potential neurological effects through inhibition of voltage-gated sodium channel and reduction of neuronal calcium influx. VPN has noteworthy antioxidant, anti-inflammatory, and anti-apoptotic effects with inhibitory effect on glial and astrocyte cells during and following ischemic stroke (IS). VPN is effective as adjuvant therapy in the management of epilepsy; it reduces seizure frequency by 50% in a dose of 2 mg/kg/day. VPN improves psychomotor performances through modulation of brain monoamine pathway mainly on dopamine and serotonin, which play an integral role in attenuation of depressive symptoms. VPN recover cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE1 with augmentation of cyclic adenosin monophosphate and cyclic guanosin monophosphate ratio, enhancement of cholinergic neurotransmission, and inhibition of neuronal inflammatory mediators. Therefore, VPN is an effective agent in the management of IS and plays an integral role in the prevention and attenuation of poststroke epilepsy, depression, and cognitive deficit through direct cAMP/cGMP-dependent pathway or indirectly through anti-inflammatory and antioxidant effects.

Vinpocetine suppresses pathological vascular remodeling by inhibiting vascular smooth muscle cell proliferation and migration

Abnormal vascular smooth muscle cell (SMC) activation is associated with various vascular disorders such as atherosclerosis, in-stent restenosis, vein graft disease, and transplantation-associated vasculopathy. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. However, its role in pathological vascular remodeling remains unexplored. Herein, we show that systemic administration of vinpocetine significantly reduced neointimal formation in carotid arteries after ligation injury. Vinpocetine also markedly decreased spontaneous remodeling of human saphenous vein explants in ex vivo culture. In cultured SMCs, vinpocetine dose-dependently suppressed cell proliferation and caused G1-phase cell cycle arrest, which is associated with a decrease in cyclin D1 and an increase in p27Kip1 levels. In addition, vinpocetine dose-dependently inhibited platelet-derived growth factor (PDGF)-stimulated SMC migration as determined by the two-dimensional migration assays and three-dimensional aortic medial explant invasive assay. Moreover, vinpocetine significantly reduced PDGF-induced type I collagen and fibronectin expression. It is noteworthy that PDGF-stimulated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), but not protein kinase B, was specifically inhibited by vinpocetine. Vinpocetine powerfully attenuated intracellular reactive oxidative species (ROS) production, which largely mediates the inhibitory effects of vinpocetine on ERK1/2 activation and SMC growth. Taken together, our results reveal a novel function of vinpocetine in attenuating neointimal hyperplasia and pathological vascular remodeling, at least partially through suppressing ROS production and ERK1/2 activation in SMCs. Given the safety profile of vinpocetine, this study provides insight into the therapeutic potential of vinpocetine in proliferative vascular disorders.

Vinpocetine (A comprehensive profile)

Vinpocetine (VIN) is a herbal supplement extracted from the periwinkle plant. It is a multi-action agent, which is used to treat various neurological disorders such as Alzheimer's and Parkinson's disease. Vinpocetine has also anti-inflammatory, analgesic, antioxidant property and treats various thinking and memory problems. Currently, vinpocetine is also available in the market as a dietary supplement to enhance cognition and memory. This profile explains the physicochemical properties, methods of preparation, content of related impurities and different spectroscopical behavior of vinpocetine. It also discusses the reported methods of analysis of the drug, which include Compendial Methods, Electrochemical Methods, Spectrophotometric Methods and Chromatographic Methods of analysis. Furthermore, this profile explains the stability of the drug subjected to stress conditions of acid, alkaline and photolytic degradation. In addition, the clinical applications of the drug, its uses, side effects, dosing information, pharmacokinetics and mechanism of action are also discussed.

Updates of Recent Vinpocetine Research in Treating Cardiovascular Diseases

Vinpocetine is a derivative of vincamine. It has been used to prevent and treat cerebrovascular disorders such as stoke and dementia, and remains widely available in dietary supplements that often marketed as nootropics. Due to its excellent safety profile at therapeutic dose regimen, vinpocetine has raised research interest in its new applications in various experimental disease models. Here we review recent studies that uncovered novel functions of vinpocetine in cardiovascular diseases, including atherosclerosis, obesity, neointimal hyperplasia, vasoconstriction, pathological cardiac remodeling and ischemia stroke. Molecular mechanisms underlined the protective effects of vinpocetine are also discussed. These novel findings may suggest a broadened usage of vinpocetine against relevant cardiovascular diseases in human.

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis

Purpose: Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Methods: Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. Results: We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Conclusions: Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.

[The role of vinpocetine in the treatment of cerebrovascular diseases based in human studies]

Introduction: It shows the importance of cerebrovascular diseases that they are the third main cause of death exceeded only by coronary artery diseases and cancer. Cerebral ischemia leads to irreversible brain damage, thereby it is important to rescue the hypoperfused areas. Patients without stroke but with chronic cerebral hypoperfusion can also benefit from the increasing of the cerebral blood flow. Methods: The aim of this review was to summarize the indications and the potential effects of vinpocetine in acute and chronic cerebrovascular diseases based on clinical studies. Results: There is no evidence that vinpocetine treatment is applicable in acute ischemic stroke, only few study with low patient number showed a slight but significant improvement in the patients conditions. In chronic cerebrovascular patients after single dose and long-term vinpocetine therapy, PET, TCD, SPECT and NIRS examinations showed increasing perfusion and elevated glucose and O 2 consumption of the examined areas, furthermore significant improvement of the rheologic factors was detected. A meta-analysis of international clinical studies showed a significant improvement in cognitive achievement in chronic stroke patients after oral therapy. Conclusion: The cited studies showed the potential multi-pharmacological effects of vinpocetine and its beneficial hemorheological potential. The drug also improves the blood flow and the metabolism of the affected brain areas. There is increasing evidence that vinpocetine improves the quality of life in chronic cerebrovascular patients.

Vinpocetine effects on cognitive impairments produced by flunitrazepam

The effects of pre-treatment with vinpocetine 40 mg, on flunitrazepam-induced impairment of memory, were studied in 8 normal volunteers. Tests of Critical Flicker Fusion Threshold, a Sternberg Memory Scanning Task, along with subjective ratings of drug action were used. Drug effects were found to be modest. Treatment with vinpocetine was associated with improvements in short-term memory processes.

Psychopharmacological effects of vinpocetine in normal healthy volunteers

Twelve healthy female volunteers received pre-treatments with vinpocetine 10, 20, 40 mg and placebo (t.d.s.) for two days according to a randomised, double-blind crossover design. On the third day of treatment and 1 h following morning dosage, subjects completed a battery of psychological tests including Critical Flicker Fusion (CFF), Choice Reaction Time (CRT), Subjective Ratings of Drug Effects (LARS) and a Sternberg Memory Scanning Test. No statistically significant changes from placebo were observed on CFF, CRT or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was found to be significantly improved following treatment with vinpocetine 40 mg when compared to placebo and results suggested a localised effect of the drug on the serial comparison stage of the reaction process.

Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine

The asymptomatic ischemic cerebrovascular disorders (AICVD) is an early manifestation of cerebrovascular disease. It is also known as latent insufficiency of the cerebrovascular circulation or as asymptomatic cerebrovascular disorders. Recently, the term subclinical disease, detected noninvasively, has been introduced by American Heart Association. The diagnosis is based on the following criteria: evidence of vascular risk factors; episodic nonspecific complaints without any focal cerebral symptoms; mild cognitive deficit, detected by neuropsychological tests; carotid ultrasonography often shows intimal-medial thickening, atherosclerotic plaques and carotid stenosis; CT and MRI occasionally reveal silent cerebral infarctions, white matter hyperintensities or cerebral atrophy; regional hypoperfusion above the ischemic threshold is also seen by rCBF measurements. Treatment of the AICVD, modifying the vascular risk factors and using neuroprotective agents, should be the cornerstone of primary prevention of ischemic stroke and cognitive decline, caused by cerebrovascular disorders. Vinpocetine has been found to interfere with various stages of the ischemic cascade: ATP depletion, activation of voltage-sensitive Na(+)- and Ca(++)-channels, glutamate and free radicals release. The inhibition of the voltage-sensitive Na(+)-channels appears to be especially relevant to the neuroprotective effect of vinpocetine. Pronounced antioxidant activity of the drug could also contribute to the neuroprotection. PET studies in primates and man showed that 11C labelled vinpocetine passes the blood-brain barrier rapidly. Heterogeneous brain distribution of the compound was observed mainly in the thalamus, basal ganglia, occipital, parietal and temporal cortex, regions which are closely related to the cognitive functions. PET studies in chronic ischemic stroke patients revealed favourable effects of vinpocetine on rCBF and glucose metabolism in the thalamus, basal ganglia and primary visual cortex. It seems, vinpocetine, affecting the multiple mechanisms of the AICVD, could be of benefit for the treatment in this early stage of cerebrovascular disease. Vinpocetine may also become a new therapeutic approach to prophylactic neuroprotection in patients at high risk of ischemic stroke.

The influence of hypoxia and prolonged exercise on attentional performance at high and extreme altitudes: A pilot study

Introduction: Exposure to hypoxic conditions is reported to impair cognitive performance. Further, moderate physical exercise improves cognitive function, but little is known about the influence of exercise on cognitive function in hypoxia. Therefore, the current study aimed to examine the influence of hypoxia (HYP) and prolonged exercise (EX) on attentional performance. Methods: A total of 80 participants (female: n = 29; male: n = 51) were assigned to four groups: HYP + EX (n = 15), HYP (n = 25), EX (n = 21) and normoxia (NOR) (n = 21). The Frankfurt Attention Inventory-2 (FAIR-2) was performed at four testing points (day 1, 14, 16 and 18) to assess attentional performance. All groups completed a pretest (D1) and a follow-up test (D18). In HYP + EX conditions, the cognitive task was performed in a hypoxic state after prolonged exercise (D14: 3950 m, D16: 5739 m) during a mountain climb on Mt. Kilimanjaro. Participants in HYP were tested under intermittent hypoxia at rest in a hypoxic chamber (D14: 3500 m, D16: 5800 m), and those in EX were tested under normoxia after prolonged exercise during a 7-day backcountry ski hiking tour. NOR was a control group, and participants completed all tests under normoxia and at rest. Results: Hypoxia impaired the attentional functions performance value (PV) and continuity value (CV) for the HYP + EX (p = 0.000) and HYP (L: p = 0.025; K: p = 0.043) groups at 5739 m and 5800 m, respectively, but not the function quality value (QV). In contrast, the EX group did not exhibit changes in attentional function. Conclusion: The current results suggest that attentional performance is impaired during extreme normobaric and hypobaric hypoxic exposure. We further conclude that greater cognitive impairment under hypobaric hypoxia during a mountain climb compared with normobaric hypoxia at rest is not caused by prolonged exercise, but may be influenced by other factors (e.g. low temperatures, dehydration, or sleep deprivation) that remain to be verified.

Normobaric Hypoxia and Submaximal Exercise Effects on Running Memory and Mood State in Women

Background: An acute bout of exercise can improve cognitive function in normoxic and hypoxic conditions. However, limited research supports the improvement of cognitive function and mood state in women. The purpose of this study was to examine the effects of hypoxia and exercise on working memory and mood state in women. Methods: There were 15 healthy women (age = 22 ± 2 yr) who completed the Automated Neuropsychological Assessment Metrics-4th Edition (ANAM), including the Running Memory Continuous Performance Task (RMCPT) and Total Mood Disturbance (TMD) in normoxia (21% O2), at rest in normoxia and hypoxia (12.5% O2), and during cycling exercise at 60% and 40% Vo2max in hypoxia. Results: RMCPT was not significantly impaired at 30 (100.3 ± 17.2) and 60 (96.6 ± 17.3) min rest in hypoxia compared to baseline in normoxia (97.0 ± 17.0). However, RMCPT was significantly improved during exercise (106.7 ± 20.8) at 60% Vo2max compared to 60 min rest in hypoxia. Following 30 (-89.4 ± 48.3) and 60 min of exposure to hypoxia (-79.8 ± 55.9) at rest, TMD was impaired compared with baseline (-107.1 ± 46.2). TMD was significantly improved during exercise (-108.5 ± 42.7) at 40% Vo2max compared with 30 min rest in hypoxia. Also, RMCPT was significantly improved during exercise (104.0 ± 19.1) at 60% Vo2max compared to 60 min rest in hypoxia (96.6 ± 17.3). Discussion: Hypoxia and an acute bout of exercise partially influence RMCPT and TMD. Furthermore, a moderate-intensity bout of exercise (60%) may be a more potent stimulant for improving cognitive function than low-intensity (40%) exercise. The present data should be considered by aeromedical personnel performing cognitive tasks in hypoxia.Seo Y, Gerhart HD, Stavres J, Fennell C, Draper S, Glickman EL. Normobaric hypoxia and submaximal exercise effects on running memory and mood state in women. Aerosp Med Hum Perform. 2017; 88(7):627-632.

Effect of acute hypoxia on cognition: A systematic review and meta-regression analysis

A systematic meta-regression analysis of the effects of acute hypoxia on the performance of central executive and non-executive tasks, and the effects of the moderating variables, arterial partial pressure of oxygen (PaO2) and hypobaric versus normobaric hypoxia, was undertaken. Studies were included if they were performed on healthy humans; within-subject design was used; data were reported giving the PaO2 or that allowed the PaO2 to be estimated (e.g. arterial oxygen saturation and/or altitude); and the duration of being in a hypoxic state prior to cognitive testing was ≤6days. Twenty-two experiments met the criteria for inclusion and demonstrated a moderate, negative mean effect size (g=-0.49, 95% CI -0.64 to -0.34, p<0.001). There were no significant differences between central executive and non-executive, perception/attention and short-term memory, tasks. Low (35-60mmHg) PaO2 was the key predictor of cognitive performance (R2=0.45, p<0.001) and this was independent of whether the exposure was in hypobaric hypoxic or normobaric hypoxic conditions.

Cognitive performance is associated with cerebral oxygenation and peripheral oxygen saturation, but not plasma catecholamines, during graded normobaric hypoxia

New findings: What is the central question of this study? What are the mechanisms responsible for the decline in cognitive performance following exposure to acute normobaric hypoxia? What are the main findings and their importance? We found that (1) performance of a complex central executive task (n-back) was reduced at FIO2 0.12; (2) there was a strong correlation between performance of the n-back task and reductions in SpO2 and cerebral oxygenation; and (3) plasma adrenaline, noradrenaline, cortisol and copeptin were not correlated with cognitive performance. Abstract: It is well established that hypoxia impairs cognitive function; however, the physiological mechanisms responsible for these effects have received relatively little attention. This study examined the effects of graded reductions in fraction of inspired oxygen ( FIO2 ) on oxygen saturation ( SpO2 ), cerebral oxygenation, cardiorespiratory variables, activity of the sympathoadrenal system (adrenaline, noradrenaline) and hypothalamic-pituitary-adrenal axis (cortisol, copeptin), and cognitive performance. Twelve healthy males [mean (SD), age: 22 (4) years, height: 178 (5) cm, mass: 75 (9) kg, FEV1 /FVC ratio: 85 (5)%] completed a four-task battery of cognitive tests to examine inhibition, selective attention (Eriksen flanker), executive function (n-back) and simple and choice reaction time (Deary-Liewald). Tests were completed before and following 60 min of exposure to FIO2 0.2093, 0.17, 0.145 and 0.12. Following 60 min of exposure, response accuracy in the n-back task was significantly reduced in FIO2 0.12 compared to baseline [82 (9) vs. 93 (5)%; P < 0.001] and compared to all other conditions at the same time point [ FIO2 0.2093: 92 (3)%; FIO2 0.17: 91 (6)%; FIO2 0.145: 85 (10)%; FIO2 12: 82 (9)%; all P < 0.05]. The performance of the other tasks was maintained. Δaccuracy and Δreaction time of the n-back task was correlated with both Δ SpO2 [r(9) = 0.66, P < 0.001 and r(9) = -0.36, P = 0.037, respectively] and Δcerebral oxygenation [r(7) = 0.55, P < 0.001 and r(7) = -0.38, P = 0.045, respectively]. Plasma adrenaline, noradrenaline, cortisol and copeptin were not significantly elevated in any condition or correlated with any of the tests of cognitive performance. These findings suggest that reductions in peripheral oxygen saturation and cerebral oxygenation, and not increased activity of the sympathoadrenal system and hypothalamic-pituitary-adrenal axis, as previously speculated, are responsible for a decrease in cognitive performance during normobaric hypoxia.

Enhanced oral bioavailability of vinpocetine through mechanochemical salt formation: physico-chemical characterization and in vivo studies

Purpose: Enhancing oral bioavailability of vinpocetine by forming its amorphous citrate salt through a solvent-free mechanochemical process, in presence of micronised crospovidone and citric acid. Methods: The impact of formulation and process variables (amount of polymer and citric acid, and milling time) on vinpocetine solubilization kinetics from the coground was studied through an experimental design. The best performing samples were characterized by employing a multidisciplinary approach, involving Differential scanning calorimetry, X-ray diffraction, Raman imaging/spectroscopy, X-ray photoelectron spectroscopy, solid-state NMR spectroscopy, porosimetry and in vivo studies on rats to ascertain the salt formation, their solid-state characteristics and oral bioavailability in comparison to vinpocetine citrate salt (Oxopocetine(®)). Results: The analyses attested that the mechanochemical process is a viable way to produce in absence of solvents vinpocetine citrate salt in an amorphous state. Conclusion: From the in vivo studies on rats the obtained salt was four times more bioavailable than its physical mixture and bioequivalent to the commercial salt produced by conventional synthetic process implying the use of solvent.

Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-κB activation in the paw and spinal cord

Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone (PBQ) and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH) levels, superoxide anion, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels, as well as nuclear factor kappa B (NF-κB) activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases), as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL-1β and TNF-α levels; and NF-κB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-κB activation at both peripheral and spinal cord levels.

Vinpocetine: nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a step-through passive avoidance response in rats

Vinpocetine, vincamine, aniracetam, and Hydergine, compounds with purported cognition activating activity, were evaluated for their ability to prevent scopolamine-induced and hypoxia-induced impairment of passive avoidance retention (24 hr) in rats. Vinpocetine (peak effect dose [PED]= 200 mg/kg PO), aniracetam (PED = 100 mg/kg PO), vincamine (PED = 30 mg/kg PO), and Hydergine (PED = 1 mg/kg PO) prevented memory disruption by scopolamine. Vinpocetine (PED = 3 mg/kg PO) and aniracetam (PED = 30 mg/kg PO) were also effective in preventing disruption of passive avoidance retention impaired by 7% oxygen hypoxia. In contrast, Hydergine (0.05 to 3 mg/kg PO) and vincamine (0.3 to 100 mg/kg PO) were not effective against hypoxia-induced impairment. Hydergine at doses greater than 10 mg/kg PO markedly impaired motor function. In both tests the protection was dose-related for all test substances in an inverted U-shaped manner. Mecamylamine (1, 3, 10 mg/kg SC), (-)-nicotine (0.1 to 0.4 mg/kg SC), apovincaminic acid (1-400 mg/kg PO) and pemoline (1-100 mg/kg PO) did not protect against memory impairment induced by either procedure. These data support the view that vinpocetine, a compound chemically distinct from the pyrrolidinones, has a cognitive activating ability as defined in models of both scopolamine-induced and hypoxia-induced memory impairment in rats.

Vinpocetine enhances retrieval of a step-through passive avoidance response in rats

Vinpocetine, vincamine, apovincaminic acid, vinconate, aniracetam, Hydergine, and pemoline were evaluated for their ability to enhance retrieval of a step-through passive avoidance response in rats. The percentage of rats performing the avoidance response was found to decrease as a function of the number of days between training and retention testing (Day 1, 100%; Day 2, 65%; Day 3, 23%; Days 4 and 5, 0%). Vinpocetine administered 60 minutes prior to testing for retention significantly increased the number of rats performing the passive avoidance response. Retrieval enhancement was dose-related in an inverted U-shaped function with the effective doses at 18 and 30 mg/kg PO. In contrast, apovincaminic acid (1-400 mg/kg PO), vincamine (1-200 mg/kg PO), vinconate (1-200 mg/kg PO), aniracetam (1-300 mg/kg PO), Hydergine (0.1-10 mg/kg PO), and pemoline (1-30 mg/kg PO) were not effective. These data support the view that vinpocetine has cognition-activating abilities as defined in an animal model of memory retrieval.

Vinpocetine regulates levels of circulating TLRs in Parkinson's disease patients

Background: The pathogenesis of Parkinson's disease (PD) is complex; it includes mitochondrial dysfunction, oxidative stress, and neuroinflammation. Notably, Toll-like receptors (TLRs) may activate inflammatory or anti-inflammatory responses in Parkinson's disease. Vinpocetine has been tested as an anti-inflammatory in both animal and in vitro research. Thus, it is important to test whether the anti-inflammatory properties of vinpocetine may have a protective effect in PD patients. Methods: Eighty-nine Parkinson's disease patients and 42 healthy controls were recruited for this study. All patients were randomly assigned to either the traditional therapy group (T PD group, n = 46) or the vinpocetine group (V PD group, n = 43), in a blinded manner. Both treatments were administered for 14 days. Results: Administration of vinpocetine reduced mRNA levels of TLR2/4, as well as protein levels of the downstream signalling molecules, MyD88 and NF-κB; moreover, it lowered the expression levels of serum inflammatory cytokines, TNF-α and MCP-1. Notably, vinpocetine increased TLR3 mRNA levels, as well as protein levels of the downstream signalling molecules TRIF-β and IRF-3, and serum levels of the anti-inflammatory cytokines IL-10 and IL-8. Furthermore, vinpocetine produced a robust increase in the Mini Mental State Examination score, compared to that achieved by using levodopa therapy. Conclusion: Vinpocetine treatment may exhibit anti-inflammatory activity and alleviate cognitive impairment.

[Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions]

Introduction: Vinpocetine has been widely used in the treatment of ischaemic cerebrovascular diseases and dementias of vascular type. Chronic cerebral hypoperfusion plays an important role in the development of certain types of dementia. In consequence of complex mode of action vinpocetine plays a significant role in the improvement of cerebral hypoperfusion. The symptoms of mild cognitive impairment considered as "predementia" are similar to those of dementia, although milder. Aims: The authors investigated the characteristics of the blood flow parameters of patients with ischemic stroke and mild cognitive impairment both in resting conditions or following chemical stimulus as well as they investigated the severity of mental deterioration in the two patient groups. In a pilot study the authors examined the influence of 12-week long oral vinpocetine therapy on the blood flow parameters and cognitive functions in the two patient groups. Methods: The authors studied the blood flow velocity of a. cerebri media in resting conditions and after 30 sec of breath holding with transcranial Doppler before treatment and after a 12-week long oral vinpocetine treatment. At the same time psychometric tests (MMSE, ADAS-Cog) were used in order to examine cognitive functions, while the general condition of the patients were scored by Clinical Global Impression (CGI) scale. Results: After a 12-week long oral vinpocetine treatment the increase of blood flow velocity in resting conditions compared to the baseline values was significant in the vascular group. The percent increase of mean velocity after the breath holding TCD test showed a significant increase compared to the baseline in both patient groups. The authors found a significant improvement of cognitive functions after a 12-week long oral vinpocetine therapy using psychometric tests. The improvement was identical in both groups. The general condition of patients improved significantly according to both the investigator's and the patients' opinion; patients with mild cognitive impairment judged the improvement higher. Conclusions: Vinpocetine improved the cerebrovascular reserve capacity in both patient groups and favourably influenced the cognitive status and general condition of patients with chronic hypoperfusion. The authors recommend the use of vinpocetine for the treatment of patients with mild cognitive impairment.

Vinpocetine Improves Scopolamine Induced Learning and Memory Dysfunction in C57 BL/6J Mice

Vinpocetine is an inhibitor of phosphodiesterase type 1 (PDE1), which has been used for treating stroke for over 40 years. However, according to current clinical dosage and treatment period, its direct effect on memory is unclear. In this study, we investigated whether vinpocetine could reverse the scopolamine (SCO)-induced cognitive deficits in animals. Behavioral experiments, including open field, Y-maze, and fear conditioning tests were used to determine the possible role of vinpocetine on scopolamine-induced memory dysfunction. In the open field and Y-maze tests, there were significant differences between the control (CON) group and SCO group. Vinpocetine (4 mg/kg) administration for consecutive 28 d significantly improved the scopolamine-induced memory dysfunction. In the fear conditioning test, vinpocetine (2, 4 mg/kg) administration had certain beneficial effect on emotional memory. Our results suggest that vinpocetine could improve cognitive function in memory deficient mice and high clinic dosage might be better.

Memory Enhancers for Alzheimer's Dementia: Focus on cGMP

Cyclic guanosine-3',5'-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate enzymes, each of which comprises several isoforms with different mechanisms of activation, synthesizes cGMP. cGMP signaling is mainly executed by the activation of protein kinase G and cyclic nucleotide gated channels, whereas it is terminated by its hydrolysis to GMP operated by both specific and dual-substrate phosphodiesterases. In the central nervous system, cGMP has attracted the attention of neuroscientists especially for its key role in the synaptic plasticity phenomenon of long-term potentiation that is instrumental to memory formation and consolidation, thus setting off a "gold rush" for new drugs that could be effective for the treatment of cognitive deficits. In this article, we summarize the state of the art on the neurochemistry of the cGMP system and then review the pre-clinical and clinical evidence on the use of cGMP enhancers in Alzheimer's disease (AD) therapy. Although preclinical data demonstrates the beneficial effects of cGMP on cognitive deficits in AD animal models, the results of the clinical studies carried out to date are not conclusive. More trials with a dose-finding design on selected AD patient's cohorts, possibly investigating also combination therapies, are still needed to evaluate the clinical potential of cGMP enhancers.

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

Vinpocetine (VPN) is a synthetic ethyl-ester derivative of the alkaloid apovincamine from Vinca minor leaves. VPN is a selective inhibitor of phosphodiesterase type 1 (PDE1) that has potential neurological effects through inhibition of voltage-gated sodium channel and reduction of neuronal calcium influx. VPN has noteworthy antioxidant, anti-inflammatory, and anti-apoptotic effects with inhibitory effect on glial and astrocyte cells during and following ischemic stroke (IS). VPN is effective as adjuvant therapy in the management of epilepsy; it reduces seizure frequency by 50% in a dose of 2 mg/kg/day. VPN improves psychomotor performances through modulation of brain monoamine pathway mainly on dopamine and serotonin, which play an integral role in attenuation of depressive symptoms. VPN recover cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE1 with augmentation of cyclic adenosin monophosphate and cyclic guanosin monophosphate ratio, enhancement of cholinergic neurotransmission, and inhibition of neuronal inflammatory mediators. Therefore, VPN is an effective agent in the management of IS and plays an integral role in the prevention and attenuation of poststroke epilepsy, depression, and cognitive deficit through direct cAMP/cGMP-dependent pathway or indirectly through anti-inflammatory and antioxidant effects.

Vinpocetine attenuates lipid accumulation and atherosclerosis formation

Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis.

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