ArticleLiterature Review

An update on Vinpocetine: New discoveries and clinical implications

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Abstract

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.

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... This highlights the potential impact of 4AQs in modern medicine. Although both drugs are reported to be safe, with good tolerability, and can be used even during pregnancy (Browning 2014; Plantone and Koudriavtseva 2018), adverse effects are recorded even after application of therapeutic doses, and over doses can be fatal (Browning 2014;Zhang et al. 2018). The adverse effects of CQ and HCQ can be classified into two categories: (1) non-serious side effects that do not preclude medicine continuation like gastrointestinal and skin manifestations; and (2) serious/risky side effects that require therapy discontinuation, like retinal and cardiac toxicities, which are always not associated with complete recovery. ...
... Vinpocetine (ethyl apovincaminate; Vin) is a semisynthetic compound belongs to the class of nootropic medicines. Vinpocetine is a derivative of monoterpenoid indole alkaloid vincamine, which is extracted from Vinca minor leaves (Zhang et al. 2018). Clinically, Vin is used for the management of cerebrovascular diseases, such as stroke and cerebral hemorrhage, as well as cognitive disorders (Panda et al. 2022). ...
... Clinically, Vin is used for the management of cerebrovascular diseases, such as stroke and cerebral hemorrhage, as well as cognitive disorders (Panda et al. 2022). Vinpocetine is a phosphodiesterase-1 (PDE-1) inhibitor that can regulate the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Zhang et al. 2018). A growing body of evidence also reported the anti-inflammatory properties of Vin (Jeon et al. 2010;Lourenco-Gonzalez et al. 2019;Ruiz-Miyazawa et al. 2015;Zhang and Yang 2014). ...
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Chloroquine (CQ) and hydroxychloroquine (HCQ) are classical antimalarial drugs, and recently have been used for other applications including coronavirus disease 2019 (COVID-19). Although they are considered safe, cardiomyopathy may associate CQ and HCQ applications particularly at overdoses. The goal of the present study was to evaluate the potential protective effect of the nootropic agent vinpocetine against CQ and HCQ adverse effects with a specific focus on the heart. For this purpose, a mouse model of CQ (0.5 up to 2.5 g/kg)/HCQ (1 up to 2 g/kg) toxicity was used, and the effect of vinpocetine was evaluated by survival, biochemical, as well as histopathological analyses. Survival analysis revealed that CQ and HCQ caused dose-dependent lethality, which was prevented by co-treatment with vinpocetine (100 mg/kg, oral or intraperitoneal). To gain deeper understanding, a dose of 1 g/kg CQ—which did not cause death within the first 24 h after administration—was applied with and without vinpocetine administration (100 mg/kg, intraperitoneal). The CQ vehicle group showed marked cardiotoxicity as evidenced by significant alterations of blood biomarkers including troponione-1, creatine phosphokinase (CPK), creatine kinase-myocardial band (CK-MB), ferritin, and potassium levels. This was confirmed at the tissue level by massive alteration of the heart tissue morphology and coincided with massive oxidative stress. Interestingly, co-administration of vinpocetine strongly ameliorated CQ-induced alterations and restored the antioxidant-defense system of the heart. These data suggest that vinpocetine could be used as an adjuvant therapy together with CQ/HCQ applications.
... Vinpo has a cerebroprotective impact that can ameliorate brain disorders, including memory disturbances, cognitive impairment, stroke, and dementia (Zhao et al. 2011). Besides possessing a high safety profile, no substantial toxicity for Vinpo has been reported on long-term use so far (Zhang et al. 2018). Vinpo causes vasodilation by inhibiting the cyclic nucleotide phosphodiesterase-1 (PDE-1), voltage-gated sodium channels, and calcium channels, and raising oxygen and glucose consumption in the brain. ...
... Oral vinpocetine 20 mg/kg (Petric et al. 2023;Zhang et al. 2018) suspended in CMC (Vinpo) or Lactobacillus (El-Baz et al. 2023) as mentioned earlier (Lacto). The other four groups were fed HFD and either administered no treatment (HFD), vinporal 10 mg/kg (Vinpo 10 + HFD), Vinporal 20 mg/kg (Vinpo 20 + HFD) or vinporal 20 mg/kg and Lactobacillus (Vinpo 20/ Lacto + HFD). ...
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Therapeutics that interfere with the damage/pathogen-associated molecular patterns (DAMPs/PAMPs) have evolved as promising candidates for hepatic inflammation like that occurring in non-alcoholic fatty liver disease (NAFLD). In the current study, we examined the therapeutic impact of the phosphodiesterase-1 inhibitor vinpocetine (Vinpo), alone or when combined with Lactobacillus, on hepatic abnormalities caused by a 13-week high-fat diet (HFD) and diabetes in rats. The results show that Vinpo (10 and 20 mg/kg/day) dose-dependently curbed HFD-induced elevation of liver injury parameters in serum (ALT, AST) and tissue histopathology. These effects were concordant with Vinpo’s potential to ameliorate HFD-induced fibrosis (Histological fibrosis score, hydroxyproline, TGF-β1) and oxidative stress (MDA, NOx) alongside restoring the antioxidant-related parameters (GSH, SOD, Nrf-2, HO-1) in the liver. Mechanistically, Vinpo attenuated the hepatocellular release of DAMPs like high mobility group box (HMGB)1 alongside lowering the overactivation of the pattern recognition receptors including, toll-like receptor (TLR)4 and receptor for advanced glycation end-products (RAGE). Consequently, there was less activation of the transcription factor nuclear factor-kappa B that lowered production of the proinflammatory cytokines TNF-α and IL-6 in Vinpo-treated HFD/diabetes rats. Compared to Vinpo treatment alone, Lactobacillus probiotics as adjunctive therapy with Vinpo significantly improved the disease-associated inflammation and oxidative stress injury, as well as the insulin resistance and lipid profile abnormalities via enhancing the restoration of the symbiotic microbiota. In conclusion, combining Vinpo and Lactobacillus probiotics may be a successful approach for limiting NAFLD in humans. Supplementary Information The online version contains supplementary material available at 10.1186/s13568-024-01731-2.
... BALB/c albino male mice were used as the suitable animal strain for the experiment. Forty mice aged (10)(11)(12) weeks weighing (20)(21)(22)(23)(24)(25) grams were randomly allocated into four groups (using block randomization) with ten animals in each group (n = 10). Group 1 (Normal control)/animal groups received only 0.9% normal saline through oropharyngeal (OP) aspiration in a volume equivalent to that of the induced group based on body weight. ...
... A recent study that investigated the effect of VCN in suppressing the progression of non-alcoholic steatohepatitis (NASH) in mice mentioned that the anti-inflammatory of VCN could be mediated by inhibition of NLRP3 inflammasome activation and hence the NF-κB signaling pathway which results in a reduction in the production of pro-inflammatory cytokines 74 . Zhang and colleagues mentioned that VCN can inhibit IκB kinase (IKK), which plays a critical role in cellular inflammatory response and increases expression of NF-κB 24 . ...
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This study aimed to investigate the potential anti-fibrotic activity of vinpocetine in an experimental model of pulmonary fibrosis by bleomycin and in the MRC-5 cell line. Pulmonary fibrosis was induced in BALB/c mice by oropharyngeal aspiration of a single dose of bleomycin (5 mg/kg). The remaining induced animals received a daily dose of pirfenidone (as a standard anti-fibrotic drug) (300 mg/kg/PO) and vinpocetine (20 mg/kg/PO) on day 7 of the induction till the end of the experiment (day 21). The results of the experiment revealed that vinpocetine managed to alleviate the fibrotic endpoints by statistically improving (P ≤ 0.05) the weight index, histopathological score, reduced expression of fibrotic-related proteins in immune-stained lung sections, as well as fibrotic markers measured in serum samples. It also alleviated tissue levels of oxidative stress and inflammatory and pro-fibrotic mediators significantly elevated in bleomycin-only induced animals (P ≤ 0.05). Vinpocetine managed to express a remarkable attenuating effect in pulmonary fibrosis both in vivo and in vitro either directly by interfering with the classical TGF-β1/Smad2/3 signaling pathway or indirectly by upregulating the expression of Nrf2 enhancing the antioxidant system, activating PPAR-γ and downregulating the NLRP3/NF-κB pathway making it a candidate for further clinical investigation in cases of pulmonary fibrosis.
... Although vinpocetine has been used clinically in the treatment of cerebrovascular disorders due to its neuroprotective and nootropic effects [82], in the summary of the characteristics of the drug Cavinton ® , only occasional, rare, and very rare side effects of mild intensity, dizziness, headache, and hypotension were described. When it is used for therapeutic purposes, it has a good safety profile; a summary of clinical studies showed no serious adverse effects [83]. ...
... When it is used for therapeutic purposes, it has a good safety profile; a summary of clinical studies showed no serious adverse effects [83]. However, vincamine-adulterated supplements promoted to enhance memory and mental attention indirectly endanger the consumer's health by making it impossible to establish the correct diagnosis and treatment of a patient with neurological disorders and by unknowingly combining them with contraindicated medicines, such as drugs that prolong the QT interval [63,82]. The biggest concern is that they may contain multiple unauthorized substances and/or unapproved drugs in typical pharmaco-logical doses [63]. ...
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Health concerns associated with the consumption of food supplements rise in parallel with the rise in the popularity and market availability of these products. In pursuit of data related to the unauthorized presence of pharmaceuticals in food supplements, the Rapid Alert System for Food and Feed (RASFF) database was searched for the 2011–2022 period. The most “popular” pharmaceuticals for the adulteration of food supplements were phosphodiesterase-5 inhibitors (235 records); anorexics and laxatives (76), including sibutramine and its active metabolite N-didesmethyl sibutramine, phenolphthalein and 2,4-dinitrophenol; stimulants, among which 1,3-dimethylamine (97), and synephrine (53) were the most numerous; nootropic drugs (24); anabolics and prohormones (16); and cannabinoid cannabidiol (14) (pending authorization as a novel food ingredient). Over 65% of notifications of interest were classified as serious risks, and over 80% of these were alert or border rejection notifications, mainly generated as a result of official control on the market. The alarming number of RASFF notifications should be considered a public health issue, demanding clear and targeted recommendation for action for the legislature and authorities. A harmonized nutrivigilance system should be considered as a tool to detect and scrutinize the adverse health effects of food supplements, along with measures to improve their safety, quality, and testing.
... Vinpocetine is a synthetic chemical substance derived from vincamine, a substance found in the periwinkle plant (Vinca minor) [13]. Vinpocetine might increase blood flow to the brain and protect brain neurons against injury [14]. Additionally, it is used to enhance memory and increase brain metabolism [15]. ...
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The development of new drugs for the inhibition of hepatocellular carcinoma (HCC) development and progression is a critical and urgent need. The median survival rate for HCC patients remains disappointingly low. Vinpocetine is a safe nootropic agent that is often used to enhance cognitive function. The impact of vinpocetine on HCC development and progression has not been fully explored. Our main objective was to investigate the possible inhibitory role of vinpocetine in rats exposed to diethylnitrosamine. We observed that vinpocetine increased the survival rate of these rats and improved the ultrastructure of their livers. Additionally, vinpocetine reduced the liver weight index, mitigated liver oxidative stress, and improved liver function. In both in vitro and in vivo settings, vinpocetine demonstrated antiproliferative and apoptotic properties. It downregulated the expression of CCND1 and Ki-67 while exhibiting anti-BCL-2 effects and enhancing the levels of Bax and cleaved caspase-3. Vinpocetine also successfully deactivated NF-κB, STAT3, and HIF-1α, along with their associated transcription proteins, thereby exerting anti-inflammatory and anti-angiogenic role. Furthermore, vinpocetine showed promise in reducing the levels of ICAM-1 and TGF-β1 indicating its potential role in tissue remodeling. These findings strongly suggest that vinpocetine holds promise as a hepatoprotective agent by targeting a range of oncogenic proteins simultaneously. However, further approaches are needed to validate and establish causal links between our observed effects allowing for a more in-depth exploration of the mechanisms underlying vinpocetine’s effects and identifying pivotal determinants of outcomes.
... Vinpocetine (Vinpo), a phosphodiesterase type-1 (PDE1) inhibitor, is clinically recommended for managing diverse cerebrovascular impairments without noteworthy adverse effects noted during its application (Patyar et al. 2011). It has a comprehensive spectrum of properties, like anti-inflammatory, anti-fibrotic (Zhang et al. 2018b), and anti-STAT3 (Kim et al. 2019). Previous research has disclosed Vinpo's capacity to improve renal function in acute renal damage models Azouz et al. 2022). ...
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Tubulointerstitial fibrosis (TIF) is present with chronic kidney disease (CKD). Vinpocetine (Vinpo) is used for treating cerebrovascular deficits, exhibiting some kidney-beneficial effects; however, its role in TIF is uncertain. So, the aim of this study was to investigate its potential impact on adenine-induced fibrotic CKD and explore the underlying mechanistic aspects. Eighteen male Wistar rats were categorized into three groups (n = 6 each). Group I was kept as controls and given saline; group II received adenine (300 mg/kg, twice weekly, i.p.) for induction of the CKD model; and group III was administered Vinpo (20 mg/kg/d, orally) concurrently with adenine. All treatments were administered for 4 weeks. Vinpo revealed an improvement in renal function and an alleviation of inflammation triggered by adenine via diminishing serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels. Further, Vinpo repressed the epithelial-mesenchymal transition (EMT) with preserved E-cadherin mRNA expression and lowered gene and immune expression of fibronectin and vimentin, respectively, besides attenuating the elevated G2/M arrest-related molecules (renal Ki67 protein contents and p21 gene expression). Renal pathological alterations caused by adenine were attenuated upon Vinpo administration. Interestingly, Vinpo suppressed abnormal renal β-catenin immunoreactivity, Snail 1, and MMP-7 gene expression while simultaneously restored Klotho protein expression by downregulating DNA methyltransferase 1 enzyme (DNMT1) protein expression in the kidney. These data indicated that Vinpo effectively mitigated EMT and G2/M arrest-induced renal fibrosis in adenine-induced CKD rats by targeting DNMT1-associated Klotho suppression, subsequently inhibiting β-catenin and its fibrotic downstream genes.
... Similarly, genetic depletion of PDE1 attenuated cardiomyocyte hypertrophy, death, and fibrosis in vitro and in vivo [44]. A review conducted by Rosansarz informs that Angiotensin II (AT-II) and TGF-beta 1 collaborate in a signaling network to facilitate cardiac remodeling, a vital process in developing heart disease and clinical outcomes [45]. ...
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Background: Diabetic cardiomyopathy (DCM) poses a significant risk for heart failure in individuals with diabetes, yet its underlying mechanisms remain incompletely understood. Elevated blood sugar levels initiate harmful processes, including apoptosis, collagen accumulation, and fibrosis in the heart. Vinpocetine, a derivative of Vinca minor L., has demonstrated diverse pharmacological effects, including vasodilation, anti-inflammatory properties, and enhanced cellular metabolism. This study aims to investigate Vinpocetine’s protective and remodeling effects in diabetic cardiomyopathy by evaluating biochemical and histopathological parameters. Methods: Twenty-one adult male Wistar rats were induced with diabetes using streptozocin and divided into Diabetes and Diabetes + Vinpocetine groups. Histopathological analyses, TGF-β1 immunoexpression, and measurements of plasma markers (TGF-β, pro-BNP, Troponin T) were performed. Biochemical analyses included HIF-1 alpha and neuregulin-1β quantification and evaluation of lipid peroxidation. Results: Vinpocetine significantly reduced cardiac muscle thickness, TGF-β1 expression, and plasma in diabetic rats. HIF-1 alpha and neuregulin-1β levels increased with Vinpocetine treatment. Histopathological observations confirmed reduced fibrosis and structural abnormalities in Vinpocetine-treated hearts. Conclusions: This study provides comprehensive evidence supporting the protective effects of Vinpocetine against diabetic cardiomyopathy. Vinpocetine treatment improved cardiac morphology, immunohistochemistry, and modulation of biochemical markers, suggesting its potential as a therapeutic intervention to attenuate the negative impact of diabetes on heart function.
... PDE inhibitors, crucial in the metabolism of cAMP and cyclic GMP, modulate the release of inflammatory cytokines as intracellular secondary messengers [22]. Vinpocetine (Vinp), a PDE 1 inhibitor and derivative of the alkaloid vincamine, has been clinically employed for over 30 years to address cerebrovascular disorders such as dementia and stroke [23]. Numerous studies have explored the anti-inflammatory effects of Vinp, revealing its ability to inhibit I B kinase as a key mechanism [24]. ...
... VPN has an anti-inflammatory effect by inhibiting the expression of nuclear factor kappa B (NF-κB) through stabilization of IκB which is an inhibitor of NF-κB. Moreover, VPN have anti-platelet activity, thereby; improves brain blood flow and brain metabolism [6]. ...
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Atherosclerosis (AS) formation is enhanced by different mechanisms including cytokine generation, vascular smooth muscle cell proliferation, and migration. One of the recent treatments towards endothelial dysfunction and AS is Vinpocetine (VPN). VPN is a potent inhibitor of phosphodiesterase enzyme 1 (PDE-1) and has anti-inflammatory and antioxidant effects through inhibition the expression of nuclear factor kappa B (NF-κB). VPN has been shown to be effective against the development and progression of AS. However, the underlying molecular mechanism was not fully clarified. Consequently, objective of the present review was to discuss the mechanistic role of VPN in the pathogenesis AS. Most of pro-inflammatory cytokines that released from macrophages are inhibited by action of VPN through NF-κB-dependent mechanism. VPN blocks monocyte adhesion and migration by constraining the expression and action of pro-inflammatory cytokines. As well, VPN is effective in reducing of oxidative stress a cornerstone in the pathogenesis of AS through inhibition of NF-κB and PDE1. VPN promotes plaque stability and prevents the erosion and rupture of atherosclerotic plaque. In conclusion, VPN through mitigation of inflammatory and oxidative stress, and improvement of plaque stability effects could be effective agent in the management of AS.
... The drug is a synthetic derivative of vincamine (one of the main alkaloid molecules found in the vinca minor plant [16]), which is used for the treatment of cerebral disorders and diseases. It also increases the cerebral flow in the ischemic areas thus showing a neuroprotective effect against brain ischemia in patients with cerebrovascular diseases [17,18]. ...
... Vincamine Vincamine (Fig. 4d) belongs to the class of monoterpenoidindole alkaloids. Although Vincamine has pharmacological effects on both the cardiovascular and central nervous systems, its primary impact is on the blood vessels in the brain, and it is commonly used to prevent and treat cerebrovascular diseases, improve brain metabolism and immune function, and aid in wound healing, among other uses (Zhang et al. 2018). ...
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Even after a century of substantial advancements in oncology medicines, cancer still ranks as one of the top causes of death worldwide. As a result, there is an ongoing and pressing need for the development of new cancer drugs. Natural compounds and their semi-synthetic derivatives continue to show promise as potential therapeutic leads, due to their high chemical diversity, biochemical specificity, significant molecular activities, and pharmacological properties. They serve as excellent starting points for the discovery of new drugs, inspiring new breakthroughs in biology, chemistry, and medicine. In recent years, scientists have made significant advancements in the development of naturally occurring or partly synthesized analogues with improved bioactivity, simpler synthetic targets and reduced toxicity. This review aims to summarize the importance and biological actions of natural compounds identified form plants and their role in prevention of cancer treatment.
... It improves blood flow by cerebral vasodilator action and also increases cerebral metabolism by increasing oxygen and glucose uptake and stimulating neuronal ATP production. Also acts as an antioxidant and prevents the neurotoxic increase in sodium and calcium levels 23 . Vinpocetine enhances spatial memory by modulating the cholinergic system 24 . ...
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Sleep plays a vital role to help in normal biological functions that are required for normal cognitive functioning. This study was done to determine the cognition-modulating effects of coenzyme Q10 (CoQ10), ramipril, and vinpocetine on REM sleep-deprived acute insomniac rat models. A total of Forty-eight albino rats were divided into eight groups (Gr) (n=6).). Gr. 1 was REM control and Gr. 2 was REM sleep-deprived rats treated with water. Gr. 3 to Gr.8 - REM sleep-deprived rats were administered corn oil, donepezil, vinpocetine, coenzyme Q10+corn oil, ramipril, and (coenzyme Q10 + corn oil + ramipril) respectively. Except for the control Gr 1, REM sleep deprivation was induced in Gr. 2 and 8 daily for 7 days. All the rats were subjected to a Morris water maze (MWM) to test the navigation memory dysfunction after 7 days of acute insomnia. The rats were deprived of REM sleep by using a modified multiple platform method. The body weight of the animals was measured on day 1 and day 7. On day 1 and Day 2 acquisition trials, all groups of rats showed comparable latency time required to reach the hidden platform. However, on day 3 and Day 4, rats treated with coenzyme Q10, ramipril, and the combination (CoQ10+ Ramipril) showed a significant decrease in latency time (p<0.01). In the probe trial, sleep-deprived rats showed a significant decrease (p<0.001) in the percentage of time spent in the target quadrant as compared to the REM control. However, there was a significant increase in the percentage time spent in CoQ10, ramipril, the combination (CoQ10+ ramipril), donepezil, and vinpocetine as compared to sleep-deprived rats (p<0.05). At the end of day 7 of insomnia, when the body weight of rats was compared with day 1, there was a significant decrease in weight gain was seen with the sleep-deprived rats treated with corn oil, ramipril, vinpocetine, CoQ10, and (CoQ10+ramipril) (p<0.05). The present study shows that coenzyme Q10, ramipril, and their combination improve sleep deprivation induced cognition impairment.
... Various formulations of curcumin and berberine, such as nanoparticle and cyclodextrin inclusion complexes, elevated the bioavailability and demonstrated anti-seizure effects in both zebrafish and mice [41,78,79]. Therefore, it is likely that factors, such as physicochemical properties, blood-brain barrier permeability, and other unknown mechanisms, may be involved in the inconsistency of anti-seizure effects of natural compounds among the various models tested here [80][81][82][83][84][85][86]. ...
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Introduction One-third of people with epilepsy continue to experience seizures despite treatment with existing anti-seizure medications (ASMs). The failure of modern ASMs to substantially improve epilepsy prognosis has been partly attributed to overreliance on acute rodent models in preclinical drug development as they do not adequately recapitulate the mechanisms of human epilepsy, are labor-intensive and unsuitable for high-throughput screening (HTS). There is an urgent need to find human-relevant HTS models in preclinical drug development to identify novel anti-seizure compounds. Objectives This paper developed high-throughput preclinical screening models to identify new ASMs. Methods 14 natural compounds (α-asarone, curcumin, vinpocetine, magnolol, ligustrazine, osthole, tanshinone IIA, piperine, gastrodin, quercetin, berberine, chrysin, schizandrin A and resveratrol) were assessed for their ability to suppress epileptiform activity as measured by multi-electrode arrays (MEA) in neural cultures derived from human induced pluripotent stem cells (iPSCs). In parallel, they were tested for anti-seizure effects in zebrafish and mouse models, which have been widely used in development of modern ASMs. The effects of the compounds in these models were compared. Two approved ASMs were used as positive controls. Results Epileptiform activity could be induced in iPSCs-derived neurons following treatment with 4-aminopyridine (4-AP) and inhibited by standard ASMs, carbamazepine, and phenytoin. Eight of the 14 natural compounds significantly inhibited the epileptiform activity in iPSCs-derived neurons. Among them, piperine, magnolol, α-asarone, and osthole showed significant anti-seizure effects both in zebrafish and mice. Comparative analysis showed that compounds ineffective in the iPSCs-derived neural model also showed no anti-seizure effects in the zebrafish or mouse models. Conclusion Our findings support the use of iPSCs-derived human neurons for first-line high-throughput screening to identify compounds with anti-seizure properties and exclude ineffective compounds. Effective compounds may then be selected for animal evaluation before clinical testing. This integrated approach may improve the efficiency of developing novel ASMs.
... Moreover, additional research has indicated that vinpocetine acts as an effective anti-inflammatory drug by inhibiting IB kinase, an essential enzyme in the NFB-dependent inflammatory response (Paul and Candelario-Jalil 2021). Vinpocetine is widely utilized in numerous European and Asian countries for the prevention of cerebrovascular diseases and cognitive deficits, and it can penetrate the blood-brain barrier when administered orally or intravenously (Bereczki and Fekete 2008;Zhang et al. 2018b). It is also readily available as a dietary supplement. ...
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Stroke is the third leading cause of years lost due to disability and the second-largest cause of mortality worldwide. Most occurrences of stroke are brought on by the sudden occlusion of an artery (ischemic stroke), but sometimes they are brought on by bleeding into brain tissue after a blood vessel has ruptured (hemorrhagic stroke). Alteplase is the only therapy the American Food and Drug Administration has approved for ischemic stroke under the thrombolysis category. Current views as well as relevant clinical research on the diagnosis, assessment, and management of stroke are reviewed to suggest appropriate treatment strategies. We searched PubMed and Google Scholar for the available therapeutic regimes in the past, present, and future. With the advent of endovascular therapy in 2015 and intravenous thrombolysis in 1995, the therapeutic options for ischemic stroke have expanded significantly. A novel approach such as vagus nerve stimulation could be life-changing for many stroke patients. Therapeutic hypothermia, the process of cooling the body or brain to preserve organ integrity, is one of the most potent neuroprotectants in both clinical and preclinical contexts. The rapid intervention has been linked to more favorable clinical results. This study focuses on the pathogenesis of stroke, as well as its recent advancements, future prospects, and potential therapeutic targets in stroke therapy. Graphical Abstract
... However, the use of vinpocetine as a popular dietary supplement remains controversial [15][16][17]. Despite recent renewed scientific attention [18][19][20][21][22][23], the existing literature on vinpocetine's pharmacological properties, safety, effectiveness, and toxicity remains insufficiently comprehensive [24,25]. Our goal is to provide a pharmacological overview of vinpocetine and propose a population pharmacokinetic (PopPK) model of apovincaminic acid (AVA), an active metabolite of vinpocetine. ...
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This paper examines the use of vinpocetine in the context of clinical pharmacology. The main and active metabolite of vinpocetine is apovincaminic acid (AVA). Due to the scarce information in the literature on AVA pharmacokinetics, we propose a population pharmacokinetic (PopPK) model for AVA based on a study in healthy volunteers with three different formulations of vinpocetine. The suggested PopPK model (and simulations) could be helpful in ensuring the more effective and safer use of the vinpocetine in the future given the increasing range of suggested indications for its use.
... Vinpocetine (VPN) is a vincamine alkaloid derivative ( Figure 2). It's mostly used to treat neurological illnesses including Alzheimer's and Parkinson's, as well as to increase brain blood flow (6,7). Vinpocetine works by inhibiting the enzyme phosphodiesterase type-1, which enhances cerebral blood flow specifically (8). ...
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A quick, accurate, and cost-effective UV spectroscopy method was developed to estimate the Vinpocetine concentration in bulk, tablet dosage formulations and niosomes formulations, using a solvent ratio of (6:4) methanol: water. According to ICH guidelines, the proposed technique was validated and developed. In spite of linearity, precision, accuracy, specificity, LOD, and LOQ, like parameters were validated by using UV/visible spectroscopy technique to analyze a spiked Vinpocetine solution. The wavelength at which the drug's maximum absorbance peak was obtained at 274 nm and the solvents used as methanol: water (6:4 w/v). The ethanol injection technique was used to prepare niosomes to analyze Vinpocetine in UV / visible spectrophotometric method.During the inter and intra-day studies, it was discovered that the developed UV technique was accurate, with % relative standard deviation ranging from 0.27 to 0.46 and 0.26 to 0.46, respectively. Vinpocetine overall recovery percentage was discovered to be between 98.42 to 99.82 %. LOQ and LOD were calculated to estimate the method's sensitivity, and they were observed to be 0.4565 µg/ml and 0.1506 µg/ml, respectively. The estimation of Vinpocetine content in bulk form, marketed formulations and niosomes was achieved using the developed methodology. : A quick, accurate, and economical UV spectrophotometric method has been developed. As a result, the suggested UV spectroscopic technique has been developed to estimate the vinpocetine concentration in bulk, tablet dosage formulations, and niosomes formulations.
... VIN belongs to BCS class II with low oral bioavailability (7%) as a result of slower dissolution rate in the intestinal tract and a significant first-pass effect. It is prescribed for the treatment of cerebral vascular and cerebral degenerative diseases such as Alzheimer's disease [13,14]. VIN induces cell apoptosis and impairs the migration of strongly metastatic cells [15]. ...
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Background This study was aimed to design mannose-conjugated solid lipid nanoparticles (MSLNs) for the targeted delivery of Atorvastatin Calcium (ATS) and Vinpocetine (VIN) to augment its therapeutic efficacy against breast cancer. SLNs were prepared by hot emulsification ultra-probe sonication method and conjugated with mannose. In vitro cell line, in vivo pharmacokinetic and in vivo tumor regression studies were performed for MSLNs. Results MSLNs had an average particle size of 435.4 ± 3 nm with polydispersity index 0.298 ± 0.03 and a zeta potential of − 28.2 ± 1 emv. Entrapment efficiency was found to be 69.17 ± 0.92%, 71.18 ± 0.68% for ATS and VIN, respectively. The IC50 value of MSLNs was 1.46 µg/ml, which is efficient to control the growth of MDA MB231 cells as compared to the individual drugs and combinatorial SLNs. The combination index was found to be 0.7. MSLNs inhibited cell growth via necrosis by promoting to apoptosis through arresting SubG1 phase. The relative bioavailability of ATS and VIN loaded in MSLNs was 1.47 and 5.70, respectively, as compared to the marketed formulation. Maximal tumor volume reduction and higher survival rate was found for the MSLNs group (76.03%, P = 0.0001) as compared to the control group ( P = 0.0364), individual drugs SLNs group. Conclusion The results revealed that the MSLNs formulation augmented activity against breast cancer by inhibiting the cell growth. This promising drug delivery reduces the doses for both the drugs and attains minimal dose-associated side effects with synergism by reaching the specific target site, furthermore improving the therapeutic efficacy.
... These findings may support the use of VNP in human disease prevention and therapy. 75,68 Therefore, we tested the antipsoriatic potential of VNP in a mouse model of psoriasis induced by IMQ. We examined the effects of VNP on psoriasis symptoms, including redness, flaking/peeling, and thickening/induration of the skin, as well as on histopathological changes and inflammatory biomarkers, such as NF-kB and tissue cytokine levels. ...
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Psoriasis is an uncontrolled, long-lasting inflammatory dermatosis distinguished by thickened, erythematous, and flaky skin lesions. Massive amounts of inflammatory cytokines are produced when immune system imbalances are driven by genetic and environmental triggers. Vinpocetine (VNP), a man-made analogue of the compound vincamine found in the dwarf periwinkle herb, has robust anti-inflammatory, immunomodulatory, and anti-oxidative effects; alleviates the epidermal penetration of immune cells, such as eosinophils and neutrophils; and abolishes the generation of pro-inflammatory molecules. Objective This study was aimed at exploring the effects of long-term topical VNP, both alone and co-administered with clobetasol propionate, in an imiquimod-induced mouse model of psoriasiform dermatitis. Methods The study protocol consisted of 48 Swiss albino mice, randomly divided into six groups of eight mice each. In group I, petroleum jelly was administered daily for 8 days. In group II, imiquimod was administered topically at 62.5 mg daily for 8 days. In groups III, VI, V, and VI, 0.05% clobetasol propionate, 1% VNP, 3% VNP, and 3% VNP plus 0.05% clobetasol were administered topically for an additional 8 days after the induction, thus resulting in a total trial length of 16 days. Results Topical VNP at various doses alleviated the severity of imiquimod-induced psoriatic lesions—including erythema, silvery-white scaling, and thickening—and reversed the histopathological abnormalities. Moreover, imiquimod-exposed animals treated with VNP showed markedly diminished concentrations of inflammatory biomarkers, including tumour necrosis factor-α, interleukin (IL)-8, IL-17A, IL-23, IL-37, nuclear factor-kappa B (NF-κB), and transforming growth factor-β1. Conclusion This research provides new evidence that VNP, alone and in combination with clobetasol, may serve as a potential adjuvant for long-term management of autoimmune and autoinflammatory skin diseases, particularly psoriasis, by attenuating psoriatic lesion severity, suppressing cytokine generation, and limiting NF-κB-mediated inflammation.
... Short half-life [11] 8. Curcuminoids Natural phenol Low water solubility and half-life variation at different pH [12] 9. Vinpocetine Semisynthetic derivative alkaloid of vincamine Poorly water soluble [13] 10. Triptolide Active diterpene Poor water solubility and toxic effects adverse drug reaction, hyper susceptibility of skin [14] 11. ...
... 18 With an observed functional potency of~6 lM, vinpocetine is more potent at GABA A receptors than it is on most other reported targets (IC 50 values of 10-50 lM). 19 Meador et al. 13 observed blood levels of vinpocetine of~15 ng/ml in humans following peroral doses of 20 mg three times daily. This corresponds to a concentration of~40 nM, which appears low in comparison with the observed functional potencies of vinpocetine. ...
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... Vinpocetine is a phosphodiesterase inhibitor with neuroprotective activities reducing neuroinflammation by inhibiting the IκB kinase complex, impeding the expression of pro-inflammatory mediators [120,121], and improving memory impairment by reducing oxidative stress and modulation of cholinergic function [122]. Moghaddam et al. [123] synthesized nanoethosomes loaded with vinpocetine for transdermal delivery. ...
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Vinpocetine and its derivatives were extensively employed in the treatment of ischemic stroke, serving as effective cerebrovascular vasodilators. They could also be utilized for neuroprotection, anti-inflammatory purposes, anti-aging interventions, insomnia treatment, and antidepressant effects. However, due to issues such as hepatic first-pass effect, low bioavailability, and poor patient compliance with multiple dosing, the secondary development of Vinpocetine to address these limitations became a prominent area of research. Five primary methodologies were employed for the synthesis of Vinpocetine derivatives. These included substitution on the A ring to modify the 14-ester group, alteration of the 16-ethyl group, simplification of the D and E rings, and modification of the conformation of Vinpocetine. This paper summarized the current synthesis and activity studies of Vinpocetine and its derivatives, with the aim of providing a reference for the discovery of more potent derivatives of Vinpocetine.
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Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3′,5′‐monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease‐modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs.
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Objective Vinpocetine (Vinp), a derivative of alkaloid vincristine with anti-inflammatory and antioxidant effects, has been shown to have neuroprotective effects in Parkinson's disease (PD). Its role and mechanisms, however, are not fully understood. Therefore, the aim of this study was to investigate the effects and possible mechanisms of Vinp on PD cells. Methods SH-SY5Y cells were treated with Vinp and then with rotenone to induce a cellular model of PD. The proliferation level and apoptosis rate of SH-SY5Y cells after different treatments were detected by MTT and flow cytometry assays, respectively. Western blot was used to determine the relative protein expression of α-Synuclein (α-Syn) in differently treated cells. Additionally, commercial kits and ELISA were used to determine oxidative stress-related indicators (superoxide dismutase [SOD], malondialdehyde [MDA], and reactive oxygen species [ROS]) and inflammatory factors (tumor necrosis factor α [TNF-α], interleukin-5 [IL-5], and interleukin-1β [IL-1β]) in SH-SY5Y cells after different treatments, respectively. Results Vinp at different concentrations (5, 10, and 50 µM) had no significant effect on the proliferation and apoptosis of SH-SY5Y cells. For rotenone-induced SH-SY5Y cells, Vinp pretreatment could significantly reduce α-Syn expression, increased cell viability and decreased apoptosis, oxidative stress (downregulation of ROS and MDA levels and upregulation of SOD activity) and inflammation (increased levels of TNF-α, IL-5, and IL-1β). In contrast, overexpression of α-Syn in SHSY5Y cells with Vinp pretreatment and rotenone induction partially reversed the aforementioned protective effects of Vinp, causing a decrease in proliferation, an increase in apoptosis rate, inflammation, and oxidative stress. Conclusion Vinp exerted neuroprotective effects by downregulating α-Syn to promote proliferation, inhibit apoptosis, and inhibit oxidative stress and inflammation in rotenone-induced SH-SY5Y cells.
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Background: Inflammasome activation is known to be involved in nonalcoholic steatohepatitis (NASH). Vinpocetine is a derivative of vincamine and is reported to suppress the activation of inflammasome. Methods: This study explored the therapeutical potential of Vinpocetine on NASH. Mice were fed with a choline-deficient (MCD) or chow diet in the presence or absence of Vinpocetine for 8 weeks. H&E staining and biochemical assays were determined to evaluate the hepatic steatosis and fibrosis symptoms. In addition, primary hepatocytes and Kupffer cells were isolated and induced by MCD or lipopolysaccharides/cholesterol crystals with or without Vinpocetine. ELISAs, qPCR, and Western blotting were applied to determine the levels of NASH-related biomarkers in both in vivo mouse model and in vitro cell models. Results: Treatment of Vinpocetine did not cause observable side effects against and MCD-induced cells and mouse NASH model. However, treatment of Vinpocetine ameliorated hepatic steatosis and fibrosis and suppressed the levels of alanine transaminase and aspartate transferase in the mouse NASH model. In addition, treatment of Vinpocetine suppressed the mRNA and protein levels of inflammasome components both in vitro and in vivo. Conclusion: Vinpocetine suppressed NASH in mice by mediating inflammasome components via nuclear factor κB signaling.
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Vincamine is a naturally occurring indole alkaloid showing antioxidant activity and has been used clinically for the prevention and treatment of cerebrovascular disorders and insufficiencies. It has been well documented that antioxidants may contribute to cancer treatment, and thus, vincamine has been investigated recently for its potential antitumor activity. Vincamine was found to show cancer cell cytotoxicity and to modulate several important proteins involved in tumor growth, including acetylcholinesterase (AChE), mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and T-box 3 (TBX3). Several bisindole alkaloids, including vinblastine and vincristine and their synthetic derivatives, vindesine, vinflunine, and vinorelbine, have been used as clinically effective cancer chemotherapeutic agents. In the present review, the discovery and development of vincamine as a useful therapeutic agent and its antioxidant and antitumor activity are summarized, with its antioxidant-related mechanisms of anticancer potential being described. Also, discussed herein are the design of the potential vincamine-based oncolytic agents, which could contribute to the discovery of further new agents for cancer treatment.
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Objectives: Methotrexate (MTX) is an antimetabolite agent widely used to manage a variety of tumors and autoimmune diseases. Nonetheless, MTX-induced intestinal intoxication is a serious adverse effect limiting its clinical utility. Inflammation and oxidative stress are possible mechanisms for MTX-induced intestinal toxicity. Vinpocetine (VNP) is a derivative of the alkaloid vincamine with potent anti-inflammatory and antioxidant effects. The current study investigated the protective intestinal impact of VNP in attenuating MTX-induced intestinal intoxication in rats. Materials and methods: VNP was administered orally in a dose of 20 mg/kg, while MTX was injected intraperitoneal in a dose of 20 mg/kg. Results: VNP administration attenuated drastic histological changes induced by MTX and preserved both normal villus and crypt histology. VNP significantly attenuated oxidative injury by upregulating intestinal Nrf2 and HO-1 expression. VNP attenuated inflammation by reducing MPO, NO2-, TNF-α, and IL-1β levels mediated by downregulating NF-κB, NDAPH-oxidase, IRF3, p-JAK-1, and p-STAT-3 expressions. Moreover, VNP potently counteracted intestinal necroptosis by effectively downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins. Conclusion: Therefore, VNP may represent a promising approach that can attenuate intestinal toxicity in patients receiving MTX.
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Vinpocetine (Vinpo) is a neuroprotective vasodilator drug. It is an effective therapeutic agent for a variety of cerebrovascular and cognitive disorders. However, its potential protective efficacy on intestinal ischemia/reperfusion (I/R) injury remains elusive. The present study aimed to investigate the effect of Vinpo on intestinal I/R injury and to explore its modulatory effect on sirtuin (SIRT1)/ Suppressor of cytokine signaling (SOCS3)/ Signal Transducer and Activator of Transcription (STAT3) signaling. Twenty-four male Wistar albino rats were randomly allocated into four groups. G1 (sham): rats were subjected to surgical stress without I/R, GII (I/R): rats were subjected to 60 min/2-h I/R, GIII (Vinpo + I/R): rats were pre-treated with Vinpo (20 mg/kg/day, P.O. daily) for 2 weeks before intestinal I/R; GIV (EX527 + Vinpo + I/R): rats received both Vinpo (20 mg/kg/day, P.O.) and EX527 (5 mg/kg, once every 2 days, i.p) for 2 weeks before intestinal I/R. The current results showed that Vinpo improved the intestinal histopathological picture, enhanced M1 to M2 macrophage polarization and alleviated the I/R-induced increase in interleukins (IL-6, IL-1β), tumor necrosis factor (TNF-α), inducible nitric oxide synthase (i-NOS), and nitric oxide (NO). Additionally, Vinpo pretreatment upregulated SIRT1 mRNA expression/protein level and SOCS3 mRNA expression while downregulating P-STAT3 immunoreactivity. The effects of Vinpo were attenuated by the SIRT1 inhibitor EX527. We concluded that Vinpo ameliorated the intestinal I/R injury and enhanced M2 anti-inflammatory macrophage polarization through modulation of SIRT1/SOCS3/STAT3/i-NOS cascade.
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Therapeutics that interfere with the damage/pathogen-associated molecular patterns (DAMPs/PAMPs) have evolved as promising candidates in the context of hepatic inflammation like that occurring in the non-alcoholic fatty liver disease (NAFLD). Herein, we investigated the therapeutic impact phosphodiesterase-1 inhibitor vinpocetine (Vinpo), alone or when combined with Lactobacillus, on hepatic abnormalities caused by a 13-week high-fat diet (HFD) and diabetes in rats. The results have shown that Vinpo (10 and 20 mg/kg/day) dose-dependently limited HFD-instigated rise of hepatic injury parameters in serum (ALT, AST) and tissue (histological necroinflammation score). These effects were concordant with Vinpo potential to ameliorate HFD-induced fibrosis (Histological fibrosis score, hydroxyproline, TGF-β1) and oxidative stress (MDA, NOx) alongside restoring the antioxidants (GSH, SOD, Nrf-2, HO-1) in the liver. Mechanistically, Vinpo attenuated the hepatocellular release of DAMPs like HMGB1 alongside lowering the overactivation of the pattern recognition receptors TLR4 and RAGE. Consequently, there was a less activation and nuclear translocation of the nuclear factor-kappa B that was ensued with a decline in overexpression of the proinflammatory cytokines TNF-α and IL-6 in Vinpo-treated HFD/diabetes-rats. In comparison to Vinpo treatment alone, Lactobacillus probiotics as an adjunctive therapy with Vinpo significantly improved the disease-associated inflammation and oxidative stress injury, as well as the insulin resistance and lipid profile abnormalities via enhancing the restoration of the symbiotic gut microbiota. In conclusion, combining Vinpo and Lactobacillus probiotics may be a successful approach for limiting the NAFLD in humans.
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The first nootropic prohibited in sport was fonturacetam (4-phenylpiracetam, carphedon) in 1998. Presented here 25 years later is a broad-scale consideration of the history, pharmacology, prevalence, regulations, and doping potential of nootropics viewed through a lens of 50 selected dietary supplements (DS) marketed as "cognitive enhancement," "brain health," "brain boosters," or "nootropics," with a focus on unauthorized ingredients. Nootropic DS have risen to prominence over the last decade often as multicomponent formulations of bioactive ingredients presenting compelling pharmacological questions and potential public health concerns. Many popular nootropics are unauthorized food or DS ingredients according to the European Commission including huperzine A, yohimbine, and dimethylaminoethanol; unapproved pharmaceuticals like phenibut or emoxypine (mexidol); previously registered drugs like meclofenoxate or reserpine; EU authorized pharmaceuticals like piracetam or vinpocetine; infamous doping agents like methylhexaneamine or dimethylbutylamine; and other investigational substances and peptides. Several are authorized DS ingredients in the United States resulting in significant global variability as to what qualifies as a legal nootropic. Prohibited stimulants or ß2-agonists commonly used in "pre-workout," "weight loss," or "thermogenic" DS such as octodrine, hordenine, or higenamine are often stacked with nootropic substances. While stimulants and ß2-agonists are defined as doping agents by the World Anti-Doping Agency (WADA), many nootropics are not, although some may qualify as non-approved substances or related substances under catch-all language in the WADA Prohibited List. Synergistic combinations, excessive dosing, or recently researched pharmacology may justify listing certain nootropics as doping agents or warrant additional attention in future regulations.
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Vinpocetine (VPN) is an ethyl apovincaminate that has anti-inflammatory and antioxidant effects by inhibiting the expression of nuclear factor kappa B (NF-κB) and phosphodiesterase enzyme 1 (PDE-1). VPN is used in the management of stroke, dementia, and other neurodegenerative brain diseases. VPN may be effective in treating Parkinson’s disease (PD). Therefore, this review aimed to clarify the mechanistic role of VPN in the management of PD. VPN has protective and restorative effects against neuronal injury by reducing neuroinflammation, and improvement of synaptic plasticity and cerebral blood flow. VPN protects dopaminergic neurons by reducing oxidative stress, lipid peroxidation, glutamate neurotoxicity, and regulation of Ca+ 2 overloads. VPN can alleviate PD neuropathology through its anti-inflammatory, antioxidant, antiapoptotic and neurogenic effects. VPN through inhibition of PDE1 improves cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) signaling in the dopaminergic neurons of the substantia nigra (SN). VPN improves PD neuropathology through PDE1 inhibition with a subsequent increase of the cAMP/cGMP signaling pathway. Therefore, increasing cAMP leads to antioxidant effects, while augmentation of cGMP by VPN leads to anti-inflammatory effects which reduced neurotoxicity and development of motor severity in PD. In conclusion, this review indicated that VPN could be effective in the management of PD.
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The effects of vinpocetine against hippocampal neuronal damage and on local cerebral blood flow (LCBF) were examined in a rat model of forebrain ischemia (10-min occlusion of the carotid arteries and hypotension). Histological evaluation of neuronal loss in the hippocampus was performed 7 days after ischemia. LCBF was measured before ischemia as well as after 2 min and 1 hr of recirculation. Vinpocetine (10mg/kg) administered pre- or post-ischcmically reduced the hippocampal neuronal necrosis, while pre-ischemic administration of 2 or 20 mg/kg vinpocetine was ineffective. Since vinpocetine increased the LCBF after 1 hr of recirculation, it cannot be excluded that blood flow improvements contribute to its neuroprotective activity. On the other hand, there is no clear evidence that an elevation of post-ischemic hypoperfusion could protect neurons against ischemic damage. It is, therefore, suggested that vinpocetine acts directly on brain cells.
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Pulmonary arterial hypertension (PAH) is a lethal disease that often affects the young. Although Bone Morphogenetic Protein Receptor Type 2 gene (BMPR2) mutations are related with idiopathic and heritable PAH, the low penetrance and variable expressivity in PAH suggest the existence of other genetic and/or environmental factors. In this study, we aimed to identify novel genetic factors associated with PAH, irrespective of BMPR2 mutation. We performed genome-wide association study (GWAS) in a Japanese population comprising 44 individuals with idiopathic and heritable PAH, and 2,993 controls. Seven loci identified in the genome-wide study were submitted to the validation study, and a novel susceptibility locus, PDE1A|DNAJC10, was identified that maps to 2q32.1 (rs71427857, P = 7.9 × 10⁻⁹, odds ratio in the validation study = 5.18; 95% CI 1.86 – 14.42). We also found the augmentation of PDE1A protein in distal remodeled pulmonary artery walls in idiopathic PAH patients. Given that phosphodiesterase 5 inhibitors are effective for the treatment of idiopathic and heritable PAH, our findings suggest that PDE1A could be a novel therapeutic target of PAH.
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Vinpocetine protects against a range of degenerative conditions and insults of the central nervous system via multiple modes of action. Little is known however of its effects on metabolism. This may be highly relevant as vinpocetine is highly protective against ischemia, a process which inhibits normal metabolic function. This study characterizes vinpocetine's effects on metabolism using the ischemic retina as a model. Vinpocetine reduced the metabolic demand of the retina following ex vivo hypoxia and ischemia to normal levels based on lactate dehydrogenase (LDH) activity. Vinpocetine delivered similar effects in an in vivo model of retinal ischemia-reperfusion, possibly through increasing glucose availability. Vinpocetine's effects on glucose also appeared to improve glutamate homeostasis in ischemic Müller cells. Other actions of vinpocetine following ischemia/reperfusion, such as reduced cell death and improved retinal function, were possibly a combination of the drug's actions on metabolism and other retinal pathways. Vinpocetine's metabolic effects appeared independent of its other known actions in ischemia as it recovered retinal function in a separate metabolic model where the glutamate to glutamine metabolic pathway was inhibited in Müller cells. The results of this study indicate that vinpocetine mediates ischemic damage partly through altered metabolism and has potential beneficial effects as a treatment for ischemia of neuronal tissues. Copyright © 2015, American Journal of Physiology - Cell Physiology.
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Rationale: Neointimal hyperplasia characterized by abnormal accumulation of vascular smooth muscle cells (SMCs) is a hallmark of occlusive disorders such as atherosclerosis, postangioplasty restenosis, vein graft stenosis, and allograft vasculopathy. Cyclic nucleotides are vital in SMC proliferation and migration, which are regulated by cyclic nucleotide phosphodiesterases (PDEs). Objective: Our goal is to understand the regulation and function of PDEs in SMC pathogenesis of vascular diseases. Methods and results: We performed screening for genes differentially expressed in normal contractile versus proliferating synthetic SMCs. We observed that PDE1C expression was low in contractile SMCs but drastically elevated in synthetic SMCs in vitro and in various mouse vascular injury models in vivo. In addition, PDE1C was highly induced in neointimal SMCs of human coronary arteries. More importantly, injury-induced neointimal formation was significantly attenuated by PDE1C deficiency or PDE1 inhibition in vivo. PDE1 inhibition suppressed vascular remodeling of human saphenous vein explants ex vivo. In cultured SMCs, PDE1C deficiency or PDE1 inhibition attenuated SMC proliferation and migration. Mechanistic studies revealed that PDE1C plays a critical role in regulating the stability of growth factor receptors, such as PDGF receptor β (PDGFRβ) known to be important in pathological vascular remodeling. PDE1C interacts with low-density lipoprotein receptor-related protein-1 and PDGFRβ, thus regulating PDGFRβ endocytosis and lysosome-dependent degradation in an low-density lipoprotein receptor-related protein-1-dependent manner. A transmembrane adenylyl cyclase cAMP-dependent protein kinase cascade modulated by PDE1C is critical in regulating PDGFRβ degradation. Conclusions: These findings demonstrated that PDE1C is an important regulator of SMC proliferation, migration, and neointimal hyperplasia, in part through modulating endosome/lysosome-dependent PDGFRβ protein degradation via low-density lipoprotein receptor-related protein-1.
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Immune responses play an important role in the pathophysiology of atherosclerosis and ischemic stroke. Atherosclerosis is a common condition that increases the risk of stroke. Hyperlipidemia damages endothelial cells, thus initiating chemokine pathways and the release of inflammatory cytokines-this represents the first step in the inflammatory response to atherosclerosis. Blocking blood flow in the brain leads to ischemic stroke, and deprives neurons of oxygen and energy. Damaged neurons release danger-associated molecular patterns, which promote the activation of innate immune cells and the release of inflammatory cytokines. The nuclear factor κ-light-chain-enhancer of activated B cells κB (NF-κB) pathway plays a key role in the pathogenesis of atherosclerosis and ischemic stroke. Vinpocetine is believed to be a potent anti-inflammatory agent and has been used to treat cerebrovascular disorders. Vinpocetine improves neuronal plasticity and reduces the release of inflammatory cytokines and chemokines from endothelial cells, vascular smooth muscle cells, macrophages, and microglia, by inhibiting the inhibitor of the NF-κB pathway. This review clarifies the anti-inflammatory role of vinpocetine in atherosclerosis and ischemic stroke.
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Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Since both cAMP and cGMP signaling are essential in a variety of cellular functions, including neuroplasticity and neuroprotection, PDE-Is are receiving increased attention as possible targets for treatment of age-related cognitive decline as well as Alzheimer's disease (AD). In this review we will give a translational overview of the preclinical and clinical data on PDE-Is and cognition enhancement focusing on aging and AD. PDE2, 4 and 5 inhibitors improved memory performance in both aged animals and models of AD. Treatment with a PDE3-I or PDE7-I has not been tested in aged animals yet, but in mouse models of AD both PDE-Is improved memory performance. Unfortunately, there are no peer-reviewed studies on the effects of PDE-I treatment in aged human subjects except the possible positive effect on memory impairment of the PDE1-I vinpocetine. Three other types of PDE-Is have been tested on cognition in mild to moderate AD patients: the PDE3-I cilostazol is being tested as a co-treatment to the acetylcholinesterase inhibitor donepezil, but with inconsistent results; the PDE4-I MK-0952 has been tested, although the outcome has not been disclosed yet; and the PDE9-I PF-04447943 was reported to have no effects on cognition. Obviously, the demonstration of clinical proof of concept for cognition enhancing effects of PDE-Is and the generation of isoform selective PDE-Is are the final hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-associated cognitive decline or AD.
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Background: Diabetes exacerbates abnormal vascular smooth muscle cell (VSMC) accumulation in response to arterial wall injury. Vinpocetine has been shown to improve vascular remolding; however, little is known about the direct effects of vinpocetine on vascular complications mediated by diabetes. The objective of this study was to determine the effects of vinpocetine on hyperglycemia-facilitated neointimal hyperplasia and explore its possible mechanism. Materials and methods: Nondiabetic and diabetic rats were subjected to balloon injury of the carotid artery followed by 3-week treatment with either vinpocetine (10 mg/kg/day) or saline. Morphological analysis and proliferating cell nuclear antigen (PCNA) immunostaining were performed on day 21. Rat VSMCs proliferation was determined with 5-ethynyl-20-deoxyuridine cell proliferation assays. Chemokinesis was monitored with scratch assays, and production of reactive oxygen species (ROS) was assessed using a 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) flow cytometric assay. Apoptosis was detected by annexin V-FITC/PI flow cytometric assay. Cell signaling was assessed by immunblotting. Results: Vinpocetine prevented intimal hyperplasia in carotid arteries in both normal (I/M ratio: 93.83 ± 26.45% versus 143.2 ± 38.18%, P<0.05) and diabetic animals (I/M ratio: 120.5 ± 42.55% versus 233.46 ± 33.98%, P<0.05) when compared to saline. The in vitro study demonstrated that vinpocetine significantly inhibited VSMCs proliferation and chemokinesis as well as ROS generation and apoptotic resistance, which was induced by high glucose (HG) treatment. Vinpocetine significantly abolished HG-induced phosphorylation of Akt and JNK1/2 without affecting their total levels. For downstream targets, HG-induced phosphorylation of IκBα was significantly inhibited by vinpocetine. Vinpocetine also attenuated HG-enhanced expression of PCNA, cyclin D1 and Bcl-2. Conclusions: Vinpocetine attenuated neointimal formation in diabetic rats and inhibited HG-induced VSMCs proliferation, chemokinesis and apoptotic resistance by preventing ROS activation and affecting MAPK, PI3K/Akt, and NF-κB signaling.
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Recent studies have found additional roles for vinpocetine, a potent phosphodiesterase type I inhibitor, in anti-proliferation and anti-inflammation of vascular smooth muscle cells and cancer cells via different mechanisms. In this study, we attempted to investigate whether vinpocetine protected against atherosclerotic development in apoE(-/-) mice and explore the underlying anti-atherogenic mechanisms in macrophages. Vinpocetine markedly decreased atherosclerotic lesion size in apoE(-/-) mice measured by oil red O. Masson's trichrome staining and immunohistochemical analyses revealed that vinpocetine significantly increased the thickness of fibrous cap, reduced the size of lipid-rich necrotic core and attenuated inflammation. In vitro experiments exhibited a significant decrease in monocyte adhesion treated with vinpocetine. Further, active TNF-α, IL-6, monocyte chemoattractant protein-1and matrix metalloproteinase-9 expression induced by ox-LDL were attenuated by vinpocetine in a dose-dependent manner. Similarly, ox-LDL-induced reactive oxygen species were significantly repressed by vinpocetine. Both western blot and luciferase activity assay showed that vinpocetine inhibited the enhanced Akt, IKKα/β, IκBα phosphorylation and NF-κB activity induced by ox-LDL, and the inhibition of NF-κB activity was partly caused by Akt dephosphorylation. However, knockdown of PDE1B did not affect Akt, IKKα/β and IκBα phosphorylation. These results suggest that vinpocetine exerts anti-atherogenic effects through inhibition of monocyte adhesion, oxidative stress and inflammatory response, which are mediated by Akt/NF-κB dependent pathway but independent of PDE1 blockade in macrophages.
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Hepatic ischemia–reperfusion (IR) injury is a clinical problem that leads to cellular damage and organ dysfunction mediated mainly via production of reactive oxygen species and inflammatory cytokines. Vinpocetine has long been used in cerebrovascular disorders. This study aimed to explore the protective effect of vinpocetine in IR injury to the liver. Ischemia was induced in rats by clamping the common hepatic artery and portal vein for 30 min followed by 30 min of reperfusion. Serum transaminases and liver lactate dehydrogenase (LDH) activities, liver inflammatory cytokines, oxidative stress biomarkers, and liver histopathology were assessed. IR resulted in marked histopathology changes in liver tissues coupled with elevations in serum transaminases and liver LDH activities. IR also increased the production of liver lipid peroxides, nitric oxide, and inflammatory cytokines interleukin-1β and interleukin-6, in parallel with a reduction in reduced glutathione and interleukin-10 in the liver. Pretreatment with vinpocetine protected against liver IR-induced injury, in a dose-dependent manner, as evidenced by the attenuation of oxidative stress as well as inflammatory and liver injury biomarkers. The effects of vinpocetine were comparable with that of curcumin, a natural antioxidant, and could be attributed to its antioxidant and anti-inflammatory properties.
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Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca2+/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage–operated Ca2+ channels, glutamate receptors and voltage dependent Na+-channels; the latest being especially relevant to the neuroprotective action of vinpocetine. The good brain penetration profile and heterogenous brain distribution pattern (mainly in the thalamus, basal ganglia and visual cortex) of labelled vinpocetin were demonstrated by positron emission tomography in primates and man. Multicentric, randomized, placebo-controlled clinical studies proved the efficacy of orally administered vinpocetin in patients with organic psychosyndrome. Recently positron emission tomography studies have proved that vinpocetine is able to redistribute regional cerebral blood flow and enhance glucose supply of brain tissue in ischemic post-stroke patients.
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Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca(2+)/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.
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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.
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Neuronal plasticity is an essential property of the brain that is impaired in different neurological conditions. Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. These neuronal plasticity enhancement properties make PDE1 inhibitors good candidates as therapeutic agents in many neurological conditions. However, the lack of specificity of the drugs currently available poses a challenge to the systematic evaluation of the beneficial effect of these agents. The development of more specific drugs may pave the way for the use of PDE1 inhibitors as therapeutic agents in cases of neurodevelopmental conditions such as fetal alcohol spectrum disorders and in degenerative disorders such as Alzheimer's and Parkinson's.
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Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3' 5'-monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng·min(-1)) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (E(max)168% ± 8% vs 136% ± 4%) and small mesenteric arteries (SMA; E(max)170% ± 6% vs 143% ± 3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 μmol/L) reduced PE-induced contraction in aortas from Ang II rats (E(max)94% ± 12%) but not in controls (154% ± 7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1 ± 0.1 vs 5.9 ± 0.06), but not in controls (6.0 ± 0.03 vs 6.1 ± 0.04). Sildenafil (10 μmol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 μmol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (E(max)82% ± 12% vs 445 ± 5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1 ± 0.3 vs 5.3 ± 0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from Ang II, contributing to increased contractile responsiveness.
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Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-alpha-induced NF-kappaB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-alpha- or LPS-induced up-regulation of proinflammatory mediators, including TNF-alpha, IL-1beta, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-alpha- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-kappaB-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca(2+) regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases.
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Immunity and inflammation play critical roles in the pathogenesis of acute ischemic stroke. Therefore, immune intervention, as a new therapeutic strategy, is worthy of exploration. Here, we tested the inflammation modulator, vinpocetine, for its effect on the outcomes of stroke. For this multi-center study, we recruited 60 patients with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h but lasted less than 48 h. These patients, after random division into two groups, received either standard management alone (controls) or standard management plus vinpocetine (30 mg per day intravenously for 14 consecutive days, Gedeon Richter Plc., Hungary). Vinpocetine treatment did not change the lymphocyte count; however, nuclear factor kappa-light-chain-enhancer of activated B cell activation was inhibited as seen not only by the increased transcription of IκBα mRNA but also by the impeded phosphorylation and degradation of IκBα and subsequent induction of pro-inflammatory mediators. These effects led to significantly reduced secondary lesion enlargement and an attenuated inflammation reaction. Compared to controls, patients treated with vinpocetine had a better recovery of neurological function and improved clinical outcomes during the acute phase and at 3-month follow-up. These findings identify vinpocetine as an inflammation modulator that could improve clinical outcomes after acute ischemic stroke. This study also indicated the important role of immunity and inflammation in the pathogenesis of acute ischemic stroke and the significance of immunomodulatory treatment. Clinical trial registration information: www.clinicaltrials.gov . Identifier: NCT02878772.
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Background and purpose: Phosphodiesterase enzymes (PDE1-11) break down cyclic nucleotides and are important in the regulation of the cardiovascular system. The purpose of the present study was to investigate the effect on the cardiovascular system of two novel selective PDE1 inhibitors, Lu AF41228 and Lu AF58027. Experimental approach: We used rat mesenteric small arteries (internal diameters of 200-300 µm), RT-PCR and measurement of isometric wall tension. The effect of Lu AF41228 and Lu AF58027 on heart rate and blood pressure was assessed in both anesthetized and conscious male rats. Key results: Nanomolar concentrations of Lu AF41228 and Lu AF58027 inhibited PDE1A, PDE1B, and PDE1C enzyme activity, while micromolar concentrations were required to observe inhibitory effects at other PDEs. RT-PCR revealed expression of PDE1A, PDE1B, and PDE1C in rat brain, heart, and aorta, but only PDE1A and PDE1B in mesenteric arteries. In rat isolated mesenteric arteries contracted with phenylephrine or U46619, Lu AF41228 and Lu AF58027 induced concentration-dependent relaxations which were markedly reduced by inhibitors of guanylate cyclase, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), and adenylate cyclase, SQ22536 (9-(tetrahydro-2-furanyl)-9H-purin-6-amine, 9-THF-Ade), and in preparations without endothelium. In anesthetized rats Lu AF41228 and Lu AF58027 dose-dependently lowered mean blood pressure and increased heart rate. In conscious rats with telemetric pressure transducers, repeated dosing of Lu AF41228 lowered mean arterial blood pressure 10-15 mmHg and increased heart rate. Conclusions and implications: The findings that these novel PDE1 inhibitors induce vasodilation and blood pressure lowering suggest a potential use of these vasodilators in the treatment of hypertension and vasospasm.
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Neuroprotection against 100 [micro]M veratridine-induced cell death and inhibition of voltage-dependent sodium currents by phenytoin, carbamazepine, lidocaine and vinpocetine were studied in rat primary cerebrocortical cultures. Neuroprotective efficacies and sodium channel blocking potencies of these drugs failed to show a correlation, suggesting that (i) mechanisms other than sodium channel blockade may be involved in the neuroprotection, and/or (ii) inhibitory efficacy against veratridine- and voltage-activated channels may differ remarkably. (C) Lippincott-Raven Publishers.
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Acute kidney injury (AKI) represents a complex clinical condition associated with significant morbidity and mortality. Approximately 19%-33% AKI episodes in hospitalized patients are related to drug-induced nephrotoxicity. Although considered safe, non-steroidal anti-inflammatory drugs such as diclofenac have received special attention in the past years due to the potential risk of renal damage. Vinpocetine is a nootropic drug known to have anti-inflammatory properties. In the present study, we investigated the effect and mechanisms of vinpocetine in a model of diclofenac-induced AKI. We observed that diclofenac increased proteinuria and blood urea, creatinine, and oxidative stress levels 24 h after its administration. In renal tissue, diclofenac also increased oxidative stress and induced morphological changes consistent with renal damage. Moreover, diclofenac induced kidney cells apoptosis, up-regulated proinflammatory cytokines, and induced the activation of NF-κB in renal tissue. On the other hand, vinpocetine reduced diclofenac-induced blood urea and creatinine. In the kidneys, vinpocetine inhibited diclofenac-induced oxidative stress, morphological changes, apoptosis, cytokine production, and NF-κB activation. To our knowledge, this is the first study demonstrating that diclofenac-induced AKI increases NF-κB activation, and that vinpocetine reduces the nephrotoxic effects of diclofenac. Therefore, vinpocetine is a promising molecule for the treatment of diclofenac-induced AKI.
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Vinpocetine is a potent antioxidant and free radical scavenger. We investigated the effects of vinpocetine on torsion/detorsion (T/D) induced testicular damage, HSP-70 expression and germ cell apoptosis in rats. Sixty Wistar albino adult male rats were divided into five groups of 12. The groups comprised a control group, a sham treated group, a T/D group, a vinpocetine treated group, and a T/D plus vinpocetine treated group. The left testis of each rat was subjected to unilateral torsion followed by detorsion after 2 h. Vinpocetine was administered intraperitoneally immediately and for 10 days following detorsion. At the end of the study, the rats were sacrificed and their testes removed and processed. HSP-70 expression, apoptosis and histopathological damage scores were determined for each group. Testicular T/D caused significant increases in apoptosis and HSP-70 expression, and a significant decrease in Johnsen’s testicular biopsy scores and mean seminiferous tubule diameter. Vinpocetine ameliorated testicular histopathology and HSP-70 expression in the T/D + vinpocetine group. Consequently, vinpocetine may prevent testicular injury following testicular torsion owing to its antioxidant effects.
Article
Plasmacytoid dendritic cells (pDCs) exert dual roles in immune responses through inducing inflammation and maintaining immune tolerance. A switch of pDC phenotype from pro-inflammation to tolerance has therapeutic promise in the treatment of autoimmune diseases. Vinpocetine, a vasoactive vinca alkaloid extracted from the periwinkle plant, has recently emerged as an immunomodulatory agent. In this study, we evaluated the effect of vinpocetine on phenotype of pDCs isolated from C57BL/6 mice and explored its possible mechanism. Our data showed that vinpocetine significantly downregulated the expression of CD40, CD80, and CD86 on pDCs and increased the expression of translocator protein (TSPO), the specific receptor of vinpocetine, in pDCs. Vinpocetine significantly inhibited the Toll-like receptor 9 signaling pathway and reduced the secretion of related cytokines in pDCs through TSPO. Furthermore, viability of pDCs was significantly promoted by vinpocetine. These findings imply that vinpocetine serves as an immunomodulatory agent for pDCs and may be applied for the treatment of pDCs-related autoimmune diseases.
Article
Vinpocetine has been shown to have beneficial effects for tissues of the central nervous system subjected to ischemia and other related metabolic insults. We recently showed vinpocetine promotes glucose availability, prevents unregulated cation channel permeability and regulates glial reactivity when present during retinal ischemia. Less is known however about the ability of vinpocetine to protect against future ischemic insults. This study explores the effect of vinpocetine when used as a pre-treatment in an ex vivo model for retinal ischemia using cation channel permeability of agmatine (AGB) combined with immunohistochemistry as a measure for cell functionality. We found that vinpocetine pre-treatment reduced cation channel permeability and apoptotic marker immunoreactivity in the GCL and increased parvalbumin immunoreactivity of inner retinal neurons in the inner nuclear layer following ischemic insult. Vinpocetine pre-treatment also reduced Müller cell reactivity following ischemic insults of up to 120 min compared to untreated controls. Many of vinpocetine's effects however were transient in nature suggesting the drug can protect retinal neurons against future ischemic damage but may have limited long-term applications.
Article
Objective The objective of this study was to evaluate the efficacy and safety of intravenous vinpocetine administration as part of a comprehensive treatment for acute cerebral infarction in a Chinese population. Methods610 acute cerebral infarction patients were randomized into two groups: the vinpocetine group (469 patients) received cytidine disphosphate choline 0.4–0.5 g in combination with aspirin 75–100 mg or clopidogrel 75 mg once daily, plus vinpocetine 30 mg intravenously once daily for 7 days, while the control group (141 patients) received cytidine disphosphate choline 0.4–0.5 g in combination with aspirin 75–100 mg or clopidogrel 75 mg once daily for 7 days. Additionally, patients received medications for symptoms such as hypertension, hyperglycemia, hyperlipidemia, and intracranial hypertension when necessary. Mini-Mental State Examination (MMSE), National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale, and Barthel Index (BI) scores and transcranial doppler (TCD) were assessed at baseline, 7, 14, and 90 days after treatment. Adverse events (AEs) and abnormalities in blood, urine, liver, and kidney function were monitored. ResultsMMSE, NIHSS, and BI scores were significantly higher in the vinpocetine group than in the control group 90 days after treatment, indicating significantly improved cognitive skill, neurological function, and quality of life (QOL) in the vinpocetine group versus the control group. Importantly, such effects of vinpocetine were maintained over time. In addition, TCD monitoring showed significantly increased cerebral blood flow associated with vinpocetine versus control. No significant difference in safety was noted between the two groups. Conclusions When used as part of treatment for acute cerebral infarction, vinpocetine improves patients’ cerebral blood flow, cognitive quality, neurological functions, and QOL. Vinpocetine could be an effective and safe component of treatment regimen for acute cerebral infarction.
Article
Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1d/- mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1d/- mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1d/- to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1d/- mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1d/- mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9-and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of PDE1A single nucleotide polymorphisms with diastolic blood pressure (DBP; β =0.28, P=2.47×10-5) and carotid intima-media thickness (cIMT; β =-0.0061, P=2.89×10-5). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy.
Article
Vascular smooth muscle cells (VSMCs) play critical roles in arterial remodeling with aging, hypertension, and atherosclerosis. VSMCs exist in diverse phenotypes and exhibit phenotypic plasticity, e.g. changing from a quiescent/contractile phenotype to an active, myofibroblast-like, often called "synthetic" phenotype. Synthetic VSMC cells are able to proliferate, migrate, and secrete extracellular matrix (ECM) proteinases and ECM proteins. In addition, they produce pro-inflammatory molecules, providing an inflammatory microenvironment for leukocyte penetration, accumulation and activation. The aging VSMCs have also shown changes in cellular phenotype, responsiveness to contracting and relaxing mediators, replicating potential, matrix synthesis, inflammatory mediators and intracellular signaling. VSMC dysfunction plays a key role in age-associated vascular remodeling. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing cyclic nucleotide hydrolysis, play a critical role in regulating the amplitude, duration, and compartmentalization of cyclic nucleotide signaling. Abnormal alterations of PDEs and subsequent changes of cyclic nucleotide homeostasis have been implicated in a number of different diseases. In the study published in this issue, Nino et al have shown that in cultured senescent human VSMCs, PDE1A and PDE1C mRNA levels are sognificanly up-regulated and Inhibition of PDE1 activity with vinpocetine reduced cellular senescent makers in senescent VSMCs. Moreover, in the premature aging mice with genomic instability (Ercc1(d/-)), impaired aortic ring relaxation in response to sodium nitroprusside (SNP, a NO donor) was also largely improved by vinpocetine. More interestingly, using data from human Genome-Wide Association Studies (GWAS), it has been found that PDE1A single nucleotide polymorphisms (SNP) is significantly associated with diastolic blood pressure and carotid intima/media thickening, two hallmarks of human vascular dysfunction in aging. These findings establish a strong relationship between PDE1 expression regulation and vascular abnormalities in aging.
Article
Mucin overproduction is a hallmark of otitis media (OM). Streptococcus pneumoniae is one of the most common bacterial pathogens causing OM. Mucin MUC5AC plays an important role in mucociliary clearance of bacterial pathogens. However, if uncontrolled, excessive mucus contributes significantly to conductive hearing loss. Currently, there is a lack of effective therapeutic agents that suppress mucus overproduction. In this study, we show that a currently existing antistroke drug, vinpocetine, a derivative of the alkaloid vincamine, inhibited S. pneumoniae-induced mucin MUC5AC upregulation in cultured middle ear epithelial cells and in the middle ear of mice. Moreover, vinpocetine inhibited MUC5AC upregulation by inhibiting the MAPK ERK pathway in an MKP-1-dependent manner. Importantly, ototopical administration of vinpocetine postinfection inhibited MUC5AC expression and middle ear inflammation induced by S. pneumoniae and reduced hearing loss and pneumococcal loads in a well-established mouse model of OM. Thus, these studies identified vinpocetine as a potential therapeutic agent for inhibiting mucus production in the pathogenesis of OM.
Article
In response to lipopolysaccharide (LPS), tissue resident macrophages and recruited neutrophils produce inflammatory mediators through activation of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. These mediators include inflammatory cytokines and reactive oxygen species that, in turn, sensitize nociceptors and lead to inflammatory pain. Vinpocetine is a nootropic drug widely used to treat cognitive and neurovascular disorders, and more recently its anti-inflammatory properties through inhibition of NF-κB activation have been described. In the present study, we used the intraplantar and intraperitoneal LPS stimulus in mice to investigate the effects of vinpocetine pre-treatment (3, 10, or 30 mg/kg by gavage) in hyperalgesia, leukocyte recruitment, oxidative stress, and pro-inflammatory cytokine production (TNF-α, IL-1β, and IL-33). LPS-induced NF-κB activation and cytokine production were investigated using RAW 264.7 macrophage cell in vitro. Vinpocetine (30 mg/kg) significantly reduces hyperalgesia to mechanical and thermal stimuli, and myeloperoxidase (MPO) activity (a neutrophil marker) in the plantar paw skin, and also inhibits neutrophil and mononuclear cell recruitment, superoxide anion and nitric oxide production, oxidative stress, and cytokine production (TNF-α, IL-1β and IL-33) in the peritoneal cavity. At least in part, these effects seem to be mediated by direct effects of vinpocetine on macrophages, since it inhibited the production of the same cytokines (TNF-α, IL-1β and IL-33) and the NF-κB activation in LPS-stimulated RAW 264.7 macrophages. Our results suggest that vinpocetine represents an important therapeutic approach to treat inflammation and pain induced by a gram-negative bacterial component by targeting NF-κB activation and NF-κB-related cytokine production in macrophages. Copyright © 2015. Published by Elsevier Ireland Ltd.