Doxorubicin (DOX) is an effective antineoplastic agent whose clinical use is limited by cardiotoxicity. This study aimed to evaluate the potential protective effects of vinpocetine (VINPO) in an acute DOX-induced cardiotoxicity model in rats. Thirty-two male Wistar albino rats were randomly assigned to four groups: Control, DOX (20mg/kg, single intraperitoneal dose), VINPO (10mg/kg for 3 days), and VINPO + DOX. Forty-eight hours after DOX administration, electrocardiography (ECG), heart rate (HR), blood pressure (BP), and oxygen saturation were recorded. Serum troponin-I, creatin kinase (CK), and CK-MB mass levels were measured. Myocardial and vascular tissues were analyzed for malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH). Histopathological and caspase-3 immunohistochemical evaluations were also performed. DOX administration resulted in significant alterations in vascular antioxidant enzyme activities and increased myocardial histopathological injury scores compared with controls. VINPO partially modulated certain oxidative stress parameters, particularly vascular SOD and CAT activities. However, serum cardiac biomarkers, ECG parameters, and caspase-3 immunoreactivity did not differ significantly among groups. Histopathological myocardial injury was not significantly improved in the VINPO + DOX group compared with DOX alone. VINPO demonstrated modest modulatory effects on selected oxidative stress parameters in acute DOX-induced cardiotoxicity. However, these effects were not consistently supported by functional or histopathological findings. Further studies using more severe or longer-term cardiotoxicity models are warranted to clarify its cardioprotective potential.

An innovative and eco-friendly approach was developed for estimating vinpocetine (VPO) in its pharmaceutical dosage form. The proposed method relied on using a fluorescent nanoprobe synthesized from black-eyed Cowpeas beans and thiourea via microwave irradiation within 4 min for the first time. The synthesized nitrogen and sulfur-doped carbon quantum dots (N, S-doped CQDs) demonstrated an excellent fluorescence peak at 382 nm after excitation at 320 nm. Vinpocetine's superior capability for quantitatively quenching the prepared N, S-doped CQDs' fluorescence enabled its spectrofluorimetric estimation for the first time. The proposed method showed excellent linearity over a concentration range from 5.0 to 85.0 μM with a high sensitivity level illustrated by the low values of LOD and LOQ (1.03 and 3.13 μM, respectively). The method was applied to content-uniformity testing and confirmed compliance with dosage uniformity requirements. The method met the acceptance criteria adopted by the ICH guidelines regarding the validation parameters. The cytotoxicity impact of the generated N, S-doped CQDs was investigated, and the results revealed their high biocompatibility. The environmental friendliness of the proposed method was assessed by implementing ComplexMoGAPI, AGREE, and AGSA tools, and the findings promote its future applicability and sustainability in the analytical quality control sector.

A high-strength dense supramolecular gellan gel - metal-phenolic network gel: Application in the control of crystallization behavior of Active Pharmaceutical Ingredients.

There are no curative treatments for Parkinson's disease (PD), and current treatments focus on symptomatic management. This study aimed to investigate the beneficial effects of combining L-DOPA/Carbidopa with essential cofactors (vitamin (VIT) B complex and coenzyme Q10 (CoQ10)), alone or in conjunction with vinpocetine (VIN) or cocoa, as a potential strategy to enhance neuroprotection in rotenone (RT)-induced PD rat model, highlighting mechanistic insights into their underlying neuroprotective mechanisms and focusing on addressing oxidative stress, inflammation, autophagy, and apoptosis. These combinations were tested on adult male Wistar rats allocated into six groups. Group I received saline (normal control), while groups II-VI were injected with RT for 19 days to induce PD. Group II received RT alone, group III received daily oral L-DOPA/Carbidopa, and groups IV-VI received L-DOPA/Carbidopa with VIT B complex and CoQ10, either alone (Group IV) or combined with cocoa (Group V) or VIN (Group VI). These treatments markedly improved RT-induced perturbations in locomotor and cognitive outcomes; neurotransmitters' levels; oxidative stress (Nrf2/HO-1, MDA, INOS, SOD and TAC); inflammatory (NF-κB, TNF-α, IL-1β, GFAP and COX-2); neurotrophic (AKT/CREB/BDNF); apoptotic (BAX, caspase-3, AIF, and Bcl-2); and autophagic (AMPK/SIRT-1/Beclin-1) biomarkers; histopathological findings and tyrosine hydroxylase (TH) immunoexpression. Furthermore, the best outcomes were observed in cocoa and VIN combinations. These results indicated that combining L-DOPA with CoQ10 and VIT B complex in conjunction with either VIN or cocoa could provide a potential strategy for managing motor impairments and preventing neurodegeneration in PD. The interaction between key signaling pathways, including Nrf2/HO-1, NF-kB, AMPK/SIRT-1, and AKT/GSK-3β/CREB/BDNF, likely mediates this effect. However, further clinical validation is required to assess this approach's real-world applicability and therapeutic potential.

ABSTRACT Alzheimer’s disease (AD), which is marked by gradual neuronal decline and subsequent loss of cognitive functions and memory, poses significant treatment challenges. The present study involved the development, in vitro, and in vivo evaluation of a novel intranasal mucoadhesive in-situ gel of vinpocetine (VIN) with the aim to target the brain. An innovative gel formulation composed of poloxamer 407, HPMC E15 LV, and citric acid as a solubilizer was developed by 23 Factorial Design. The developed optimal formulation exhibited favorable rheological properties as it displayed ideal gelation time (31.6 ± 1.52 sec), optimum gelling temperature (32 ± 1.0 °C), enhanced mucoadhesive strength (6622 ± 2.64 dynes/cm2), prolonged adhesion (7.22 ± 0.57 hrs) compared with the baseline formulation (F18), and improved drug release in 12 hrs (39.59 ± 1.6%). In vivo, pharmacokinetics revealed a significant increase in Cmax (∼2-fold) and AUC0-t (∼2-fold) in the brain with the in-situ intranasal gel compared to the oral route. In the rat model of AD, in-situ intranasal gel demonstrated significantly greater efficacy (p < 0.001) than oral administration in alleviating AD symptoms as evidenced by behavioral and histological studies. Thus, VIN in-situ gel can be safe and noninvasive for nose-to-brain drug delivery.

Objectives 5-Fluorouracil (5-FU) is a chemotherapy drug commonly prescribed in cancer management. Unfortunately, intestinal mucositis restricts 5-FU clinical use. Vinpocetine (VNP) is a synthetic alkaloid that is derived from vincamine. Our study was conducted to elucidate the intestinal protective effects of VNP on 5-FU intestinal injury in rats and explore the underlying mechanisms. Materials and methods 5-FU was injected i.p. for five days, while VNP was given P.O (5 and 10 mg/kg). Results VNP effectively mitigates oxidative stress by a significant increase in GSH and SOD and decreasing MDA content mediated by Nrf2, HO-1 upregulation, and significant Keap1 downregulation. VNP mitigated inflammatory perturbations by decreasing MPO, TNF-α, IL-1β, and IL-6 facilitated by downregulating NF-κB and TLR4 and upregulating SOCS3 levels. In addition, the RIPK1, RIPK3, MLKL, and caspase-8 expression levels were significantly decreased, evidenced improvement of intestinal necroptosis by VNP. Conclusion Hence, VNP potently prevents intestinal injury induced by 5-FU by modulating Keap1/Nrf2/HO-1, NF-κB/TLR4/SOCS3, and RIPK1/RIPK3/MLKL signals.

Traumatic brain injury (TBI), also known as intracranial injury, is a common condition with the highest incidence rate among neurodegenerative disorders and poses a significant public health burden. Various methods are used in the treatment of TBI, but the effects of cold-induced traumatic brain injury have not been thoroughly studied. In this context, vinpocetine (VPN), derived from Vinca minor, exhibits notable anti-inflammatory and antioxidant properties. VPN is known for its neuroprotective role and is generally utilized for treating various neurodegenerative disorders. However, the function of VPN after cold-induced TBI needs to be studied in more detail. This study aims to investigate the neuroprotective effects of VPN at varying doses (5mg/kg or 10mg/kg) after cold-induced TBI. C57BL/6 mice were sacrificed 2 or 28days after cold-induced TBI. Results indicate that VPN administration significantly reduces brain infarct volume, brain swelling, blood-brain barrier disruption, and DNA fragmentation in a dose-dependent manner. Additionally, VPN enhances neuronal survival in the ipsilesional cortex. In the long term, VPN treatment (5mg/kg/day or 10mg/kg/day, initiated 48h post-TBI) improved locomotor activity, cell proliferation, neurogenesis, and decreased whole brain atrophy, specifically motor cortex atrophy. We performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to elucidate the underlying mechanisms to profile proteins and signaling pathways influenced by prolonged VPN treatment post-TBI. Notably, we found that 192 different proteins were significantly altered by VPN treatment, which is a matter of further investigation for the development of therapeutic targets. Our study has shown that VPN may have a neuroprotective role in cold-induced TBI.

The current study was assigned to determine the putative preventive role of vinpocetine (VIN) in cervical hyperkeratosis (CHK) in female rats. Estradiol Benzoate (EB) was utilized in a dose f (60 μg/100 g, i.m) three times/week for 4 weeks to induce cervical hyperkeratosis. VIN was administered alone in a dose of (10 mg/kg/day, orally) for 4 weeks and in the presence of EB. Levels of malondialdehyde (MDA), total nitrites (NOx), reduced glutathione (GSH), interleukin-18 (IL-18), IL-1β, tumor necrosis factor-alpha (TNF-α) were measured in cervical tissue. The expression of NLRP3/GSDMD/Caspase-1, and SIRT1/Nrf2 was determined using ELISA. Cervical histopathological examination was also done. EB significantly raised MDA, NOx, TNF-α, IL-18, IL-1β, and GSDMD and up-regulated NLRP3/Caspase-1 proteins. However, GSH, SIRT1, and Nrf2 levels were reduced in cervical tissue. VIN significantly alleviates all biochemical and histopathological abnormalities. VIN considerably mitigates EB-induced cervical hyperkeratosis via NLRP3-induced pyroptosis and SIRT1/Nrf2 signaling pathway.

Vinpocetine (VP) is distributed after oral and intravenous administration, and its uptake in the thalamus, basal ganglia, and visual cortex. Due to poor bioavailability (~7%) and marked first-pass effect (~75%), including a short half-life (2-3 h), oral administration of VP is limited. It requires frequent administration of the drug to obtain a therapeutic effect. Attempts to overcome these difficulties include the use of new drug delivery systems and/or alternative routes of drug administration. One possibility is the common administration of lipid emulsion and drug using the same catheter. However, this procedure is not recommended due to potential interaction and lack of safety data. For this purpose, we checked the compatibility of VP solutions with eight commercially available parenteral nutrition admixtures, i.e., Lipoflex special, Omegaflex special, Lipoflex peri, Omegaflex peri, Kabiven, SmofKabiven, Kabiven Peripheral, and Olimel Peri N4E. Coadministration is only possible if the stability of the drug and the lipid emulsion is confirmed. The available data are scarce and only concern the incompatibility of VP with ibuprofen. Compatibility tests were carried out in simulated administration through a Y-site connector using clinical flow rates. The stability of the drug and lipid emulsion was assessed by visual inspection and measurement of pH, osmolality, particle size as mean droplet diameter (MDD) and percentage of lipids residing in globules larger than 5 µm (PFAT5), zeta potential, polydispersity index, and lipid-free parenteral nutrition admixture(PNA) turbidity. The results of the compatibility of VP with eight commercial PN admixtures showed that all lipid emulsions show different signs of destabilization. In the studied samples, particles larger than 1000 nm, a significant increase in MDD, zeta potential, and loss of homogeneity visible as an increase in the polydispersity index were observed. Most of the samples had PFAT5 above the USP limit (0.05%). Taking into account the obtained data, VP should not be administered with the studied lipid emulsions for parenteral nutrition.

Background: One of the most commonly used anti-cancer medications for various tumors is 5-fluorouracil (5-FU). However due to the accompanying nephrotoxicity, its clinical use is restricted. Vinpocetine (VNP) is a derivative of vincamine alkaloid used to treat cognitive disorders and cerebrovascular diseases. Methods: In this study, 40 adult male Wistar rats were randomized into five groups, untreated animals (control), treated with VNP (20mg/kg), 5-FU (30mg/kg), 5-FU+VNP (10mg/kg), and 5-FU+VNP (20mg/kg). The results of all groups were compared to 5-FU rats. Results: VNP improved renal function by reducing serum urea, creatinine, and NGAL levels while it increased the serum level of albumin. VNP restored the oxidant-antioxidant balance of renal tissues mediated by increasing Nrf2/HO-1 expression. VNP suppressed the inflammation by decreasing MPO and NO2 and reducing IL-1β, TNF-α, and IL-6 levels mediated by suppressing TLR4 and NF-κB expression. Moreover, VNP downregulates NLRP3, ASC, and cleaved caspase 1. Histological analysis of kidney tissues validated our findings. Of note, VNP's Reno protective effects were dose-dependent. Conclusion: Our data suggest that co-treatment of VNP with 5-FU is a promising agent for mitigating 5-FU-induced nephrotoxicity by NF-κB/TLR4, Nrf2/ARE, and NLRP3/ASC/Caspase-1 signals.

Methotrexate (MTX) is an anti-folate chemotherapeutic commonly used to treat cancer and autoimmune diseases. Despite its widespread clinical use, MTX has been linked to serious neurotoxicity side effects. Vinpocetine (VNP) has been widely used clinically to treat many neurological conditions. This study was conducted to study the potential neuroprotective effects of VNP against MTX hippocampal intoxication in rats. Thirty-two rats were randomly allocated into 4 groups: (I) control (Vehicle); (II) VNP-treated group (20 mg/kg/day, p.o); (III) MTX-control (20 mg/kg/once, i.p.) group; and (IV) the VNP + MTX group. VNP was administered orally for 10 days, during which MTX was given intraperitoneally once at the end of day 5. Our data indicated that VNP administration significantly improved MTX-induced neuronal cell death, odema, vacuolation and degeneration. VNP attenuated oxidative injury mediated by significant upregulation of the Nrf2, HO-1, and GCLC genes, while the Keap-1 mRNA expression downregulated. Moreover, VNP suppressed cytokines release mediated by increasing IκB expression level while it caused a marked downregulation in NF-κB and AP-1 (C-FOS and C-JUN) levels. Additionally, VNP attenuated apoptosis by reducing hippocampal Bax levels while increasing Bcl2 levels in MTX-intoxicated rats. In conclusion, our results suggested that VNP significantly attenuated MTX hippocampal intoxication by regulating Keap-1/Nrf2, NF-κB/AP-1, and apoptosis signaling in these effects.

Vinpocetine (VIN) is a synthetic drug derived from the natural alkaloid vincamine. The antioxidation and anti-inflammation effects of VIN allow it to be used for multiple therapeutic purposes. So, the research aims to discover the possibility of using VIN to improve the nephrotoxicity of acrylamide (ACR). Twenty-four male albino rats were used in the trial: rats in the control group received 0.5 mL of oral saline, rats in the VIN group received an oral dose of VIN (5 mg/kg), rats in the ACR group received an oral dose of ACR (38.27 mg/kg), and rats in the VIN + ACR group received VIN and then ACR 1 h later. Rat blood and kidneys were collected 10 days after the experiment began to assess biochemical parameters and to examine both renal histopathological and immunohistochemistry. The ACR-treated rats showed high levels of serum kidney function biomarkers (creatinine, urea, and uric acid), serum protein biomarkers (total protein, albumin, and globulin), renal kidney injury molecule (KIM)-1, renal malondialdehyde (MDA), and renal caspase-3 immunoexpression. Moreover, ACR lowed both renal superoxide dismutase (SOD) activity and renal glutathione (GSH) level and caused renal histological alterations. While administration of VIN improved serum kidney function biomarkers, serum protein biomarkers, renal KIM-1, renal oxidative stress biomarkers (MDA, SOD, and GSH), renal caspase-3 immunoexpression, and renal histological alterations induced by ACR. The study confirmed the ability of VIN to reduce the nephrotoxic effects of ACR, which was evident through the results of biochemical parameters and histological and immunohistochemical examinations of the kidney tissues.

This study presents the first insights into vinpocetine (VIN) behavior, a nootropic compound, on a glassy carbon electrode (GCE). Cyclic voltammetry (CV) revealed an irreversible oxidation peak at +1.0 V (vs. Ag/AgCl), with pH dependency indicating proton involvement in the electrochemical reaction. Density functional theory (DFT) optimized VIN's molecular geometry, while Fukui functions and dual descriptors elucidated its reactivity for a more straightforward exploration of the complete electrooxidation mechanism. Differential pulse voltammetry (DPV) demonstrated VIN sensing capabilities within a concentration range of 0.20 to 12.8 mg L-1, with a theoretical limit of detection (LOD) at 0.07 mg L-1, using optimized conditions of supporting electrolyte. The method showed selectivity in the presence of excipients and interfering species commonly found in pharmaceutical formulations. Recovery tests yielded 95.5% (n = 3), and quantification in pharmaceutical formulations showed no significant differences compared to the reference method based on HPLC DAD. This novel electroanalytical method holds promise for VIN nootropic sensing and routine pharmaceutical analysis.

Development and optimization of in-situ gel containing chitosan nanoparticles for possible nose-to-brain delivery of vinpocetine

BackgroundThis 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.ResultsMSLNs 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.ConclusionThe 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.

Attenuated effects of topical vinpocetine in an imiquimod-induced mouse model of psoriasis

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.

Alzheimer's disease (AD) is a devastating illness with limited therapeutic interventions. The aim of this study is to investigate the pathophysiological mechanisms underlying AD and explore the potential neuroprotective effects of cocoa, either alone or in combination with other nutraceuticals, in an animal model of aluminum-induced AD. Rats were divided into nine groups: control, aluminum chloride (AlCl3) alone, AlCl3 with cocoa alone, AlCl3 with vinpocetine (VIN), AlCl3 with epigallocatechin-3-gallate (EGCG), AlCl3 with coenzyme Q10 (CoQ10), AlCl3 with wheatgrass (WG), AlCl3 with vitamin (Vit) B complex, and AlCl3 with a combination of Vit C, Vit E, and selenium (Se). The animals were treated for five weeks, and we assessed behavioral, histopathological, and biochemical changes, focusing on oxidative stress, inflammation, Wnt/GSK-3β/β-catenin signaling, ER stress, autophagy, and apoptosis. AlCl3 administration induced oxidative stress, as evidenced by elevated levels of malondialdehyde (MDA) and downregulation of cellular antioxidants (Nrf2, HO-1, SOD, and TAC). AlCl3 also upregulated inflammatory biomarkers (TNF-α and IL-1β) and GSK-3β, leading to increased tau phosphorylation, decreased brain-derived neurotrophic factor (BDNF) expression, and downregulation of the Wnt/β-catenin pathway. Furthermore, AlCl3 intensified C/EBP, p-PERK, GRP-78, and CHOP, indicating sustained ER stress, and decreased Beclin-1 and anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. These alterations contributed to the observed behavioral and histological changes in the AlCl3-induced AD model. Administration of cocoa, either alone or in combination with other nutraceuticals, particularly VIN or EGCG, demonstrated remarkable amelioration of all assessed parameters. The combination of cocoa with nutraceuticals attenuated the AD-mediated deterioration by modulating interrelated pathophysiological pathways, including inflammation, antioxidant responses, GSK-3β-Wnt/β-catenin signaling, ER stress, and apoptosis. These findings provide insights into the intricate pathogenesis of AD and highlight the neuroprotective effects of nutraceuticals through multiple signaling pathways.

Vinpocetine prevents rotenone-induced Parkinson disease motor and non-motor symptoms through attenuation of oxidative stress, neuroinflammation and α-synuclein expressions in rats

Exploring the potential to enhance drug distribution in the brain subregion via intranasal delivery of nanoemulsion in combination with borneol as a guider