Regulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles.

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.

Vinpocetine alleviated alveolar epithelial cells injury in experimental pulmonary fibrosis by targeting PPAR-γ/NLRP3/NF-κB and TGF-ß1/Smad2/3 pathways.

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-ß1/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.

The ameliorative effect of vinpocetine against gentamicin-induced uterine-injury in rats involves the inflammasome/caspase-1/IL-1ß pathway.

BACKGROUND: There is limited data regarding the hazardous effect of gentamicin (GM) on the uterus and whether or not vinpocetine (Vinpo) ameliorates it. The present study aimed to identify the possible protective effect of Vinpo in GM-induced uterine injury in rats. METHODS: Female rats were assorted in control-group, Vinpo-group, GM-group, and Vinpo plus GM group. Serum and uterine GM concentration were measured. Uterine oxidative stress parameters besides inflammatory and apoptotic biomarkers were evaluated. Uterine histopathological examination and interlukin-1beta (IL-1ß) immune-histochemical study were detected. RESULTS: GM significantly increased uterine oxidative stress, inflammatory and apoptotic biomarkers. Histopathological picture of uterine damage and increased IL-1ß immunoexpression were detected. Vinpo significantly ameliorated the distributed GM concentration, oxidative stress, inflammatory and apoptotic biomarkers with a prompt improvement in histopathological picture and a decrease in IL-1ß immunoexpression. CONCLUSION: Vinpo protective effect against GM-induced uterine injury involves modulation of inflammasome/caspase-1/IL-1ß signaling pathway.

Vinpocetine improved neuropsychiatric and epileptic outcomes in a patient with a GABRA1 loss-of-function variant.

Vinpocetine is a synthetic derivative of the alkaloid vincamine and has been used as a dietary supplement for decades. Following a positive report of the use of vinpocetine in a patient with a loss-of-function GABRB3 variant, we here describe another patient with a loss-of-function GABRA1 variant (p.(Arg112Gln)) who benefited from vinpocetine treatment. This patient was diagnosed with autism spectrum disorder, psychiatric complications, and therapy-resistant focal epilepsy. Upon add-on treatment with 40 mg vinpocetine daily for 16 months, the patient experienced an overall improved quality of life as well as seizure freedom. Our findings corroborate that vinpocetine can attenuate epilepsy-associated behavioral issues in patients with loss-of-function GABAA receptor gene variants.

New insights on the potential effect of vinpocetine in Parkinson's disease: one of the neglected warden and baffling topics.

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.

Vinpocetine mitigates DMH-induce pre-neoplastic colon damage in rats through inhibition of pro-inflammatory cytokines.

Colorectal cancer (CRC) is currently recognized as the third most prevalent cancer worldwide. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine. It has been found effective in ameliorating the growth and progression of cancerous cells. However, its pharmacological effect on colon damage remains elusive. Hence, in this study, we have shown the role of vinpocetine in DMH-induced colon carcinogenesis. At first, male albino Wistar rats were administered with DMH consistently for four weeks to induce pre-neoplastic colon damage. Afterward, animals were treated with vinpocetine (4.2 and 8.4 mg/kg/day p.o.) for 15 days. Serum samples were collected to assess the physiological parameters, including ELISA and NMR metabolomics. Colon from all the groups was collected and processed separately for histopathology and western blot analysis. Vinpocetine attenuated the altered plasma parameters; lipid profile and showed anti-proliferative action as evidenced by suppressed COX-2 stimulation and decreased levels of IL-1ß, IL-2, IL-6, and IL-10. Vinpocetine is significantly effective in preventing CRC which may be associated with its anti-inflammatory and antioxidant potential. Accordingly, vinpocetine could serve as a potential anticancer agent for CRC treatment and thus be considered for future clinical and therapeutic research.

Phosphodiesterase1 inhibitor "Vinpocetine" ameliorates the inflammation, apoptosis and oxidative stress induced by cyclophosphamide in urinary bladder: an experimental study.

BACKGROUND: Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CP). Vincamine (vinca alkaloid) is the source of the synthetic derivative vinpocetine (Vinpo). Worldwide, Vinpo is used as a cerebroprotective drug. As it has anti-oxidant, anti-thrombotic and anti-inflammatory effects but the power of Vinpo to prevent CP induced cystitis has not been studied. AIM OF STUDY: This research was planned to explore the effect of Vinpo (10-30 mg/kg, orally) administered 1 or 4 h before inducing cystitis by CP injection (300 mg/kg, i.p.) on the urinary bladder of mice. RESULTS: Administration of Vinpo 30 mg/kg, 4 h before CP injection ameliorated inflammatory markers. It reduced inducible nitric oxide synthase (iNOS), tumor necrosis factor- α (TNF-α), and BCL2 Associated X (Bax) expression in the bladder and increased the total antioxidant capacity level. Histological examination of the bladder has further supported these results. The present study suggests a protective effect of Vinpo (30 mg/kg, 4 h before CP injection) against CP-induced bladder inflammation. CONCLUSION: This proposes that Vinpo 30 mg/kg may become a promising pharmacological drug to prevent urinary adverse effects in patients treated with chemotherapy using CP.

Synthesis and Activity Evaluation of Vinpocetine-Derived Indole Alkaloids.

This study focuses on the synthesis of novel vinpocetine derivatives (2-25) and their biological evaluation. The chemical structures of the synthesized compounds were fully characterized using techniques such as 1H NMR, 13C NMR, and HRMS. The inhibitory activity of the synthesized compounds on PDE1A was evaluated, and the results revealed that compounds 3, 4, 5, 12, 14, 21, and 25 exhibited superior inhibitory activity compared to vinpocetine. Compound 4, with a para-methylphenyl substitution, showed a 5-fold improvement in inhibitory activity with an IC50 value of 3.53 ± 0.25 µM. Additionally, compound 25, with 3-chlorothiazole substitution, displayed an 8-fold increase in inhibitory activity compared to vinpocetine (IC50 = 2.08 ± 0.16 µM). Molecular docking studies were conducted to understand the binding models of compounds 4 and 25 within the active site of PDE1A. The molecular docking study revealed additional binding interactions, such as π-π stacking and hydrogen bonding, contributing to the enhanced inhibitory activity and stability of the ligand-protein complexes. Overall, the synthesized vinpocetine derivatives demonstrated promising inhibitory activity on PDE1A, and the molecular docking studies provided insights into their binding modes, supporting further development of these compounds as potential candidates for drug research and development.

Vinpocetine restores cognitive and motor functions in Traumatic brain injury challenged rats.

Traumatic brain damage is common worldwide and the treatments are not well-defined. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine and is clinically being used for various brain disorders. Here in the current study, we have investigated the neuroprotective potential of vinpocetine against traumatic brain injury. TBI was induced by the Marmarou weight drop method in rats. Brain damage was evaluated using cognitive and motor functions and the alterations in biomolecules. Injured rats were treated with different doses of vinpocetine (2.5, 5, and 10 mg/kg) for 4 weeks. Traumatic brain injury in rats produced significant deterioration of cognition and motor functions, which was accompanied by increased oxidative stress and significant alterations in brain monoamine levels as compared with the sham control group (p < 0.05). Vinpocetine alleviated TBI-induced oxidative burden, altered neurochemistry, and improved the cognitive and motor functions as compared with that of the TBI control group (p < 0.05). The observed neuroprotective potential of vinpocetine may be due to the observed antioxidant potential and its ability to restore the levels of brain neurochemicals under stressed conditions. The outcomes of the current study may help the repositioning of vinpocetine for preventing or treating traumatic brain injuries.

The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma.

Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent.

Vinpocetine, a PDE1 modulator, regulates markers of cerebral health, inflammation, and oxidative stress in a rat model of prenatal alcohol-induced experimental attention deficit hyperactivity disorder.

Prenatal alcohol exposure (PAE) has been shown to induce symptomatology associated with attention deficit hyperactivity disorder (ADHD) by altering neurodevelopmental trajectories. Phosphodiesterase-1 (PDE1) is expressed centrally and has been used in various experimental brain conditions. We investigated the role of vinpocetine, a PDE1 inhibitor, on behavioral phenotypes and important biochemical deficits associated with a PAE rat model of ADHD. Protein markers of cerebral health (synapsin-IIa, BDNF, and pCREB), inflammation (IL-6, IL-10, and TNF-α), and oxidative stress (TBARS, GSH, and SOD) were analyzed in three brain regions (frontal cortex, striatum, and cerebellum). Hyperactivity, inattention, and anxiety introduced in the offspring due to PAE were assayed using open-field, Y-maze, and elevated plus maze, respectively. Administration of vinpocetine (10 & 20 mg/kg, p.o. [by mouth]) to PAE rat offspring for 4 weeks resulted in improvement of the behavioral profile of the animals. Additionally, levels of protein markers such as synapsin-IIa, BDNF, pCREB, IL-10, SOD, and GSH were found to be significantly increased, with a significant reduction in markers such as TNF-α, IL-6, and TBARS in selected brain regions of vinpocetine-treated animals. Vinpocetine, a selective PDE1 inhibitor, rectified behavioral phenotypes associated with ADHD, possibly by improving cerebral function, reducing brain inflammation, and reducing brain oxidative stress. This study provides preliminary analysis and suggests that the PDE1 enzyme may be an important pharmacological tool to study ADHD as a result of PAE.

Photopharmacology of Antimitotic Agents.

Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.

Vinpocetine (A comprehensive profile).

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

Effects of vinpocetine on atopic dermatitis after administration via three different routes in HR-1 hairless mice.

This study aimed to examine the effects of vinpocetine on atopic dermatitis (AD) by administering it via oral, intraperitoneal, and topical routes to HR-1 hairless mice. AD was induced in the mice for five weeks with ovalbumin, and vinpocetine was administered twice daily through each route of administration for two weeks after the induction of AD. Vinpocetine (20, 10, and 2 mg/kg) was administered by oral, intraperitoneal, and topical routes, respectively. The administration of vinpocetine suppressed the increase in serum immunoglobulin (Ig) E and IgG1 levels and the production of interleukin (IL)-4 and IL-13-cytokines linked to T helper 2 cells in skin tissue. In addition, the invasion of inflammatory cells, including eosinophils, into the skin tissue was reduced, and changes in skin structure were also suppressed. These results show the potential for the use of vinpocetine in patients with AD and even for targeted treatment against PDE. In most of the experiments, symptom relief in the groups receiving oral and topical vinpocetine was slightly superior to that in the group receiving vinpocetine intraperitoneally. In particular, topical application of vinpocetine was found to be the most effective route when considering the dose of vinpocetine used in each route.

Vinpocetine attenuates fluoxetine-induced liver damage in rats; Role of Nrf2 and PPAR-γ.

BACKGROUND: Fluoxetine (FLX) has been widely used as first-line treatment in cases of depression and other neuropsychiatric disorders. Although its safety has been approved, the use of FLX was associated with liver injury and chronic liver disease. Vinpocetine (Vinpo), a nootropic drug, possesses antioxidant and anti-inflammatory effects. OBJECTIVE: This study aimed to evaluate the protective effects of Vinpo on FLX-induced liver damage pointing to the role of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and nuclear factor erythroid 2-related factor 2 (Nrf2). METHODS: Rats were randomized to four groups: control group, Vinpo group (20 mg/kg/day; orally), FLX group (10 mg/kg/day; orally), and Vinpo + FLX group. RESULTS: FLX-induced liver damage was evidenced through elevated liver function biomarkers and induced hepatic histopathological changes. Concurrent Vinpo treatment resulted in a significant decrease in hepatotoxicity biomarkers and histopathological alterations. FLX-induced oxidative stress and inflammation were attenuated by Vinpo. In addition, Vinpo attenuated the hepatic NRF2 and HO-1 levels and up-regulated PPAR-γ expression. Moreover, FLX elevated Bcl-2-associated X protein (Bax) mRNA expression and decreased B-cell lymphoma 2 (Bcl2) mRNA expression were markedly reversed by Vinpo. CONCLUSION: Vinpo possesses ameliorative effects against FLX-induced liver injury in rats. This effect may be due to attenuation of oxidative stress and inflammation, in addition to upregulation of PPAR-γ expression.

Direct and Indirect Anticancer Activity of Plant-Derived Alkaloid Conophylline.

K-Ras is one of the most important oncogenes in human oncogenesis. K-Ras transfection of normal rat fibroblasts induces phenotypic change from flat to round morphology. Then, we screened compounds inducing flat morphology in K-Ras transformed fibroblasts from microbial culture filtrates and plant extracts. As a result, the alkaloid conophylline was isolated from the leaves of Ervatamia microphylla collected in Thailand. Conophylline induced flat morphology and inhibited cellular invasion in K-Ras-transformed normal rat kidney (K-Ras-NRK) cells. It also inhibited the growth of the K-Ras-NRK tumor in mice. Cancer-associated fibroblasts are now considered to activate cancer growth. Conophylline was found to suppress secretions of various inflammatory cytokines by pancreatic cancer-associated fibroblasts. Moreover, when combined with gemcitabine, it inhibited the growth of pancreatic cancer growth in mice. Conophylline is orally active. Thus, the plant-derived alkaloid conophylline inhibited cancer growth directly and indirectly, and it shows promise as a new anticancer agent.

Vinpocetine Effect on the Juncture of Diabetes and Aging: An in-vitro study.

BACKGROUND: The rapid-growing population of diabetic patients and the elderly are among the direst challenges that the science of medicine is facing today. Targeting these two challenges can shed light on new means to control and ideally reverse this trend. In this experiment, Vinpocetine's effect on aged pancreatic beta-cell functions in correlation with oxidative stress was studied. METHODS: Islet cells were isolated from the pancreas of aged rats and exposed to Vinpocetine, dissolved in acetone and RPMI, for 48 h. Then, senescence-associated molecular parameters, including P16 and P38 gene expressions and ß-galactosidase activity, were investigated along with diabetic and inflammation markers. RESULTS: Experimental results showed that Vinpocetine could significantly increase aged islets insulin secretion and also make a meaningful reduction in oxidative stress markers. This drug can also decrease expression levels of P16 and P38, the primary genes responsible for the aging pathway. TNF-α, IL-6, and NF-κB expressions were also reduced noticeably after treatment with Vinpocetine. CONCLUSION: The current study showed that Vinpocetine, a derivative of the secondary plant metabolite called Vincamine, could break this vicious cycle of oxidative stress and aging by reducing oxidative stress and inflammation, thus inhibiting cellular aging.

Conophylline Suppresses Angiotensin II-Induced Myocardial Fibrosis In Vitro via the BMP4/JNK Pathway.

We studied the effects and mechanisms of action of conophylline in different concentrations in the original in vitro model of myocardial fibrosis (treatment of cardiac fibroblasts isolated form the hearts of newborn rats with angiotensin II). Viability, collagen content, and expression of related protein in cardiac fibroblasts were assessed using the MTT-test, Sircol assay, and Western blotting, respectively. Conophylline markedly protected the cultured cells against the development of angiotensin II-induced fibrosis, which was seen from reduced viability of fibroblasts, decreased collagen content, and down-regulation of the expression of α-smooth muscle actin (α-SMA). Conophylline did not affect the TGF-ß pathway altered by angiotensin II, but markedly decreased the level of bone morphogenetic protein-4 (BMP4) enhanced by angiotensin II and BMP4 itself. Conophylline produced no effect on phosphorylation of α-SMA and Smad homologue-1/5/8, the classic BMP4 downstream pathway elements, but reduced the level of c-Jun N-terminal kinase (JNK) elevated by BMP4. Conophylline did not inhibit the development of myocardial fibrosis in the presence of JNK activator anisomycin. Thus, conophylline inhibited angiotensin II-provoked myocardial fibrosis via the BMP4/JNK pathway.

Thermal Proteome Profiling Reveals Glutathione Peroxidase 4 as the Target of the Autophagy Inducer Conophylline.

Conophylline (CNP) is a vinca alkaloid extracted from the Tabernaemontana divaricata plant. It has been reported that CNP induces autophagy in a mammalian target of rapamycin-independent manner, and thereby inhibits protein aggregation. However, the mode of action of CNP in inducing autophagy remains unknown. In this study, we identified glutathione peroxidase 4 (GPX4) as a CNP-binding protein by using thermal proteome profiling. The technique exploits changes in the thermal stability of proteins resulting from ligand interaction, which is capable of identifying compound-binding proteins without chemical modification. GPX4, an antioxidant protein that uses reduced glutathione as a cofactor, directly catalyzes the reduction of hydrogen peroxide, organic hydroperoxides, and lipid peroxides. GPX4 suppresses lipid peroxide accumulation, and thus plays a key role in protecting cells from oxidative damage. We found that treatment with CNP caused accumulation of lipid reactive oxygen species (ROS) in cultured cells. Furthermore, similarly with CNP treatment, GPX4 deficiency caused accumulation of lipid ROS and induced autophagy. These findings indicate that GPX4 is a direct target of CNP involved in autophagy induction. SIGNIFICANCE STATEMENT: The present study identified glutathione peroxidase 4 (GPX4) as a binding protein of conophylline (CNP) by using thermal proteome profiling (TPP). This study showed that CNP treatment, similarly with the inhibition of GPX4, induced lipid reactive oxygen species accumulation and autophagy. The present findings suggest that GPX4 is the CNP target protein involved in autophagy induction. Furthermore, these results indicate that TPP is a useful technique for determining the mechanism of natural compounds.

Phosphodiesterase (1, 3 & 5) inhibitors attenuate diclofenac-induced acute kidney toxicity in rats.

Diclofenac, one of the most commonly used non-steroidal anti-inflammatory drugs, leads to severe adverse effects on the kidneys. The aim of the present study was to investigate the potential pretreatment effect of phosphodiesterase (1, 3 & 5) inhibitors on diclofenac-induced acute renal failure in rats. Rats orally received pentoxifylline (100 mg/kg), vinpocetine (20 mg/kg), cilostazol (50 mg/kg), or sildenafil (5 mg/kg) once per day for 6 consecutive days. Diclofenac (15 mg/kg) was injected on day-4, -5 and -6 in all groups except normal control group. The used phosphodiesterase inhibitors significantly reduced the diclofenac-induced elevation in the serum levels of blood urea nitrogen, creatinine and cystatin C. Moreover, the renal tissue contents of tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB as well as the protein expression of toll-like receptor (TLR) 4 and high mobility group box (HMGB) 1 were markedly reduced by the used phosphodiesterase inhibitors, as compared to the diclofenac control. This was reflected on the marked improvement in histopathological changes induced by diclofenac. Sildenafil showed the best protection regarding TNF-α and NF-κB, while cilostazol showed the best results regarding TLR4, HMGB1 and histopathological examination. This study revealed the good protective effect of these phosphodiesterase inhibitors against diclofenac-induced acute renal failure.