Antioxidant-rich Terminalia catappa fruit exerts antihypertensive effect via modulation of angiotensin-1-converting enzyme activity and H2S/NO/cGMP signalling pathway in Wistar rats.

INTRODUCTION: The present study aimed at investigating the effect of Terminalia catappa fruits on blood pressure, NO/cGMP signalling pathway, angiotensin-1-converting enzyme and arginase activity, and oxidative stress biomarkers in L-NAME-induced hypertensive rats. MATERIALS AND METHODS: Forty-two Wistar rats were divided into seven groups. Hypertension was induced via oral administration of 40 mg/kg of L-NAME for 21 days. Thereafter, the hypertensive rats were treated with Terminalia catappa fruit-supplemented diet and sildenafil citrate for 21 days. The blood pressure was measured and cardiac homogenate was prepared for biochemical analyses. RESULTS: The results showed that L-NAME caused a significant (p < 0.05) increase in systolic and diastolic blood pressure, and heart rate as well as ACE, arginase and PDE-5 activity, with a simultaneous decrease in NO and H2S levels as well as increased oxidative stress biomarkers. However, treatment with Terminalia catappa fruits-supplemented diets and sildenafil citrate lowered blood pressure and modulated ACE, arginase, and PDE-5 activity, improved NO and H2S levels, as well as antioxidant status. CONCLUSION: Findings presented in this study provide useful information on the antihypertensive property of Terminalia catappa fruits, alongside some possible mechanisms. Hence, Terminalia catappa fruits could be considered a dietary regimen and functional food in alleviating hypertension.

Catechin from Anonna senegalensis is a Potential Inhibitor of Erectile Dysfunction: Implication for Its Use in Male Sexual Enhancement.

Erectile dysfunction (ED) is a major challenge for men. The drugs for its treatment are associated with side effects. Hence, in phytomedicinal research, where Anonna senegalensis (A. senegalensis) is a candidate with abundant phytochemicals possessing various pharmacological properties, but the sex-enhancing phytochemical is elusive in the literature. This study aimed to understand the molecular interaction of its potent molecule mediating male sexual enhancement. A library of 69 compounds from A. senegalensis was docked against the ED-targeted proteins. Sildenafil citrate was used as the reference standard. Thereafter, the lead compound was screened for drug-likeness by applying the Lipinski rule of 5 (RO5), pharmacokinetic properties, and bioactivity using SwissADME and Molinspiration web servers, respectively. The results show catechin as the lead phytochemical compound with a stronger binding affinity for most of the proteins of ED. Also, catechin demonstrates good compliance with the RO5, great pharmacokinetic profiles, and could be said to be a polypharmacological molecule with good bioactivity scores. The research findings unravel the potential of catechin (a phytochemical belonging to the flavonoids class) from A. senegalensis leaf as a potential male sexual enhancement molecule via its high binding affinity for most erectile dysfunction-targeted proteins. They may require further toxicity and therapeutic evaluations in vivo.

Aqueous extract of Massularia acuminata exerts erectogenic effect by modulating critical enzymes and hormones in streptozotocin-induced erectile dysfunction in rats.

Massularia acuminata stem is often used in folkloric medicine in the management of erectile dysfunction (ED), without full scientific basis for its action. Thus, the effects of aqueous extract of M. acuminata stem (MAS) on sexual activity, hormonal action, enzymatic activity and levels of molecules associated with erectile function were assessed. ED was induced by single intraperitoneal injection of 50 mg/kg body weight of streptozotocin in rats and treated with sildenafil citrate or MAS (50 or 100 mg/kg) orally for 2 weeks. The results revealed that there was significant (p < 0.05) reduction in mounting and intromission frequencies, testosterone, luteinizing hormone, and nitric oxide levels, as well as elevation in mounting and intromission latencies, phosphodiesterase 5, arginase, acetylcholinesterase, adenosine triphosphatidase, and adenosine deaminase activities, nitric oxide, thiobarbituric acid reactive species, and glycated haemoglobin levels were observed in ED rats in comparison with the control rats. Treatment with MAS or sildenafil citrate significantly (p < 0.05) modulated the sexual behaviour, biochemical parameters and histological architecture, with 100 mg/kg of MAS having the best erectogenic effects. Furthermore, phenolic characterization revealed that catechin and kaempferol as the main phenolic compounds present in MAS, that can act in synergistically or additively with other phytochemicals to confer erectogenic effect.

A novel role of Nano selenium and sildenafil on streptozotocin-induced diabetic nephropathy in rats by modulation of inflammatory, oxidative, and apoptotic pathways.

AIMS: The present study aimed to investigate the effect of nano selenium, sildenafil, and their combination on inflammation, oxidative stress, and apoptosis in streptozotocin-induced diabetic nephropathy in rats. Herein, a new anti-inflammatory pathway for sildenafil as a high-mobility group box (HMGB1) inhibitor was proposed using the molecular docking technique. MATERIALS AND METHODS: Rats were divided into 7 groups: normal control, control nano selenium, control sildenafil, control diabetic, diabetic+ nano selenium, diabetic+ sildenafil, diabetic+ nano selenium+ sildenafil. The effects of drugs were evaluated by measuring serum urea, creatinine, lactate dehydrogenase (LDH), levels of tumor necrosis factor-alpha (TNF-α), Interleukin 1 beta (IL-1ß), HMGB1, receptor advanced glycation end product (RAGE), malondialdehyde (MDA), thioredoxin reductase (TrxR) by biochemical assays, nuclear factor-kappa b (NF-κB), toll-like receptor (TLR4) by immunohistochemistry, gene expressions of caspase 3 and monocyte chemoattractant protein (MCP-1) besides histopathological investigations of renal cells. KEY FINDINGS: Results showed beneficial effects of 8 weeks of treatment by nano selenium and sildenafil supported by improvement in kidney function, histopathological changes, and reduction in all of these parameters. These results supported molecular docking that indicated sildenafil had a high binding score and interactions with the HMGB1 receptor. SIGNIFICANCE: The current study demonstrated a renoprotective effect of nano­selenium and sildenafil by interfering at multiple pathways, especially the HMGB1/NF-κB signaling pathway.

Astragaloside IV ameliorates pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension by restraining the T follicular helper cell response and expanding T follicular regulatory cell response.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder lacking a validated and effective therapy which characterized by elevated pulmonary arterial pressure, vascular remodeling and eventual death. FDA approved sildenafil is being used as a first-line drug for PH, however, neither survival rates nor quality of life have been improved because of side effects and patient noncompliance. Thus, the exploration of novel therapeutic drugs is urgently needed. Astragaloside IV (ASIV) exhibits a protective effect on HPH, but its mechanisms of action is unclear. HYPOTHESIS: CD4+T cell subsets, Tfh and Tfr cells, may contribute to the development of chronic hypoxia-induced PH (HPH). We hypothesized that ASIV could effectively ameliorates pulmonary vascular remodeling of HPH by restraining the Tfh cell response and expanding Tfr cell response. METHODS AND RESULTS: HPH mice model was established by exposure to chronic hypoxia for 21 days. Mice were randomly assigned to six groups: NaCl group, model group, SN group (100 mg/kg of sildenafil), low-dose group (20 mg/kg of ASIV), medium-dose group (40 mg/kg of ASIV) and high-dose group (80 mg/kg of ASIV). Primary culture and identification of distal pulmonary artery smooth muscle cells (PASMCs) in mice were established. Here, we demonstrated that ASIV treatment could significantly ameliorate the increase of mean PAP, RV/ (LV+S) ratio and PAMT in HPH mice. ASIV inhibited Tfh cell differentiation and IL-21 production, but promoted Tfr cell differentiation and TGF-ß, IL-10 production. Chronic hypoxia promoted germinal center B cell responses, which inhibited by ASIV. ASIV regulated Tfh and Tfr cell differentiation by inhibiting the phosphorylation of mTOR signaling pathway, and the effect of ASIV-H was better than that observed in the SN group. ASIV inhibited the proliferation, migration and adhesion of PASMCs in vitro. Moreover, ASIV significantly downregulated the protein level of RhoA and upregulated the protein level of p27 in PASMCs under hypoxic condition. CONCLUSION: Collectively, ASIV may regulate Tfh and Tfr cell responses to subsequently repress pulmonary vascular remodeling and hypoxic pulmonary hypertension.

Exploring the potentials of some compounds from Garcinia kola seeds towards identification of novel PDE-5 inhibitors in erectile dysfunction therapy.

Erectile dysfunction (ED) is one of the main challenges occurring among men worldwide, and is characterised by trouble getting or keeping steady erection during sexual intercourse. Various drugs like sildenafil, a phosphodiesterase-5 inhibitor (PDE-5) are freely available in the pharmacies, though normally associated with several adverse. This study was designed to assess the molecular relations obtainable between catechin, garcinal, garcinoic acid and d-tocotrienol compounds isolated from Garcinia kola and targeted receptor linked to ED. These processes include the molecular docking of catechin, garcinal, garcinoic acid, d-tocotrienol, and sildenafil to receptor: PDE-5 via AutoDock Vina. Following the docking of catechin, garcinal, garcinoic acid and d-tocotrienol with the PDE-5-receptor protein, we observed that all are protein inhibitors with garcinoic acid showing better binding affinity -10.0 kcal/mol with PDE-5 receptor relevant to ED. Hence, the results provided insights into the development of garcinoic acid as a replacement for present ED management, with further analysis worth considering.

Natural phosphodiesterase 5 (PDE5) inhibitors: a computational approach.

In 1998, sildenafil was marketed as the first FDA-approved oral drug for the treatment of erectile dysfunction (ED). During the last two decades, the commercialization of other synthetic phosphodiesterase 5 (PDE5) inhibitors has been paralleled by the rise of remedies based on natural molecules from different chemical classes (flavonoids, polyphenols and alkaloids in general). In this work, a set of in silico tools were applied to study a panel of 30 natural compounds claimed to be effective against ED in the scientific literature or in folk medicine. First, pharmacokinetic properties were analysed to exclude the compounds lacking in specific drug-like features. Estimated binding energy for PDE5 and selectivity towards other PDE isoforms were then considered to highlight some promising molecules. Finally, a detailed structural investigation of the interaction pattern with PDE in comparison with sildenafil was conducted for the best performing compound of the set.

Potential activity of Aframomum daniellii (Zingiberaceae) dry seeds: A case study of its action mechanism on the Wistar rat strain with testicular deficiency.

This work was undertaken to evaluate the biological activity of the aqueous extract of the dry seeds of Aframomum daniellii seeds on the copulatory performance of rats with testicular deficiency. Hypogonadal adult male rats (30) were divided into 6 groups: group I received distilled water (10 ml/kg), group II received sildenafil citrate (5 mg/kg), group III received intramuscular injections of testosterone enanthate (3. 6 mg/kg), group IV, V, and VI received the aqueous extract of A. daniellii at the respective doses of 100, 200, and 400 mg/kg/po/day for 14 days. The copulatory performance of the animals were assessed on days 1, 7 and 14 through the following copulation parameters: Mount, intromission, and ejaculation latency (ML, IL, and EL) and frequency (MF, IF and EF), average interval of copulation (AIC) and post-ejaculatory interval (PEI)). We noticed a significant decrease of ML (p < 0.05), IL (p < 0.01), EL (p < 0.001) and the increase of MF, IF and EF (p < 0.01) particularly at doses of 100 and 400 mg/kg when compared to group I and II. In addition, we noticed a significant increase of AIC from day 7 (p < 0.05) to day 14 (p < 0.001) at the same two doses while the PEI significantly decreased from the 1st (p < 0.01) to the 14th day (p < 0.001) when compared to group I and II. These findings demonstrated that A. daniellii aqueous extract of seeds enhanced pro-sexual potential and pro-sexual desire in male rats with testicular deficiency.

Ameliorative effect of phosphodiesterase 4 and 5 inhibitors in deoxycorticosterone acetate-salt hypertensive uni-nephrectomized KKAy mice.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKAy mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule-1, and monocyte chemoattractant protein-1 levels, as well as that of renal pro-fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor-beta (TGF-ß). Moreover, compound A significantly suppressed TGF-ß-induced pro-fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms.

Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging.

Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1Δ/- mice, can be used as a tool to accelerate aging. Ercc1Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1Δ/- mice. Ercc1Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1Δ/- mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.

Screening for drugs to reduce zebrafish aggression identifies caffeine and sildenafil.

Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. In this study we have used a behavioural platform in a phenotypic screen to identify drugs that can reduce zebrafish aggression without affecting locomotion. In a three tier screen of ninety-four drugs we discovered that caffeine and sildenafil can selectively reduce aggression. Caffeine also decreased attention and increased impulsivity in the 5-choice serial reaction time task whereas sildenafil showed the opposite effect. Imaging studies revealed that both caffeine and sildenafil are active in the zebrafish brain, with prominent activation of the thalamus and cerebellum evident. They also interact with 5-HT neurotransmitter signalling. In summary, we have demonstrated that juvenile zebrafish are a suitable model to screen for novel drugs to reduce aggression, with the potential to uncover the neural circuits and signalling pathways that mediate such behavioural effects.

Evaluation of relaxant responses properties of cinnamon essential oil and its major component, cinnamaldehyde on human and rat corpus cavernosum

ABSTRACT Cinnamomum cassia (Cinnamon) is a well-known traditional medicine with therapeutic benefits for centuries. We evaluated the effects of cinnamon essential oil (CEO) and its main component cinnamaldehyde (CA) on human corpus cavernosum (HCC) and rat CC. The essential oil of cinnamon was analyzed for the confirmation of the oil profile. HCC specimens from patients undergoing penile prosthesis surgery (age 48-69 years) were utilized for functional studies. In addition, erectile responses in anesthetized control and diabetic rats were evaluated in vivo after intracavernosal injection of CEO and CA, and rat CC strips were placed in organ baths. After precontraction with phenylephrine (10µM), relaxant responses to CEO and CA were investigated. CA (96.9%) was found as the major component. The maximum relaxation responses to CEO and CA were 96.4±3.5% and 96.0±5.0% in HCC and 97.5±5.5% and 96.8±4.8% in rat CC, respectively. There was no difference between control and diabetic rats in relaxation responses to CEO and CA. The relaxant responses obtained with essential oil and CA were not attenuated in the presence of nitric oxide synthase (NOS) inhibitor, and soluble guanylate cyclase inhibitor (sGS) in CC. In vivo, erectile responses in diabetic rats were lower than in control rats, which was restored after intracavernosal injection of CEO and CA. CEO and CA improved erectile function and relaxation of isolated strips of rat CC and HCC by a NO/cGMP-independent mechanism. Further investigations are warranted to fully elucidate the restorative effects of CEO and CA on diabetic erectile dysfunction.

Evaluation of relaxant responses properties of cinnamon essential oil and its major component, cinnamaldehyde on human and rat corpus cavernosum.

Cinnamomum cassia (Cinnamon) is a well-known traditional medicine with therapeutic benefits for centuries. We evaluated the effects of cinnamon essential oil (CEO) and its main component cinnamaldehyde (CA) on human corpus cavernosum (HCC) and rat CC. The essential oil of cinnamon was analyzed for the confirmation of the oil profile. HCC specimens from patients undergoing penile prosthesis surgery (age 48-69 years) were utilized for functional studies. In addition, erectile responses in anesthetized control and diabetic rats were evaluated in vivo after intracavernosal injection of CEO and CA, and rat CC strips were placed in organ baths. After precontraction with phenylephrine (10µM), relaxant responses to CEO and CA were investigated. CA (96.9%) was found as the major component. The maximum relaxation responses to CEO and CA were 96.4±3.5% and 96.0±5.0% in HCC and 97.5±5.5% and 96.8±4.8% in rat CC, respectively. There was no difference between control and diabetic rats in relaxation responses to CEO and CA. The relaxant responses obtained with essential oil and CA were not attenuated in the presence of nitric oxide synthase (NOS) inhibitor, and soluble guanylate cyclase inhibitor (sGS) in CC. In vivo, erectile responses in diabetic rats were lower than in control rats, which was restored after intracavernosal injection of CEO and CA. CEO and CA improved erectile function and relaxation of isolated strips of rat CC and HCC by a NO/cGMP-independent mechanism. Further investigations are warranted to fully elucidate the restorative effects of CEO and CA on diabetic erectile dysfunction.

Anogeissus leiocarpus attenuates paroxetine-induced erectile dysfunction in male rats via enhanced sexual behavior, nitric oxide level and antioxidant status.

Sexual dysfunction is a side effect of the antidepressant drug paroxetine. Anogeissus leiocarpus is a medicinal plant with a wide range of biological activities which include antioxidant and antiulcer properties. With these in mind, we investigated the effect of Anogeissus leiocarpus stem bark extract on paroxetine-induced sexual dysfunction in male Wistar rats. Forty-two adult male Wistar rats were divided into seven experimental groups: normal control, PAR (10 mg/kg), PAR + sildenafil (5 mg/kg), ALE (50 and 100 mg/kg) and PAR + ALE (50 and 100 mg/kg). The experiment lasted for 21 days, after which the rats were subjected to sexual behavioral test. Various biochemical assays (phosphodiesterase-5, arginase, acetylcholinesterase, nitric oxide and MDA) were carried out on the penile tissue homogenate. From our findings, paroxetine significantly altered sexual behavior in male rats and increased phosphodiesterase-5, arginase and acetylcholinesterase activities with a concomitant decrease in nitric oxide level. Furthermore, paroxetine altered antioxidant status which revealed by increased MDA level and reduced thiol level. However, treatment with Anogeissus leiocarpus stem bark extract reversed the altered sexual behavior in male rats and boosted antioxidant status. In addition, administration of Anogeissus leiocarpus stem bark extract resulted in a significant attenuation of phosphodiesterase-5, arginase and acetylcholinesterase activities in paroxetine-induced rats. In view of the aforementioned findings, Anogeissus leiocarpus could be considered a promising natural agent in erectile dysfunction management.

Hydroalcoholic extract of Pfaffia glomerata alters the organization of the seminiferous tubules by modulating the oxidative state and the microstructural reorganization of the mice testes.

ETHNOPHARMACOLOGICAL USAGES: Leaves and roots of Pfaffia glomerata areused as aphrodisiacs, tranquilizers and antirheumatics. Due to the lack of experimental scientific data, studies are necessary to identify its medicinal properties. AIMS: The present study aimed to evaluate the effect of hydroalcoholic root extract of P. glomerata (Brazilian ginseng extract - BGE) on testicular parenchyma, and evaluate possible harmful effects through testicular oxidative stress analysis. MATERIALS AND METHODS: Adult mice were divided into 6 groups: control (water), sildenafil citrate, BGE (100, 200 and 400 mg/kg/day), and BGE (200 mg/kg every three days). RESULTS: The treatment reduced the volumetric proportions of seminiferous tubules and epithelium, the number of Sertoli cells, and increased hydrogen peroxide levels, without affecting sperm production. It also caused cell death and changes in the frequency of stages of the seminiferous epithelium cycles. The 100 mg/kg dose responds in a similar way to sildenafil citrate, promoting changes in the gonadal structure, but with efficient response to contain the damage. CONCLUSIONS: Doses of 200 mg/kg, continuous or discontinuous, induced an increase in testicular nitric oxide, as well as sildenafil citrate, showing be efficient as aphrodisiac, but promotes cell death regardless of the form of administration.

The two phases of the clinical validation of preclinical translational mechanistic research on PDE5 inhibitors since Viagra's advent. A personal perspective.

The FDA approval of Viagra (sildenafil) for the on demand treatment of erectile dysfunction (ED) through relaxation of the corporal and cavernosal vascular smooth muscle that results in an increase in blood flow to the corporal tissues stemmed from 2 decades of research, mainly at academic centers. This culminated in the finding of the nitric oxide/cGMP pathway as the mediator of penile erection, followed by some years of basic studies and clinical validation at Pfizer. Further on, new translational laboratory and animal research from our group initiated a second phase when we proposed an alternative therapeutic schedule and mechanism of action for PDE5 inhibitors (PDE5i) in both corporal veno-occlusive dysfunction (CVOD) and Peyronie's disease (PD), specifically, continuous long-term administration (CLTA) to achieve sustained levels of cGMP within the penis. Due to the extended half-life of the long-acting PDE5i, tadalafil, this new alternative encompasses preferentially daily administration, although shorter half-life PDE5i, like sildenafil and vardenafil work too, depending on the duration, dose, and frequency of their administration This novel use was initially supported by showing the antifibrotic/antioxidant effects of nitric oxide and cGMP, produced by the induction of iNOS, as a mechanism of defense against collagen deposition in the localized fibrotic plaque of PD in an avascular tissue, the tunica albuginea. Our studies on iNOS and the progressive diffuse fibrosis occurring in the smooth muscle in CVOD, led to proposing the CLTA of PDE5i for maintaining sustained cGMP levels both in PD and in CVOD in order to halt or regress the penile fibrosis. In CVOD, we showed that PDE5i protect the corporal smooth muscle and reduce myofibroblast activation and number, counteracting the underlying corporal tissue pathology that causes CVOD, and potentially ameliorating long-term CVOD or even curing it. This review is focused on this novel PDE5i anti-fibrotic therapeutic concept.

Aphrodisiac Activity of Eulophia macrobulbon Extract on Erectile Dysfunction in Male Aged Rats.

This study investigated the effect of Eulophia macrobulbon (EM) extract on sexual performance in aged-related erectile dysfunction (ED) rats. The ethanol EM extract at the doses of 15, 150, and 450 and sildenafil citrate at the dose of 5 mg/kg body weight (BW) were administered orally to the aged male rats once daily for 21 days. Mating parameters and intracavernosal pressure (ICP) were measured to evaluate their sexual and erection functions. Numbers of sperm and sperm motility as well as the diameter of seminiferous tubules were observed. The serum testosterone and 3',5'-cyclic guanosine monophosphate (cGMP) concentration in the rat penile tissue were analyzed. The results showed the significant increased sexual motivation, copulatory performance, and ICP of aged rats treated with sildenafil citrate and all doses of EM extract as compared to control aged rats. Moreover, their serum testosterone levels were slightly increased and significant increase in penile cGMP concentration was observed in these aged rats treated with sildenafil citrate and EM extract. The results suggest that treatment with EM could inhibit activity of PDE5 in penile tissue resulting in the increased cGMP level and bring to the improvement of erectile function and sexual performance.

Neuroprotective mechanisms of sildenafil and selenium in PTZ-kindling model: Implications in epilepsy.

Epilepsy is one of the furthermost common neurodegenerative diseases affecting above 50 million individuals worldwide. The pathogenesis of epileptic seizures is not satisfactorily explored, and hence more effective anti-convulsive therapies are indispensable. Current study aimed to investigate the mechanisms of the potential neuroprotective effects of sildenafil/selenium on chemically-induced convulsions in mice. Kindling model was induced using pentylenetetrazol (PTZ; 35 mg/Kg, 11 doses, intraperitoneally, every other day). PTZ-insulted groups were treated intraperitoneally with sildenafil (20 mg/Kg), selenium (0.2 mg/Kg) or their combination; 30 min before PTZ administration. PTZ-kindled model showed a significant loss of neuronal cells concurrently with nitrative/oxidative stress and lipid peroxidation. This was associated with enhanced expression of inducible nitric oxide synthase (iNOS), hemeoxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) along with increased activity of thioredoxin reductase (TrxR) in hippocampal tissue. Individual treatment with sildenafil or selenium showed partial neuroprotection, simultaneously with lower hippocampal expression of 4-hydroneonenal (4-HNE), nitrotyrosine, iNOS and HO-1, yet without reaching normal levels. Sildenafil, but not selenium, enhanced the expression of VEGF and the endothelial cell marker CD34. The joint treatment with sildenafil and selenium preserved hippocampal neuronal count, improved kindling score, blunted lipid peroxides and nitrotyrosine levels, concomitantly with iNOS inhibition, normalization of TrxR activity and HO-1 expression, and evident neo-angiogenesis. Current study demonstrated the roles of several central signalling cascades in the sildenafil/selenium-evoked neuroprotection represented in, at least in part, amelioration of nitrative/oxidative stress alongside modulation of angiogenesis. Thus, sildenafil combined with selenium could be repurposed as a potential therapeutic regimen for delaying epilepsy progression.

Aphrodisiac Activity of an Aqueous Extract of Wood Ear Mushroom, Auricularia polytricha (Heterobasidiomycetes), in Male Rats.

Auricularia polytricha is a popular mushroom found all over the world. In this study we considered the effect of an aqueous extract of A. polytricha (AEAP) on restoring sexual performance parameters to normal, evaluated by considering observations of sexual behavior. At 0, 6, 12, 18, and 24 days, the following parameters of sexual performance were identified before and throughout the observations: mount latency, intromission latency, ejaculation latency, mounting frequency, intromission frequency, ejaculation frequency, and postejaculatory interval. Treatment of rats under stress with AEAP showed promising effects on overcoming stress-induced sexual dysfunction, on sexual performance, and on accessory sexual organs and body weight. Mounting latency, intromission latency, ejaculation latency, and postejaculatory interval parameters were significantly decreased by AEAP, whereas mounting frequency, intromission frequency, and ejaculation frequency were significantly increased by AEAP. These properties were identified in sexually dynamic and indolent male rats. We conclude that AEAP has a potent aphrodisiac activity.

Cilostazol alleviates streptozotocin-induced testicular injury in rats via PI3K/Akt pathway.

AIMS: Male infertility prevalence is higher in diabetic patients. Those patients exhibit testicular oxidative damage due to sustained hyperglycemia and inflammation. The study has investigated the efficacy of cilostazol, a phosphodiesterase 3 inhibitor, on testicular damage of diabetic rats. MAIN METHODS: Streptozotocin-induced diabetes in rats was used as a model. Six control male rats and 24 diabetic male rats were divided into the following: diabetic, cilostazol at low dose, cilostazol at high dose, and sildenafil treated rat groups. Treatment period was 4 weeks. Then, serum testosterone, testicular oxidative parameters, and testicular oxidant defenses were assayed. Real time PCR was done for quantification of Phosphoinositide 3-kinase (PI3K), Akt, and nuclear factor (NF)-κB mRNA. Expression of testicular inducible nitric oxide synthase (iNOS) was assessed. KEY FINDINGS: Diabetes negatively affected the testicular tissue as evident by biochemical analysis and histopathology. Four weeks of cilostazol or sildenafil treatment improved anti-oxidative capacity, ameliorated lipid peroxidation and the pro-inflammatory iNOS expression in testicular tissue. Testosterone level and the spermatogenesis showed marked improvement. Quantitative mRNA expression showed an elevation in PI3K and Akt by cilostazol with decreasing in NF-κB level by both drugs. SIGNIFICANCE: Our findings suggest the beneficial role of cilostazol and sildenafil in diabetic testicular damage dependent on anti-inflammatory and anti-oxidant effects.