Fluoxetine enhances the antitumor effect of olfactory ensheathing cell-thymidine kinase/ganciclovir gene therapy in human glioblastoma multiforme cells through upregulation of Connexin43 levels.

Glioblastoma multiforme (GBM) is the most invasive form of primary brain astrocytoma, resulting in poor clinical outcomes. Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy is considered a promising strategy for GBM treatment. Since Connexin43 (Cx43) expression is reduced in GBM cells, increasing Cx43 levels could enhance the effectiveness of gene therapy. The present study aims to examine the impact of fluoxetine on HSV-TK/GCV gene therapy in human GBM cells using human olfactory ensheathing cells (OECs) as vectors. The effect of fluoxetine on Cx43 levels was assessed using the western blot technique. GBM-derived astrocytes and OECs-TK were Cocultured, and the effect of fluoxetine on the Antitumor effect of OEC-TK/GCV gene therapy was evaluated using MTT assay and flow cytometry. Our results showed that fluoxetine increased Cx43 levels in OECs and GBM cells and augmented the killing effect of OECs-TK on GBM cells. Western blot data revealed that fluoxetine enhanced the Bax/Bcl2 ratio and the levels of cleaved caspase-3 in the coculture of OECs-TK and GBM cells. Moreover, flow cytometry data indicated that fluoxetine increased the percentage of apoptotic cells in the coculture system. This study suggests that fluoxetine, by upregulating Cx43 levels, could strengthen the Antitumor effect of OEC-TK/GCV gene therapy on GBM cells.

Antidiabetic and neuroprotective effects of a novel repaglinide analog.

Repaglinide (RPG) is an oral insulin secretagogue used in the treatment of diabetes. In this study, a new RPG analog was synthesized. Its antidiabetic and neuroprotective effects on dorsal root ganglions (DRG) in streptozotocin (STZ)-induced diabetic rats were examined compared to RPG. To assess the effects of 2-methoxy-4-(2-((3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)amino)-2-oxoethoxy)benzoic acid (OXR), the impact of OXR on oxidative stress biomarkers, motor function, and the expression of the glutamate dehydrogenase 1 (GLUD1), SLC2A2/glucose transporter 2 (GLUT2), and glucokinase (GCK) genes in STZ-induced diabetic rats were assessed. DRGs were examined histologically using hemotoxylin and eosin staining. Molecular docking was used to investigate the interactions between OXR and the binding site of RPG, the ATP-sensitive potassium (KATP) channel. Following 5 weeks of treatment, OXR significantly increased the level of total antioxidant power, decreased reactive oxygen species, and lipid peroxidation in the DRGs of diabetic rats. OXR restored STZ-induced pathophysiological damages in DRG tissues. Administration of OXR improved motor function of rats with diabetic neuropathy. Administration of 0.5 mg/kg OXR reduced blood glucose while promoting insulin, mainly through upregulation of messenger RNA expression of GLUD1, GLUT2, and GCK in the pancreas. Molecular docking revealed a favorable binding mode of OXR to the KATP channel. In conclusion, OXR has neuroprotective effects in diabetic rats by lowering oxidative stress, lowering blood glucose, and stimulating insulin secretion. We report that 0.5 mg/kg OXR administration was the most effective concentration of the compound in this study. OXR may be a promising target for further research on neuroprotective antidiabetic molecules.

Targeting Hedgehog signaling pathway: Paving the road for cancer therapy.

The Hedgehog pathway is essential for embryonic development but also for tissue and organ homeostasis in adult organisms. Activation of this pathway leads to the expression of target genes involved in proliferation, angiogenesis and stem cell self-renewal. Moreover, abnormal persistence of Hedgehog signaling is directly involved in a wide range of human cancers. Development of novel strategies targeting the Hedgehog pathway has become a subject of increased interest in anticancer therapy. These data are sustained by pre-clinical studies demonstrating that Hedgehog pathway inhibitors could represent an effective strategy against a heterogeneous panel of malignancies. Limited activity in other tumor types could be explained by the existence of crosstalk between the Hedgehog pathway and other signaling pathways that can compensate for its function. This review describes the Hedgehog pathway in detail, with its physiological roles during embryogenesis and adult tissues, and summarizing the preclinical evidence on its inhibition, the crosstalk between Hedgehog and other cancer-related pathways and finally the potential therapeutic effects of emerging compounds.

Inhibition of bromodomain and extraterminal domain reduces growth and invasive characteristics of chemoresistant ovarian carcinoma cells.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination are the major reasons for low survival rate in the patients. The bromodomain and extraterminal domain (BET) proteins are known as epigenetic 'readers,' and their inhibitors are novel epigenetic strategies for cancer treatment. Accumulating body of evidence indicates that epigenetic modifications have critical roles in development of EOC, and overexpression of the BET family is a key step in the induction of important oncogenes. Here, we examined the mechanistic activity of I-BET151, a pan-inhibitor of the BET family, in therapy-resistant EOC cells. Our findings showed that I-BET151 diminished cell growth, clonogenic potential, and induced apoptosis. I-BET151 inhibited cell proliferation through down-modulation of FOXM1 and its targets aurora kinase B and cyclin B1. I-BET151 attenuated migration and invasion of the EOC cells by down-regulation of epithelial-mesenchymal transition markers fibronectin, ZEB2, and N-cadherin. I-BET151 synergistically enhanced cisplatin chemosensitivity by down-regulation of survivin and Bcl-2. Our data provide insights into the mechanistic activity of I-BET151 and suggest that BET inhibition has potential as a therapeutic strategy in therapy-resistant EOC. Further in vivo investigations on the therapeutic potential of I-BET151 in EOC are warranted.

Targeting mTORs by omega-3 fatty acids: A possible novel therapeutic strategy for neurodegeneration?

Neurodegenerative diseases (NDs) such as Parkinson's (PD), Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) cause significant world-wide morbidity and mortality. To date, there is no drug of cure for these, mostly age-related diseases, although approaches in delaying the pathology and/or giving patients some symptomatic relief have been adopted for the last few decades. Various studies in recent years have shown the beneficial effects of omega-3 poly unsaturated fatty acids (PUFAs) through diverse mechanisms including anti-inflammatory effects. This review now assesses the potential of this class of compounds in NDs therapy through specific action against the mammalian target of rapamycin (mTOR) signaling pathway. The role of mTOR in neurodegenerative diseases and targeted therapies by PUFAs are discussed.

Nitric oxide mediates effects of acute, not chronic, naltrexone on LPS-induced hepatic encephalopathy in cirrhotic rats.

Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NOx concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.

The increased gastroprotective effect of pioglitazone in cholestatic rats: role of nitric oxide and tumour necrosis factor alpha.

The prevalence of gastric ulcers is high in cholestatic patients, but the exact mechanism of this increased frequency remains uncertain. It has been shown that pioglitazone accelerates the healing of pre-existing gastric ulcers. The present study was designed to investigate the effect of pioglitazone, on the gastric mucosal lesions in cholestatic rats. Cholestasis was induced by surgical ligation of common bile duct and sham-operated rats served as control. Different groups of sham and cholestatic animals received solvent or pioglitazone (5, 15, 30 mg/kg) for 7 days. On the day eight rats were killed after oral ethanol administration and the area of gastric lesions was measured. The serums of rats were also collected to determine serum levels of tumour necrosis factor alpha (TNF-α), IL-1ß and bilirubin. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than sham-operated ones. Pretreatment with pioglitazone dose-dependently attenuated gastric lesions induced by ethanol in both sham and cholestatic rats, but this effect was more prominent in cholestatic ones. The effect of pioglitazone was associated with a significant fall in serum levels of TNF-α in cholestatic rats. L-NAME, a non-selective nitric oxide synthase (NOS) inhibitor, and decreased pioglitazone-induced gastroprotective effect in cholestatic rats, while aminoguanidine, a selective inducible NOS inhibitor, potentiated pioglitazone-induced gastroprotective effect in the cholestatic rats. Chronic treatment with pioglitazone exerts an enhanced gastroprotective effect on the stomach ulcers of cholestatic rats compared to sham rats probably due to constitutive NOS induction and/or inducible NOS inhibition and attenuating release of TNF-α.

Effects of D-penicillamine on pentylenetetrazole-induced seizures in mice: involvement of nitric oxide/NMDA pathways.

Besides the clinical applications of penicillamine, some reports show that use of D-penicillamine (D-pen) has been associated with adverse effects such as seizures. So, the purpose of this study was to evaluate the effects of D-pen on pentylenetetrazole (PTZ)-induced seizures in male NMRI mice. It also examined whether N-methyl-D-aspartate (NMDA) receptor/nitrergic system blockage was able to alter the probable effects of D-pen. Different doses of D-pen (0.1, 0.5, 1, 10, 100, 150, and 250 mg/kg) were administered intraperitoneally (i.p.) 90 min prior to induction of seizures. D-Penicillamine at a low dose (0.5 mg/kg, i.p.) had anticonvulsant effects, whereas at a high dose (250 mg/kg, i.p.), it was proconvulsant. Both anti- and proconvulsant effects of D-pen were blocked by a single dose of a nonspecific inhibitor of nitric oxide synthase (NOS), L-NAME (10 mg/kg, i.p.), and a single dose of a specific inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitroindazole (30 mg/kg, i.p.). A selective inhibitor of iNOS, aminoguanidine (100 mg/kg, i.p.), had no effect on these activities. An NMDA receptor antagonist, MK-801 (0.05 mg/kg, i.p.), alters the anti- and proconvulsant effects of D-pen. The results of the present study showed that the nitric oxide system and NMDA receptors may contribute to the biphasic effects of D-pen, which remain to be clarified further.

Cardiovascular abnormalities in obstructive cholestasis: the possible mechanisms.

Cholestatic liver disease is associated with widespread derangements in the cardiovascular system, such as bradycardia, hypotension, QT prolongation and peripheral vasodilation; it is also associated with increased susceptibility to postoperative renal failure and haemorrhagic shock. A number of cellular signalling pathways have been shown to contribute to these abnormalities. In this article, we briefly review recent in vivo and in vitro findings in the field in an attempt to highlight the areas of agreement and areas of controversy. In this review, we will summarize pathogenic mechanisms underlying cardiac and vascular abnormalities in obstructive cholestasis. It seems that cardiovascular dysfunction is likely because of bile acids as one of the predominant factors. Other important factors which might play roles in these abnormalities are increased nitric oxide, endogenous opioids and endocannabinoids. These three factors interact with each other to exert vasodilation and impaired cardiovascular responses to sympathetic stimulation.

Cirrhosis is associated with development of tolerance to cardiac chronotropic effect of endotoxin in rats.

BACKGROUND/AIMS: Sepsis is a common complication of cirrhosis with a high mortality. Cirrhosis is associated with cardiac chronotropic and inotropic dysfunction, which is known as cirrhotic cardiomyopathy and might be linked to endotoxaemia. This study was aimed to explore the hypothesis that the inflammatory response induced by administration of low dose of lipopolysaccharide (LPS) exacerbates cardiac chronotropic dysfunction in cirrhotic rats; and if so, whether this is associated with altered cardiac toll-like receptor expression. METHODS: Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. Four weeks after bile duct ligation or sham surgery, the subjects were given intraperitoneal injection of either saline or LPS (0.1 mg/kg). Five hours after LPS injection, the atria were isolated and spontaneously beating rate and chronotropic responsiveness to ß-adrenergic stimulation was assessed using standard organ bath. The expression of toll-like receptor 4 (TLR4) was assessed the atria using immunohistochemistry as well as quantitative RT-PCR. RESULTS: LPS injection could induce a significant hypo-responsiveness to adrenergic stimulation in sham-operated rats. However, in cirrhotic rats, the chronotropic responses did not change after acute injection of LPS. Immunohistochemical study showed that TLR4 is mainly expressed in the myocardium in control atria and its expression is markedly decreased in myocardial layer following chronic bile duct ligation. CONCLUSION: Our data showed that cirrhosis is associated with development of tolerance to cardiac chronotropic effect of LPS in rats and this might be caused by altered localization of TLR4 in myocardium.

Nitric oxide mediates the beneficial effect of chronic naltrexone on cholestasis-induced memory impairment in male rats.

Recent studies suggest an augmentation of endogenous opioids following bile duct ligation (BDL) and their pivotal role in the pathophysiology of cholestasis. In this study, the effect of naltrexone, an opioid receptor antagonist, was determined on cholestasis-induced memory impairment and the possible involvement of nitric oxide (NO) in this effect. Male Albino-Wistar rats were randomized to sham-operated and BDL-operated groups. In each group, animals were treated for up to 28 days with saline; naltrexone (10 mg/kg); naltrexone and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) inhibitor (3, 10 mg/kg); naltrexone and aminoguanidine, an inducible NOS inhibitor (100 mg/kg); or methylnaltrexone, a peripherally acting opioid receptor antagonist (3 mg/kg, intraperitoneal). Spatial recognition memory was determined in a Y-maze task on the day before surgery and days 7, 14, 21, and 28 after surgery. Memory performance was impaired 14 days after BDL in cholestatic rats and was significantly reversed by chronic treatment with naltrexone at days 14, 21, and 28 after BDL. On day 21 after BDL, chronic L-NAME produced only a nonsignificant decrease in the beneficial effect of naltrexone, whereas on day 28, chronic administration of both L-NAME and aminoguanidine significantly reversed this effect of naltrexone. It is therefore shown in this study that naltrexone improves BDL-induced memory deficit in rats. We conclude that the memory impairment in cholestatic rats might be because of an increase in the level of endogenous opioids and that naltrexone improved the spatial recognition memory by antagonizing opioid receptors. The observation that the procognitive effect of naltrexone is counteracted either by general inhibition of NOS enzymes or by selective inhibition of inducible NOS suggests the nitrergic pathway as a probable mechanism involved in the amelioration of spatial recognition memory by naltrexone in BDL rats.

Analgesic and anti-inflammatory effects of modafinil in a mouse model of neuropathic pain: A role for nitrergic and serotonergic pathways.

OBJECTIVES: To evaluate the effects of modafinil on neuropathic pain induced by sciatic nerve cuffing in mice, and possible contribution of nitrergic/inflammatory and serotonergic systems. METHODS: Neuropathic pain was induced by applying a polyethylene cuff around the left sciatic nerve. Seven days later, mice received modafinil (50, 100, and 200 mg/kg; intraperitoneal [i.p.]) and morphine (10 mg/kg, i.p.) as control. Mice also received pretreatments of the nonselective nitric oxide (NO) synthase (NOS) inhibitor L-NAME, the selective neuronal NOS inhibitor 7-nitroindazole, the selective inducible NOS inhibitor aminoguanidine, and the selective serotonin reuptake inhibitor citalopram before modafinil (100 mg/kg). von Frey test was used to evaluate mechanical allodynia. Additionally, sciatic nerves were collected for histopathological analysis. Tissue levels of NO metabolites, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were assessed. RESULTS: Animals whose sciatic nerves were cuffed had a significantly (P<0.001) decreased paw withdrawal threshold (PWT) compared with the sham-operated group. Modafinil (100 mg/kg) and morphine significantly reversed PWT (P<0.001). Pretreatments with L-NAME, 7-nitroindazole, aminoguanidine, and citalopram in different groups markedly reversed analgesic effects of modafinil. Tissue homogenates of Cuffed sciatic nerves showed significantly higher levels of NO metabolites, TNF-α and IL-6 (P<0.001). Modafinil lowered NO metabolites, TNF-α, and IL-6 levels (P<0.001). Histopathology illustrated marked axonal degeneration and shrinkage in the cuffed sciatic nerve, which were improved in the modafinil-treated group. CONCLUSIONS: Modafinil exerts analgesic and neuroprotective effects in cuff-induced neuropathic mice via possible involvement of the nitrergic/inflammatory and serotonergic systems.

The interaction of melatonin and agmatine on pentylenetetrazole-induced seizure threshold in mice.

Melatonin, the major hormone produced by the pineal gland, has a number of functions in mammals, for example, its function as an anticonvulsant. Agmatine, a biogenic amine formed by decarboxylation of L-arginine by arginine decarboxylase, also has anticonvulsant effects. This study investigated the effect of the interaction of melatonin and agmatine on seizure susceptibility in the mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. Further, the researchers investigated the involvement of melatonin receptors in this interaction using luzindole, a ML(1/2) receptor antagonist and prazosin, a ML(3) receptor antagonist. Melatonin, at 40 and 80 mg/kg, and agmatine, at 10 and 20mg/kg, exerted anticonvulsant effects. Luzindole, at 1.25 and 2.5mg/kg, or prazosin, at 0.5mg/kg, did not change the seizure threshold as compared with that of vehicle-treated mice. The anticonvulsant effect of melatonin (40 and 80 mg/kg) was prevented by luzindole (2.5mg/kg) (P<0.001) but not prazosin (0.5mg/kg), indicating the possible involvement of ML(1/2) receptors in the anticonvulsant effect of melatonin. Agmatine (5mg/kg) significantly increased the anticonvulsant effect of both the noneffective dose (20mg/kg) (P<0.05) and the effective dose (80 mg/kg) (P<0.001) of melatonin. Luzindole (2.5mg/kg), but not prazosin (0.5mg/kg), decreased the anticonvulsant effect of agmatine (20mg/kg) (P<0.05). Luzindole (2.5mg/kg), but not prazosin (0.5mg/kg), also decreased the seizure threshold when agmatine (5mg/kg) was administered before melatonin (20mg/kg); the decrease was significant compared with that of the group that received only agmatine and melatonin (P<0.001). In conclusion, melatonin and agmatine exhibit an additive effect in decreasing pentylenetetrazole-induced seizure threshold in mice, probably through ML(1/2) receptors.

Morphine sensitization in the pentylenetetrazole-induced clonic seizure threshold in mice: role of nitric oxide and µ receptors.

Behavioral sensitization occurs after repeated administration of µ-opioid receptor agonists following a drug-free period. It seems that the changes in dopaminergic systems induced by µ-opioid receptor agonists play a crucial role in behavioral sensitization to opioids. Nitric oxide also plays a role in some behavioral effects of morphine, including sensitization to the locomotor-stimulating effect. This study investigated whether morphine sensitization appears in seizure threshold and the possible role of µ-opioid receptor and nitric oxide in this sensitization. Sensitization was produced by daily injections of morphine (0.1, 0.5, 1, 5, 15, or 30 mg/kg), followed by a 10-day washout period. Then the challenge test was performed using morphine (0.1, 0.5, 1, 5, 15, or 30 mg/kg) in different groups. To assess clonic seizure threshold, pentylenetetrazole (PTZ) was administered intravenously. Subcutaneous administration of morphine (0.1 and 0.5 mg/kg) induced sensitization in PTZ-induced clonic seizures in mice. Intraperitoneal administration of L-NAME (20 mg/kg), a nonselective inhibitor of nitric oxide synthase, or naltrexone (10 mg/kg), an opioid receptor antagonist, along with morphine inhibited morphine-induced sensitization in PTZ-induced seizure threshold. In conclusion, at low doses, morphine induces sensitization in PTZ-induced clonic seizures in mice probably as a result of the interaction with µ-receptors and nitric oxide.

Effect of DETA-NONOate and papaverine on vasodilation of human internal mammary artery.

In this study, the relaxatory effect of DETA-NONOate is compared with that of papaverine on isolated human internal mammary artery. We investigated the inhibitory effects of DETA-NONOate and papaverine on phenylephrine-induced contractile response in internal mammary artery segments. The internal mammary artery segments, taken from methodologically matched patients who underwent coronary artery bypass grafting, were prepared, placed in an organ bath, and contracted with phenylephrine (10(-9) to 10(-4) mol/L) to investigate their relaxatory response to DETA-NONOate or papaverine. Phenylephrine dose-response contraction was obtained after 1, 2, and 3 h in segments pre-incubated with DETA-NONOate or papaverine for 30 min. The EC50 that presented for internal mammary artery segments incubated with DETA-NONOate was 3.523 ± 1.2696 × 10(-7) mol/L, and for papaverine was 3.467 ± 1.2145 × 10(-6) mol/L. In segments pre-incubated with DETA-NONOate, the contractile response to phenylephrine was suppressed in the first 2 h post-incubation, compared with control responsive groups (p < 0.05), but this inhibition was revoked after 3 h post-incubation. We showed that DETA-NONOate has a more significant relaxative effect by comparison with papaverine; moreover, continuous and long-lasting nitric oxide production by DETA-NONOate might be of great importance for the outcome from coronary artery bypass grafting, when internal mammary artery is used as a conduit.

1-Methyl tryptophan, an indoleamine 2,3-dioxygenase inhibitor, attenuates cardiac and hepatic dysfunction in rats with biliary cirrhosis.

Kynurenine Pathway (KP) is the dominant metabolic route of tryptophan which is catalyzed by indoleamine-2,3-dioxygenase (IDO). This pathway is upregulated in liver disease where the level of KP metabolites correlates with the severity of disease. Cirrhosis is associated with cardiac dysfunction, which manifests itself during severe physiological challenges such as liver transplantation. Cardiac dysfunction in cirrhosis is linked to systemic inflammation and impaired cardiac beta-adrenergic signaling pathways. The KP pathway is involved in modulation of cardiac signaling and is upregulated by systemic inflammation. Therefore, this study aimed to evaluate the effect of IDO inhibition on development of cardiac dysfunction in an experimental model of cirrhosis. Cirrhosis was induced by bile duct ligation (BDL). Experimental groups were given either 1-methyl tryptophan (1-MT, 1, 3, 9 mg/kg), or saline. 28 days after BDL, cardiac chronotropic response to epinephrine was assessed ex vivo. HPLC was employed to measure hepatic and cardiac levels of tryptophan, kynurenine and kynurenic acid. Cirrhosis in rats was associated with impaired cardiac chronotropic responsiveness to adrenergic stimulation. 1-MT dose-dependently improved cirrhosis-induced chronotropic dysfunction as well as elevated serum levels of CRP and IL-6 in BDL rats. Hepatic and cardiac kynurenine/tryptophan ratio were elevated in cirrhotic rats and were reduced following 1-MT administration. Chronic administration of 1-MT could also reduce hepatic inflammation, fibrosis and ductular proliferation. 1-MT attenuates cardiac dysfunction in rats with biliary cirrhosis. This protective effect is not limited to the cardiac function as liver histopathologic changes were also improved following chronic 1-MT administration.

Role of Nitric Oxide in Neurodegeneration: Function, Regulation, and Inhibition.

Reactive nitrogen species (RNS) and reactive oxygen species (ROS), collectively known as reactive oxygen and nitrogen species (RONS), are the products of normal cellular metabolism and interact with several vital biomolecules including nucleic acid, proteins, and membrane lipids and alter their function in an irreversible manner which can lead to cell death. There is an imperative role for oxidative stress in the pathogenesis of cognitive impairments and the development and progression of neural injury. Elevated production of higher amounts of nitric oxide (NO) takes place in numerous pathological conditions, such as neurodegenerative diseases, inflammation, and ischemia, which occur concurrently with elevated nitrosative/oxidative stress. The enzyme nitric oxide synthase (NOS) is responsible for the generation of NO in different cells by conversion of Larginine (Arg) to L-citrulline. Therefore, the NO signaling pathway represents a viable therapeutic target. Naturally occurring polyphenols targeting the NO signaling pathway can be of major importance in the field of neurodegeneration and related complications. Here, we comprehensively review the importance of NO and its production in the human body and afterwards highlight the importance of various natural products along with their mechanisms against various neurodegenerative diseases involving their effect on NO production.

Opioid receptor antagonist promotes angiogenesis in bile duct ligated rats.

BACKGROUND AND AIM: Angiogenesis, formation of new capillaries from existing vasculature, plays a pivotal role in different pathological states such as many chronic inflammatory diseases including the chronic liver diseases. There is increasing evidence demonstrating accumulation of endogenous opioids and their role in the pathophysiology and manifestations of cholestasis, the main feature of a number of chronic progressive liver diseases. Hence, we investigated the significance of endogenous opioids in angiogenesis in an experimental model of cholestasis. METHODS: Cholestasis was induced in male Sprague-Dawley rats by bile duct ligation and resection. Naltrexone, an opioid antagonist (20 mg/kg/day) was administered to cholestatic animals for 22 +/- 1 days. The serial sections from liver tissue were stained with von Willebrand Factor antibody and micro-vessel density was assessed by calculating mean micro-vessel number in three hot spots high power microscopic fields. RESULTS: Naltrexone treatment in bile duct ligated rats led to a marked increase in the micro-vessel number (6.34 +/- 0.21 vs 5.61 +/- 0.22) (P < 0.05), which had already increased during cholestasis. CONCLUSION: In order to clarify the impacts of opioid system blockade in cirrhosis, our findings demonstrate the promoting role of opioid antagonist in angiogenesis in a rat model of cholestasis.

Antinociceptive effect of chronic lithium on visceral hypersensitivity in a rat model of diarrhea-predominant irritable bowel syndrome: The role of nitric oxide pathway.

BACKGROUND AND AIM: Lithium, a widely used drug in bipolar-affective disorders, plays gastro-protective roles. The effects of lithium on several tissues are mediated through nitric oxide (NO), which regulates gastrointestinal motility and mucosal integrity. The aim of this study was to investigate the protective effect of chronic lithium administration on visceral hypersensitivity and to investigate the role of NO as a potential mechanism of lithium in a rat model of irritable bowel syndrome. METHODS: Colitis was induced by the intracolonic administration of acetic acid. After subsidence of inflammation on the seventh experimental day, nociception and defecation parameters were measured. A subgroup of animals had been pretreated with lithium carbonate (600 mg/L) for 35 days. Thereafter, either a non-selective NO synthase (NOS) inhibitor (N-nitro-L-arginine methyl ester [L-NAME], 10 mg/kg), a selective NOS inhibitor (aminoguanidine, 100 mg/kg), or saline were administered intraperitoneally 1 h before measurements. RESULTS: Chronic lithium attenuated the visceral hypersensitivity, increased the nociceptive threshold, and decreased stool frequency. L-NAME and aminoguanidine decreased the nociceptive threshold and reduced the protective effects of lithium on visceral hypersensitivity. Stool frequency was increased in both the lithium-treated and water-treated groups by L-NAME administration, but not aminoguanidine. The form of defecation in the lithium-treated rats shifted toward hard stools rather than being soft and formless, but NOS inhibitors did not change the stool consistency pattern. CONCLUSION: The results indicate the antinociceptive property of chronic lithium on visceral hypersensitivity. As this effect was lowered by NOS inhibitors, NO might play a role in the protective effect of lithium to some extent.

Effects of intravitreal morphine administered at different time points after reperfusion in a rabbit model of ischemic retinopathy.

PURPOSE: To investigate the effects of morphine administered after reperfusion in a rabbit model of ischemic retinopathy. METHODS: The right eyes of 54 albino New Zealand rabbits were randomly allocated into nine treatment groups (n = 6 in each group). The eyes in saline-control group received 0.1 mL of phosphate-buffered saline solution intravitreally. In the ischemia-saline group, ischemia was induced by raising the intraocular pressure to 150 mmHg for 60 minutes. Then 0.1 mL of phosphate-buffered saline solution was administered intravitreally 5 minutes after reperfusion. The eyes in three ischemia-morphine groups (ischemia-morphine 0 hour, 1 hour, and 18 hours) received 0.1 mL of morphine (10 micromol/L) intravitreally 5 minutes, 1 hour, or 18 hours after termination of 60 minutes of ischemia, respectively. The eyes in ischemia-naloxone-morphine group received 0.05 mL of naloxone (10 micromol/L) intravitreally followed by injection of 0.05 mL morphine (10 micromol/L) 5 minutes after termination of ischemia. Toxicity controls were performed with morphine (10 micromol/L) and naloxone (10 micromol/L) without ischemia. Histologic evaluation was performed for all groups on the seventh postoperative day. RESULTS: Sixty minutes of ischemia led to severe cell loss in ganglion cell layer and thinning of the inner nuclear layer in ischemia-saline group compared with that of the saline-control group (P < 0.001). Thickness of the inner plexiform layer to the inner limiting membrane (a measure of inner retinal thickness) was significantly increased due to edema (P < 0.001). Administration of morphine 5 minutes after reperfusion significantly improved all of the above mentioned indices compared with ischemia-saline group (P < 0.001). Administration of morphine 1 hour after reperfusion had also a significant effect on the improvement of above mentioned indices compared with saline-control group (P < 0.05). However, the number of ganglion cells was significantly higher in ischemia-morphine 0 hour group compared with ischemia-morphine 1 hour group (P < 0.001). Morphine treatment 18 hours after reperfusion did not change the amount of injury. Administration of naloxone 5 minutes before morphine abolished most of the morphine protective effects. CONCLUSION: Intravitreal administration of morphine immediately after reperfusion maximally protects retina against ischemia-reperfusion injury. Pharmacologic evidence suggests that this protective phenomenon may be mediated in part by opioid receptors.