scholarly journals Anticompulsive-like effect of nitric oxide synthase inhibitors in marble-burying test

2020 ◽  
Vol 1 ◽  
Author(s):  
Karina Montezuma ◽  
Caroline Biojone ◽  
Samia Joca ◽  
Plinio Casarotto ◽  
Francisco Silveira Guimarães
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Current Literature ◽  
Elevated Plus Maze ◽  
Plus Maze ◽  
Marble Burying ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Nitric Oxide Inhibitors ◽  
Oxide Synthase

Nitric oxide synthase (NOS) inhibitors decrease marble burying behavior (MBB), and the effect of several compounds that also attenuate MBB (such as classical antidepressants) engages the nitrergic system. In the present study, we tested the effect of the NOS inhibitor aminoguanidine (AMG) in attenuating MBB. For comparative reasons, we also tested the effect of selective inhibitors of neuronal (NOS1) and inducible (NOS2) isoforms NPA and 1400W, respectively. Our results indicate that AMG and NPA, but not 1400W, reduced the number of buried marbles in the marble burying test (MBT), which is considered an anticompulsive-like effect. No effect of AMG in the anxiety- or locomotor-related parameters of the elevated plus maze was observed. Taken together, our data is consistent with the current literature that suggests that nitric oxide inhibitors, putatively acting through the neuronal isoform of the synthesis enzyme (NOS1), exhibit anticompulsive-like properties.

Induction of Chronic Lymphocytic Leukemia (CLL) Apoptosis by Nitric Oxide Synthase (NOS) Inhibitors: Drug Efficacy Correlates with Lipid Solubility and NOS1 Dissociation Constant.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5044-5044
Author(s):  
Marc C. Levesque ◽  
Dipak K. Ghosh ◽  
Bethany E. Beasley ◽  
Youwei Chen ◽  
Alicia D. Volkheimer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Nitric Oxide Synthase ◽  
Cell Apoptosis ◽  
Weak Correlation ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Specific Inhibitors ◽  
Inducible Nos

Abstract The viability of CLL cells may be dependent on the autocrine production of nitric oxide because nitric oxide synthase (NOS) inhibitors induce CLL cell apoptosis and CLL cells express inducible NOS (NOS2). Our previous study indicated that the non-specific NOS inhibitor NMMA induced CLL cell apoptosis but only at high concentrations (> 1 mM) (Levesque et al., Leukemia17:442, 2003). Therefore, we performed the current study to identify NOS inhibitors that induce CLL cell apoptosis at lower concentrations and to understand factors that promote NOS inhibitor-induced CLL cell toxicity. We isolated and enriched CLL cells from the blood of CLL patients and cultured the CLL cells in media containing various concentrations of 21 different NOS inhibitors. We determined CLL cell viability following culture with each NOS inhibitor. We found that NOS inhibitors with specificity for neuronal NOS (NOS1) induced CLL cell death at concentrations lower than non-specific NOS inhibitors and lower than inducible NOS (NOS2) specific inhibitors. There was a weak correlation (r2 = 0.29, p = 0.1608) of the NOS1 (but not NOS2) half-maximal inhibitory concentration (IC50) of each NOS inhibitor for purified recombinant NOS and its ability to induce CLL cell death. We confirmed the specificity of the NOS inhibitors by inhibition of purified recombinant NOS1 and NOS2 enzyme activity, and we confirmed that NOS1 specific inhibitors induced CLL cell death by apoptosis. Because there was only a weak correlation of the NOS1 IC50 with NOS inhibitor induced CLL cell death, we considered whether other factors such as the Kd and hydrophobicity of each compound correlated with CLL cell death. We found that there was a direct correlation between the NOS1 (but not NOS2) dissociation constant (Kd) of NOS inhibitors and CLL cell death (r2 = 0.77, p = 0.0041) and a direct correlation of the partitioning coefficient (a measure of hydrophobicity) of each NOS inhibitor and its ability to induce CLL cell death (r2 = 0.68, p < 0.0001). Therefore, NOS inhibitors that bound tightly to NOS1 and were hydrophobic induced CLL cell death at lower concentrations. There was variable expression of CLL cell NOS1 mRNA (6 of 28 samples positive) and we were unable to demonstrate CLL cell expression of NOS1 protein by immunoblotting. This suggests that if NOS1 is present in CLL cells, it exists at very low levels. Taken together, we believe that low level NO production promotes CLL cell viability and that inhibition of CLL NOS induces CLL cell apoptosis. Importantly, our studies provide direction for the rational design and selection of NOS inhibitors that may be useful as CLL therapeutics.

scholarly journals Curcumin Reverses the Scopolomine-induced Cognitive Impairment by iNOS and Acetylcholinesterase Inhibition in Rodent Model of Schizophrenia

2020 ◽  
pp. 122-128
Author(s):  
Henna Khan ◽  
AMIT CHAUDHARY ◽  
RASHID ALI KHAN ◽  
WAZID ALI
Keyword(s):  
Nitric Oxide ◽  
Cognitive Impairment ◽  
Nitric Oxide Synthase ◽  
Elevated Plus Maze ◽  
Acetylcholinesterase Inhibition ◽  
Control Group ◽  
Acetyl Cholinesterase ◽  
Amnesic Effect ◽  
Plus Maze ◽  
Oxide Synthase

Schizophrenia is a severe neuro-developmental psychiatric disorder. Curcumin is a polyphenolic compound extracted from turmeric. It is known for its antioxidant, anti-inflammatory, neuroprotective, and precognitive properties. The purpose of the current study was to evaluate the role of curcumin in scopolamine induced cognitive impairment in animal model of schizophrenia. The elevated plus-maze test was utilised to study the curcumin effect on learning and memory. Curcumin (100 mg/kg, i.p.) was administered daily for 28 days in animals. Behavioural tests such as transfer latency (TL) and spontaneous alteration behaviour was assessed after the last dose of curcumin on the 28th day, followed by biochemical estimations. Present study reported that curcumin showed anti-amnesic effect in animal models of cognitive impairment of schizophrenia. Curcumin reduced the TL compared to toxic control group (scopolamine per se) (P <0.001) in elevated plus maze. In spontaneous alteration behaviour test, curcumin significantly increased percentage alteration and possible alteration as compared to toxic control group (P <0.001). A significant change in acetyl cholinesterase activity, nitrate and oxidative parameters was observed, thus, confirming its anti acetyl cholinesterase, NOS (nitric oxide synthase) inhibition and antioxidant properties (P <0.05). The present study put forward the claim of curcumin as a new and safer therapeutic alternative for the treatment of cognitive impairment in Schizophrenia. The underlying mechanism of this potential effect may be related to anticholinesterase and nitric oxide synthase inhibition activity of curcumin. Further research is warranted for confirming the suggested pathways accountable for memory alleviating effects of curcumin in Schizophrenia.

scholarly journals Regulation of cyclooxygenase activity and progesterone production in the rat corpus luteum by inducible nitric oxide synthase

Reproduction ◽  
2002 ◽  
pp. 663-669 ◽  
Author(s):  
A Hurwitz ◽  
Z Finci-Yeheskel ◽  
A Milwidsky ◽  
M Mayer
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Corpus Luteum ◽  
Prostaglandin E ◽  
No Production ◽  
Luteal Cells ◽  
Progesterone Production ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Oxide Synthase

This study explores interactions between the nitric oxide synthase (NOS) and the cyclooxygenase (COX) pathways in the regulation of progesterone production in early corpus luteum cells of rats. Nitric oxide (NO), prostaglandin E (PGE) and progesterone production was analysed in luteal cells of the rat corpus luteum exposed to inhibitors of non-specific NOS, inhibitors of inducible NOS (iNOS) and inhibitors of COX. Equine chorionic gonadotrophin (eCG)/hCG-primed rat corpus luteum cells produced NO, PGE and progesterone in a linear manner during 66 h of culture. Exposure of the cells to the non-specific NOS inhibitor, N(omega)-nitro-L-arginine (0.15 mmol l(-1)) for 48 h reduced NO, PGE and progesterone production to 21, 32 and 60% of that of the controls, respectively (P < 0.05 to P < 0.01). Another non-specific NOS inhibitor, N(omega)-methyl-L-arginine, produced similar inhibitions. Exposure of the cultured cells to S-ethylisothiourea (1 mmol l(-1)), a selective inhibitor of iNOS, suppressed the production of NO by 63%, PGE by 69% and progesterone by 48%. These findings indicate that production of PGE is regulated partly by iNOS, and that progesterone is probably regulated indirectly by the secondary changes in PGE. The addition of arachidonic acid to N(omega)-methyl-L-arginine-treated cells resulted in a significant increase in PGE and progesterone production (273 and 186%, respectively) without stimulating NO production. In contrast to the regulation exerted by the NO system on COX activity, the COX system does not modulate NO production in this model. This notion stems from the observation that the COX inhibitors acetylsalicylic acid (5 mmol l(-1)) and indomethacin (5 micromol l(-1)) suppressed PGE by 86 and 89%, respectively, and progesterone by 34 and 57%, respectively, but failed to inhibit NO production. The results from the present study indicate that iNOS-mediated NO production is involved in stimulating PGE synthesis in rat luteal cells, which may upregulate progesterone production.

Inhibition of nitric oxide synthase causes anxiolytic-like behaviour in an elevated plus-maze

Neuroreport ◽  
1995 ◽  
Vol 6 (10) ◽  
pp. 1413-1416 ◽  
Author(s):  
Vallo Volke ◽  
Sulev Kõks ◽  
Eero Vasar ◽  
Michel Bourin ◽  
Jacques Bradwejn ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Elevated Plus Maze ◽  
Plus Maze ◽  
Oxide Synthase

Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo

2011 ◽  
Vol 301 (3) ◽  
pp. H721-H729 ◽  
Author(s):  
Katsuhiko Noguchi ◽  
Naobumi Hamadate ◽  
Toshihiro Matsuzaki ◽  
Mayuko Sakanashi ◽  
Junko Nakasone ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Control Treatment ◽  
Enos Uncoupling ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
First Time

An elevation of oxidized forms of tetrahydrobiopterin (BH4), especially dihydrobiopterin (BH2), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH2 in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH2 concentration causes endothelial dysfunction in rats. To increase vascular BH2 levels, the BH2 precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH2 to BH4. MTX/SEP treatment did not significantly affect aortic BH4 levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH2 levels (291.1 ± 29.2 vs. 33.4 ± 6.4 pmol/g, P < 0.01) in association with moderate hypertension. Treatment with MTX alone did not significantly alter blood pressure or BH4 levels but decreased the BH4-to-BH2 ratio. Treatment with MTX/SEP, but not with MTX alone, impaired ACh-induced vasodilator and depressor responses compared with the control treatment (both P < 0.05) and also aggravated ACh-induced endothelium-dependent relaxations ( P < 0.05) of isolated aortas without affecting sodium nitroprusside-induced endothelium-independent relaxations. Importantly, MTX/SEP treatment significantly enhanced aortic superoxide production, which was diminished by NOS inhibitor treatment, and the impaired ACh-induced relaxations were reversed with SOD ( P < 0.05), suggesting the involvement of eNOS uncoupling. These results indicate, for the first time, that increasing BH2 causes eNOS dysfunction in vivo even in the absence of BH4 deficiency, demonstrating a novel insight into the regulation of endothelial function.

Glucose uptake during contraction in isolated skeletal muscles from neuronal nitric oxide synthase μ knockout mice

2015 ◽  
Vol 118 (9) ◽  
pp. 1113-1121 ◽  
Author(s):  
Yet Hoi Hong ◽  
Tony Frugier ◽  
Xinmei Zhang ◽  
Robyn M. Murphy ◽  
Gordon S. Lynch ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Nitric Oxide Synthase ◽  
Glucose Uptake ◽  
Ex Vivo ◽  
Organ Bath ◽  
Skeletal Muscle Glucose Uptake ◽  
Nos Inhibitor ◽  
Amp Activated Protein Kinase ◽  
Oxide Synthase

Inhibition of nitric oxide synthase (NOS) significantly attenuates the increase in skeletal muscle glucose uptake during contraction/exercise, and a greater attenuation is observed in individuals with Type 2 diabetes compared with healthy individuals. Therefore, NO appears to play an important role in mediating muscle glucose uptake during contraction. In this study, we investigated the involvement of neuronal NOSμ (nNOSμ), the main NOS isoform activated during contraction, on skeletal muscle glucose uptake during ex vivo contraction. Extensor digitorum longus muscles were isolated from nNOSμ−/−and nNOSμ+/+mice. Muscles were contracted ex vivo in a temperature-controlled (30°C) organ bath with or without the presence of the NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) and the NOS substrate L-arginine. Glucose uptake was determined by radioactive tracers. Skeletal muscle glucose uptake increased approximately fourfold during contraction in muscles from both nNOSμ−/−and nNOSμ+/+mice. L-NMMA significantly attenuated the increase in muscle glucose uptake during contraction in both genotypes. This attenuation was reversed by L-arginine, suggesting that L-NMMA attenuated the increase in muscle glucose uptake during contraction by inhibiting NOS and not via a nonspecific effect of the inhibitor. Low levels of NOS activity (∼4%) were detected in muscles from nNOSμ−/−mice, and there was no evidence of compensation from other NOS isoform or AMP-activated protein kinase which is also involved in mediating muscle glucose uptake during contraction. These results indicate that NO regulates skeletal muscle glucose uptake during ex vivo contraction independently of nNOSμ.

A radiometric analysis of nitric oxide synthase activity in Hymenolepis diminuta

Parasitology ◽  
2000 ◽  
Vol 120 (1) ◽  
pp. 91-95 ◽  
Author(s):  
N. B. TERENINA ◽  
M. V. ONUFRIEV ◽  
N. V. GULYAEVA ◽  
A. M. LINDHOLM ◽  
M. K. S. GUSTAFSSON
Keyword(s):  
Nitric Oxide ◽  
Free Radical ◽  
Nitric Oxide Synthase ◽  
Nadph Diaphorase ◽  
Hymenolepis Diminuta ◽  
Complete Reduction ◽  
Radiometric Analysis ◽  
Nos Inhibitors ◽  
Oxide Synthase ◽  
Nitric Oxide Synthase Activity

The free radical nitric oxide (NO) is a neuronal messenger which is synthesized from L-arginine and O2 by nitric oxide synthase (NOS). In the synthesis NO and L-citrulline are produced in a stoichiometric 1[ratio ]1 relation. The activity of NOS was analysed in homogenates of the rat tapeworm Hymenolepis diminuta by measuring the formation of L-[3H]citrulline after incubation with L-[3H]arginine. The nature of NOS in H. diminuta was determined by studying the effect of 3 types of NOS inhibitors: (1) L-NAME, (2) EGTA, (3) 7-nitro-indazole. All inhibitors caused a significant but not complete reduction in the formation of L-[3H]citrulline. The results are discussed against the background of nerve cells and fibres positive for NADPH-diaphorase staining in H. diminuta.

Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression

2017 ◽  
Vol 30 (3) ◽  
pp. 127-136 ◽  
Author(s):  
Laura Alves Stanquini ◽  
Caroline Biojone ◽  
Francisco Silveira Guimarães ◽  
Sâmia Regiane Joca
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Learned Helplessness ◽  
Positive Control ◽  
Repeated Treatment ◽  
Bdnf Expression ◽  
Nitric Oxide Synthase Inhibitor ◽  
Protein Levels ◽  
Nos Inhibitors ◽  
Oxide Synthase

BackgroundNitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models.ObjectiveThe aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants.MethodsAnimals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg).ResultsRepeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus.ConclusionThe results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels.

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