Genotoxic and oxidative effect of duloxetine on mouse brain and liver tissues

AbstractWe evaluated the duloxetine DNA damaging capacity utilizing the comet assay applied to mouse brain and liver cells, as well as its DNA, lipid, protein, and nitric oxide oxidative potential in the same cells. A kinetic time/dose strategy showed the effect of 2, 20, and 200 mg/kg of the drug administered intraperitoneally once in comparison with a control and a methyl methanesulfonate group. Each parameter was evaluated at 3, 9, 15, and 21 h postadministration in five mice per group, except for the DNA oxidation that was examined only at 9 h postadministration. Results showed a significant DNA damage mainly at 9 h postexposure in both organs. In the brain, with 20 and 200 mg/kg we found 50 and 80% increase over the control group (p ≤ 0.05), in the liver, the increase of 2, 20, and 200 mg/kg of duloxetine was 50, 80, and 135% in comparison with the control level (p ≤ 0.05). DNA, lipid, protein and nitric oxide oxidation increase was also observed in both organs. Our data established the DNA damaging capacity of duloxetine even with a dose from the therapeutic range (2 mg/kg), and suggest that this effect can be related with its oxidative potential.

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Role of Nitric Oxide in Regulation of Brain Stem Circulation during Hypotension

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199710000-00011 ◽

1997 ◽

Vol 17 (10) ◽

pp. 1089-1096 ◽

Cited By ~ 23

Author(s):

Kazunori Toyoda ◽

Kenichiro Fujii ◽

Setsuro Ibayashi ◽

Tetsuhiko Nagao ◽

Takanari Kitazono ◽

...

Keyword(s):

Nitric Oxide ◽

Brain Stem ◽

Topical Application ◽

Basilar Artery ◽

Group Versus ◽

Control Group ◽

Cranial Window ◽

Severe Hypotension ◽

The Brain

We tested the hypothesis that nitric oxide (NO) plays a role in CBF autoregulation in the brain stem during hypotension. In anesthetized rats, local CBF to the brain stem was determined with laser-Doppler flowmetry, and diameters of the basilar artery and its branches were measured through an open cranial window during stepwise hemorrhagic hypotension. During topical application of 10−5 mol/L and 10−4 mol/L Nω-nitro-L-arginine (L-NNA), a nonselective inhibitor of nitric oxide synthase (NOS), CBF started to decrease at higher steps of mean arterial blood pressure in proportion to the concentration of L-NNA in stepwise hypotension (45 to 60 mm Hg in the 10−5 mol/L and 60 to 75 mm Hg in the 10−4 mol/L L-NNA group versus 30 to 45 mm Hg in the control group). Dilator response of the basilar artery to severe hypotension was significantly attenuated by topical application of L-NNA (maximum dilatation at 30 mm Hg: 16 ± 8% in the 10−5 mol/L and 12 ± 5% in the 10−4 mol/L L-NNA group versus 34 ± 4% in the control group), but that of the branches was similar between the control and L-NNA groups. Topical application of 10−5 mol/L 7-nitro indazole, a selective inhibitor of neuronal NOS, did not affect changes in CBF or vessel diameter through the entire pressure range. Thus, endothelial but not neuronal NO seems to take part in the regulation of CBF to the the brain stem during hypotension around the lower limits of CBF autoregulation. The role of NO in mediating dilatation in response to hypotension appears to be greater in large arteries than in small ones.

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eNOS involved in colitis-induced mucosal blood flow increase

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00357.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. G1281-G1287 ◽

Cited By ~ 27

Author(s):

Joel Petersson ◽

Olof Schreiber ◽

Andreas Steege ◽

Andreas Patzak ◽

Anna Hellsten ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Blood Flow ◽

Vascular Resistance ◽

Control Level ◽

Mucosal Blood Flow ◽

Control Group ◽

Trinitrobenzene Sulfonic Acid ◽

Doppler Flowmetry ◽

Arterial Blood

The role of NO in inflammatory bowel disease is controversial. Studies indicate that endothelial nitric oxide synthase (eNOS) might be involved in protecting the mucosa against colonic inflammation. The aim of this study was to investigate the involvement of nitric oxide (NO) in regulating colonic mucosal blood flow in two different colitis models in rats. In anesthetized control and colitic rats, the distal colon was exteriorized and the mucosa visualized. Blood flow (laser-Doppler flowmetry) and arterial blood pressure were continuously monitored throughout the experiments, and vascular resistance was calculated. Trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS) was used to induce colitis. All groups were given the NOS inhibitor Nω-nitro-l-arginine (l-NNA) or the inducible NOS (iNOS) inhibitor l- N6-(1-iminoethyl)-lysine (l-NIL). iNOS, eNOS, and neuronal NOS (nNOS) mRNA in colonic samples were investigated with real-time RT-PCR. Before NOS inhibition, colonic mucosal blood flow, expressed as perfusion units, was higher in both colitis models compared with the controls. The blood flow was reduced in the TNBS- and DSS-treated rats during l-NNA administration but was not altered in the control group. Vascular resistance increased more in the TNBS- and DSS-treated rats than in the control rats, indicating a higher level of vasodilating NO in the colitis models. l-NIL did not alter blood pressure or blood flow in any of the groups. iNOS and eNOS mRNA increased in both colitis models, whereas nNOS remained at the control level. TNBS- and DSS-induced colitis results in increased colonic mucosal blood flow, most probably due to increased eNOS activity.

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Effect of tanshinone on the levels of nitric oxide synthase and acetylcholinesterase in the brain of alzheimer’s disease rat model

Clinical & Investigative Medicine ◽

10.25011/cim.v31i5.4871 ◽

2008 ◽

Vol 31 (5) ◽

pp. 248 ◽

Cited By ~ 15

Author(s):

You Yin ◽

Liuqing Huang ◽

Yan Liu ◽

Shaqi Huang ◽

JianHua Zhuang ◽

...

Keyword(s):

Nitric Oxide ◽

Treatment Group ◽

Nitric Oxide Synthase ◽

Rat Model ◽

Therapeutic Potential ◽

Control Group ◽

Group Model ◽

Model Group ◽

Oxide Synthase ◽

The Brain

Purpose: To determine the influence of tanshinone on the levels of nitric oxide synthase (NOS) and acetylcholinesterase (AChE) in the brain of an Altzheimer Disease (AD) rat model and on its potential therapeutic mechanism. Methods: 100 Male Sprague Dawley rats were divided into three groups: control group, model group and tanshinone treatment group. 10µg A?1-42 was injected bilaterally into the dorsal lateral region of the dentate gyrus in the hippocampus of rats in the model and tanshinone treatment groups to prepare the AD models. 24h after modeling, tanshinone, 50mg/kg, was administered by gastric perfusion to rats in the tanshinone treatment group. Later, immunohistochemical assay and Western blot analysis were used to detect expression of neuronal NOS (nNOS) and inducible NOS (iNOS) in the rat hippocampus. Activity of AChE in each subregion (CA1~CA4) of rats’ hippocampus was determined by a histochemical technique. Results: Expression of nNOS in the model group was down-regulated whereas iNOS was up-regulated. After A?1-42 injection, the number of AChE positive fibers in each subregion (CA1~CA4) of the hippocampus was decreased compared with controls. With tanshinone administration, the changes were improved to varying degrees. Conclusion: Tanshinone modulates AChE and NOS proteins concentrations in the hippocampus of AD rats. This may have therapeutic potential in AD rats.

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Chronic immobilization stress induces anxiety-related behaviors and affects brain essential minerals in male rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000682 ◽

2020 ◽

pp. 1-8

Author(s):

Zafer Sahin ◽

Alpaslan Ozkurkculer ◽

Omer Faruk Kalkan ◽

Ahmet Ozkaya ◽

Aynur Koc ◽

...

Keyword(s):

Immobilization Stress ◽

Central Area ◽

Essential Elements ◽

Male Rats ◽

Control Group ◽

Male Wistar Rats ◽

Swimming Test ◽

The Brain ◽

Center Area ◽

Chronic Immobilization Stress

Abstract. Alterations of essential elements in the brain are associated with the pathophysiology of many neuropsychiatric disorders. It is known that chronic/overwhelming stress may cause some anxiety and/or depression. We aimed to investigate the effects of two different chronic immobilization stress protocols on anxiety-related behaviors and brain minerals. Adult male Wistar rats were divided into 3 groups as follows ( n = 10/group): control, immobilization stress-1 (45 minutes daily for 7-day) and immobilization stress-2 (45 minutes twice a day for 7-day). Stress-related behaviors were evaluated by open field test and forced swimming test. In the immobilization stress-1 and immobilization stress-2 groups, percentage of time spent in the central area (6.38 ± 0.41% and 6.28 ± 1.03% respectively, p < 0.05) and rearing frequency (2.75 ± 0.41 and 3.85 ± 0.46, p < 0.01 and p < 0.05, respectively) were lower, latency to center area (49.11 ± 5.87 s and 44.92 ± 8.04 s, p < 0.01 and p < 0.01, respectively), were higher than the control group (8.65 ± 0.49%, 5.37 ± 0.44 and 15.3 ± 3.32 s, respectively). In the immobilization stress-1 group, zinc (12.65 ± 0.1 ppm, p < 0.001), magnesium (170.4 ± 1.7 ppm, p < 0.005) and phosphate (2.76 ± 0.1 ppm, p < 0.05) levels were lower than the control group (13.87 ± 0.16 ppm, 179.31 ± 1.87 ppm and 3.11 ± 0.06 ppm, respectively). In the immobilization stress-2 group, magnesium (171.56 ± 1.87 ppm, p < 0.05), phosphate (2.44 ± 0.07 ppm, p < 0.001) levels were lower, and manganese (373.68 ± 5.76 ppb, p < 0.001) and copper (2.79 ± 0.15 ppm, p < 0.05) levels were higher than the control group (179.31 ± 1.87 ppm, 3.11 ± 0.06 ppm, 327.25 ± 8.35 ppb and 2.45 ± 0.05 ppm, respectively). Our results indicated that 7-day chronic immobilization stress increased anxiety-related behaviors in both stress groups. Zinc, magnesium, phosphate, copper and manganese levels were affected in the brain.

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2118-P: Regulation of Ataxia-Telangiectasia and Rad3-Related (ATR)–Dependent DNA Damage Response by Nitric Oxide in ß-Cells

Diabetes ◽

10.2337/db20-2118-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 2118-P

Author(s):

CHAY TENG YEO ◽

BRYNDON OLESON ◽

JOHN A. CORBETT ◽

JAMIE K. SCHNUCK

Keyword(s):

Nitric Oxide ◽

Dna Damage ◽

Dna Damage Response ◽

Ataxia Telangiectasia ◽

Damage Response

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Dendrobium officinalis Flower Improves Learning and Reduces Memory Impairment by Mediating Antioxidant Effect and Balancing the Release of Neurotransmitters in Senescent Rats

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666200407080352 ◽

2020 ◽

Vol 23 (5) ◽

pp. 402-410 ◽

Cited By ~ 1

Author(s):

Lin-Zi Li ◽

Shan-Shan Lei ◽

Bo Li ◽

Fu-Chen Zhou ◽

Ye-Hui Chen ◽

...

Keyword(s):

Learning And Memory ◽

Brain Aging ◽

Morris Water Maze Test ◽

Control Group ◽

Histopathological Analysis ◽

Hippocampal Damage ◽

Common Belief ◽

Mao B ◽

Positive Effects ◽

The Brain

Aim and Objective: The Dendrobium officinalis flower (DOF) is popular in China due to common belief in its anti-aging properties and positive effects on “nourish yin”. However, there have been relatively few confirmatory pharmacological experiments conducted to date. The aim of this work was to evaluate whether DOF has beneficial effects on learning and memory in senescent rats, and, if so, to determine its potential mechanism of effect. Materials and Methods: SD rats were administrated orally DOF at a dose of 1.38, or 0.46 g/kg once a day for 8 weeks. Two other groups included a healthy untreated control group and a senescent control group. During the 7th week, a Morris water maze test was performed to assess learning and memory. At the end of the experiment, serum and brain samples were collected to measure concentrations of antioxidant enzymes, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH-Px) in serum, and the neurotransmitters, including γ-aminobutyric acid (γ-GABA), Glutamic (Glu), and monoamine oxidase B (MAO-B) in the brain. Histopathology of the hippocampus was assessed using hematoxylin-eosin (H&E) staining. Results: The results suggested that treatment with DOF improved learning as measured by escape latency, total distance, and target quadrant time, and also increased levels of γ-GABA in the brain. In addition, DOF decreased the levels of MDA, Glu, and MAO-B, and improved SOD and GSHPx. Histopathological analysis showed that DOF also significantly reduced structural lesions and neurodegeneration in the hippocampus relative to untreated senescent rats. Conclusion: DOF alleviated brain aging and improved the spatial learning abilities in senescent rats, potentially by attenuating oxidative stress and thus reducing hippocampal damage and balancing the release of neurotransmitters.

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DNA Damage and Repair in the Brain After Cerebral Ischemia

Current Topics in Medicinal Chemistry ◽

10.2174/1568026013394688 ◽

2001 ◽

Vol 1 (6) ◽

pp. 483-495 ◽

Cited By ~ 13

Author(s):

Bentham Science Publisher Philip K. Liu

Keyword(s):

Dna Damage ◽

Cerebral Ischemia ◽

Dna Damage And Repair ◽

The Brain

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Investigation of Oral Subacute Toxicity and In-Vitro Antioxidant Activity of Standardized Methanolic Extract of Quercus serrata Leaves

Current Bioactive Compounds ◽

10.2174/1573407216999201224150602 ◽

2020 ◽

Vol 16 ◽

Author(s):

Maibam Beebina Chanu ◽

Biseshwori Thongam ◽

Khumukcham Nongalleima ◽

Hans Raj Bhat ◽

Surajit Kumar Ghosh ◽

...

Keyword(s):

Nitric Oxide ◽

Antioxidant Activity ◽

Biochemical Parameters ◽

Methanolic Extract ◽

Reducing Power ◽

Quercus Serrata ◽

Control Group ◽

Blood Cell Count ◽

Toxicological Profile

Background: Quercus serrata Murray leaves have been used traditionally in the treatment of diabetes, dysmenorrhoea, inflammation and urinary tract infection. So, far no study had been reported on the toxicological profile and antioxidant properties of the plant. Objective: The present study was aimed to investigate the in-vivo toxicological profile and in-vitro antioxidant activities of the methanolic extract of standardized Quercus serrata leaves. Methods: Per-oral sub-acute toxicity study was performed in rats using three dose levels (200, 400 and 800 mg/kg b.w.) of the extract for 28-days. Control group received gum acacia suspended in water. Bodyweight was measured weekly. Biochemical parameters were analysed using the serum, the blood-cell count was done using whole blood. Pathological changes were also checked in highly perfused tissues. Further, in-vitro reducing power assay, nitric oxide scavenging assay, DPPH free-radical scavenging assay were performed to check the antioxidant activity of the extract. Results: There were no significant alterations in the blood-cell count and biochemical parameters analysed in the treatment group when compared with the normal control. Histopathology study of liver, kidney, pancreas, heart and brain revealed normal cellular architecture in the treatment groups alike the control group animals. Quercus serrata also showed a significant reduction of DPPH with IC50 4.48±0.254 µg/mL, in-vitro reducing power activity with IC50121.65±0.320 µg/mL and nitric oxide scavenging activity IC50 106.43±0.338 µg/mL. Conclusion: The above study showed that standardized methanolic extract of Quercus serrata leaves was safe after subacute oral administration in rats and has good antioxidant potential.

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Arginase Isoform Expression in Chronic Rhinosinusitis

Journal of Clinical Medicine ◽

10.3390/jcm8111809 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1809 ◽

Cited By ~ 4

Author(s):

Diana Vlad ◽

Silviu Albu

Keyword(s):

Nitric Oxide ◽

Chronic Rhinosinusitis ◽

Defense Mechanisms ◽

Upper Airway ◽

Control Group ◽

Mrna Levels ◽

Tissue Samples ◽

Endoscopic View ◽

Important Regulator ◽

Arginase I

Nitric oxide (NO) has emerged as an important regulator of upper airway inflammation, mainly as part of the local naso-sinusal defense mechanisms. Increased arginase activity can reduce NO levels by decreasing the availability of its precursor, L-arginine. Chronic rhinosinusitis (CRS) has been associated with low levels of nasal nitric oxide (nNO). Thus, the present study investigates the activity of arginase I (ARG1) and II (ARG2) in CRS and its possible involvement in the pathogenesis of this disease. Under endoscopic view, tissue samples of pathologic (n = 36) and normal (n = 29) rhinosinusal mucosa were collected. Arginase I and II mRNA levels were measured using real-time PCR. Our results showed low arginase I activity in all samples. The levels of ARG2 were significantly higher in patients with chronic rhinosinusitis compared to the control group (fold regulation (FR) 2.22 ± 0.42 vs. 1.31 ± 0.21, p = 0.016). Increased ARG2 expression was found in patients with CRS without nasal polyposis (FR 3.14 ± 1.16 vs. 1.31 ± 0.21, p = 0.0175), in non-allergic CRS (FR 2.55 ± 0.52 vs. 1.31 ± 0.21, p = 0.005), and non-asthmatic CRS (FR 2.42 ± 0.57 vs. 1.31 ± 0.21, p = 0.028). These findings suggest that the upregulation of ARG2 may play a role in the pathology of a distinctive phenotype of CRS.

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