scholarly journals Sex-dependent effects of long-term clozapine or haloperidol medication on red blood cells and liver iron metabolism in Sprague Dawley rats as a model of metabolic syndrome

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Marie-Luise Bouvier ◽  
Karin Fehsel ◽  
Andrea Schmitt ◽  
Eva Meisenzahl-Lechner ◽  
Wolfgang Gaebel ◽  
...  
Keyword(s):  
Antipsychotic Drug ◽  
Iron Metabolism ◽  
Liver Diseases ◽  
Blood Parameters ◽  
Blue Staining ◽  
Hepatic Iron ◽  
Sprague Dawley ◽  
Liver Iron ◽  
Distribution Width ◽  
Sprague Dawley Rats

Abstract Background Patients with liver diseases often have some form of anemia. Hematological dyscrasias are known side effects of antipsychotic drug medication and the occurrence of agranulocytosis under clozapine is well described. However, the sex-dependent impact of clozapine and haloperidol on erythrocytes and symptoms like anemia, and its association with hepatic iron metabolism has not yet been completely clarified. Therefore, in the present study, we investigated the effect of both antipsychotic drugs on blood parameters and iron metabolism in the liver of male and female Sprague Dawley rats. Methods After puberty, rats were treated orally with haloperidol or clozapine for 12 weeks. Blood count parameters, serum ferritin, and liver transferrin bound iron were determined by automated counter. Hemosiderin (Fe3+) was detected in liver sections by Perl’s Prussian blue staining. Liver hemoxygenase (HO-1), 5’aminolevulinate synthase (ALAS1), hepcidin, heme-regulated inhibitor (HRI), cytochrome P4501A1 (CYP1A1) and 1A2 (CYP1A2) were determined by Western blotting. Results We found anemia with decreased erythrocyte counts, associated with lower hemoglobin and hematocrit, in females with haloperidol treatment. Males with clozapine medication showed reduced hemoglobin and increased red cell distribution width (RDW) without changes in erythrocyte numbers. High levels of hepatic hemosiderin were found in the female clozapine and haloperidol medicated groups. Liver HRI was significantly elevated in male clozapine medicated rats. CYP1A2 was significantly reduced in clozapine medicated females. Conclusions The characteristics of anemia under haloperidol and clozapine medication depend on the administered antipsychotic drug and on sex. We suggest that anemia in rats under antipsychotic drug medication is a sign of an underlying liver injury induced by the drugs. Changing hepatic iron metabolism under clozapine and haloperidol may help to reduce these effects of liver diseases.

Oral contraceptives, norethindrone and mestranol: effects on tissue levels of minerals

1976 ◽  
Vol 231 (1) ◽  
pp. 98-103 ◽  
Author(s):  
KY Lei ◽  
AS Prasad ◽  
E Bowersox ◽  
D Oberleas
Keyword(s):  
Causative Factor ◽  
Atomic Absorption Spectrophotometry ◽  
Plasma Zinc ◽  
Sprague Dawley ◽  
Liver Iron ◽  
Zinc Intake ◽  
Sprague Dawley Rats ◽  
Plasma Copper ◽  
Zinc Concentrations ◽  
Zinc Levels

The study involved three levels of dietary zinc (deficient, marginal, and adequate) and four hormonal conditions; namely, no steriods, norethindrone, mestranol, and norethindrone plus mestranol. The steroids were incorporated into diets and fed to 11-wk-old female Sprague-Dawley rats. After 10 wk of treatment, various tissues were excised for mineral assays by atomic-absorption spectrophotometry. Both steroids, reduced weight gain. Mestranol depressed plasma zinc, tibia copper and magnesium, and liver iron, but elevated the zinc levels in liver and erythrocytes, plasma copper, liver magnesium and calcium, and iron content of tibia and heart. In general, the effect was most prominent with adequate zinc but diminished in magnitude with the reduction of zinc intake. In addition, norethindrone increased heart iron and tibia calcium. Mestranol appeared to be the main causative factor and may have induced a possible shift of minerals from one pool to another. As expected, zinc deficiency resulted in the reduction of zinc concentrations of plasma, tibia, kidney, and pancreas, and the elevation of copper, iron, magnesium, and calcium concentrations of various tissues.

scholarly journals Evaluation of the Carcinogenic Potential of Roxadustat (FG-4592), a Small Molecule Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase in CD-1 Mice and Sprague Dawley Rats

2017 ◽  
Vol 36 (6) ◽  
pp. 427-439 ◽  
Author(s):  
James Beck ◽  
Carroll Henschel ◽  
James Chou ◽  
Al Lin ◽  
Ughetta del Balzo
Keyword(s):  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Small Molecule Inhibitor ◽  
Prolyl Hydroxylase ◽  
Sprague Dawley ◽  
Oral Gavage ◽  
Distribution Width ◽  
Sprague Dawley Rats ◽  
Molecule Inhibitor ◽  
Carcinogenic Potential

The carcinogenic potential of roxadustat (FG-4592), a novel orally active, heterocyclic small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes in clinical development for treatment of anemia, was evaluated in CD-1 mice and Sprague Dawley rats. Inhibition of HIF-PH by roxadustat leads to a rapid increase in cytoplasmic HIF-α concentrations, followed by translocation of HIF-α to the nucleus and upregulation of HIF-responsive genes, including erythropoietin. Roxadustat was dosed by oral gavage 3 times weekly (TIW) for up to 104 weeks in mice at 0, 15, 30, and 60 mg/kg and in rats at 0, 2.5, 5, and 10 mg/kg. Treatment-associated changes in hematology parameters were consistent with the pharmacologic activity of roxadustat and included elevations in hematocrit in mice at 30 and 60 mg/kg TIW and elevations in erythrocyte count, hemoglobin, hematocrit, and red cell distribution width in rats at 10 mg/kg TIW. No increase in mortality or neoplastic effects compared with vehicle controls was observed after roxadustat treatment in either species. No treatment-related nonneoplastic findings were observed in mice, whereas nonneoplastic microscopic findings in rats were limited to atrial/aortic thromboses at 10 mg/kg TIW males and bone marrow hypercellularity in all treated male and female groups, consistent with the pharmacology of roxadustat. In conclusion, roxadustat administered by oral gavage to mice and rats TIW for up to 104 weeks resulted in dose-dependent exposure and hematologic effects with no effect on survival or development of neoplastic lesions at up to 60 mg/kg in mice and up to 10 mg/kg in rats.

scholarly journals Chronic Variable Stress Induces Hepatic Fe(II) Deposition by Up-Regulating ZIP14 Expression via miR-181 Family Pathway in Rats

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 653
Author(s):  
Shuxia Jiang ◽  
Taining Guo ◽  
Shihui Guo ◽  
Jiang Gao ◽  
Yingdong Ni ◽  
...  
Keyword(s):  
Body Weight ◽  
Liver Damage ◽  
Weight Ratio ◽  
Luciferase Reporter ◽  
Control Group ◽  
Hepatic Iron ◽  
Sprague Dawley ◽  
Reporter System ◽  
Sprague Dawley Rats ◽  
Chronic Variable Stress

It is well-known that hepatic iron dysregulation, which is harmful to health, can be caused by stress. The aim of the study was to evaluate chronic variable stress (CVS) on liver damage, hepatic ferrous iron deposition and its molecular regulatory mechanism in rats. Sprague Dawley rats at seven weeks of age were randomly divided into two groups: a control group (Con) and a CVS group. CVS reduces body weight, but increases the liver-to-body weight ratio. The exposure of rats to CVS increased plasma aspartate aminotransferase (AST), alkaline phosphatase (ALP) and hepatic malondialdehyde (MDA) levels, but decreased glutathione peroxidase (GSH-Px) activity, resulting in liver damage. CVS lowered the total amount of hepatic iron content, but induced hepatic Fe(II) accumulation. CVS up-regulated the expression of transferrin receptor 1 (TFR1) and ZRT/IRT-like protein 14 (ZIP14), but down-regulated ferritin and miR-181 family members. In addition, miR-181 family expression was found to regulate ZIP14 expression in HEK-293T cells by the dual-luciferase reporter system. These results indicate that CVS results in liver damage and induces hepatic Fe(II) accumulation, which is closely associated with the up-regulation of ZIP14 expression via the miR-181 family pathway.

scholarly journals Anticancer Potential of Ethyl Acetate Extract Fractions of Ipomoea horsfalliae Hook on DMBA- Induced Breast Cancer Model

2021 ◽  
Vol 12 (5) ◽  
pp. 6447-6459
Keyword(s):  
Breast Cancer ◽  
Ethyl Acetate ◽  
Blood Parameters ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Breast Cancer Model ◽  
Antioxidant Characteristics ◽  
Nitrate And Nitrite ◽  
Breast Tissues

The genus Ipomoea is distributed globally and honored as the largest genus of the family Convolvulaceae. Several varieties of this family have been shown to be effective in treating various diseases, including cancer. This research aimed to explore the anticancer activity of ethyl acetate fractions of Ipomoea horsfalliae Hook (EAIH) in female Sprague-Dawley rats. 7, 12-dimethylbenz (a) anthracene (DMBA) was used to produce breast cancer. The Fractions were selected based on the cytotoxicity analysis in vitro, which was reported in our earlier studies. The study employed two dosages of EAIH (25 and 50 mg/kg). Biochemical, hematological, and antioxidant characteristics were investigated. A decrease in mean tumor volume and tumor weight was detected in EAIH treated groups. The blood parameters were seen as normal. In both DMBA and doxorubicin groups, malondialdehyde was increased, and the level was significantly reduced in EAIH-treated groups. The effect of catalase was shown to be diminished in the groups given DMBA and doxorubicin but normal in the EAIH groups. Nitrate and nitrite levels increased in the DMBA control groups but were normal in the others. There was less necrosis and infiltration in breast tissues treated with doxorubicin as well as in EAIH. In animals treated with EAIH, the therapeutic effect was found to be dose-dependent. The therapies helped to repair some of the altered breast patterns. The study concludes that I. horsfolliae may be a potential anticancer candidate and need to explore further.

scholarly journals Preclinical hematological profile studies of an ayurvedic medicine Siddha Makardhwaja after chronic administration to male sprague-dawley rats

2017 ◽  
Vol 7 (1) ◽  
pp. 93
Author(s):  
Md. Mamun Sikder ◽  
Proshanta Chakraborty ◽  
Md. Ruhul Mahbub ◽  
Tasniya Nahiyan Zulfiquar ◽  
Md. Nuruzzaman Neon ◽  
...  
Keyword(s):  
Hematological Parameters ◽  
Chronic Administration ◽  
Scientific Data ◽  
Toxicity Tests ◽  
Male Rat ◽  
Sprague Dawley ◽  
Absolute Count ◽  
Distribution Width ◽  
Sprague Dawley Rats ◽  
The Absolute

Background: Siddha Makardhwaja (SMD) is a classical Ayurvedic formulation markedly used as a traditional medicine in the rural population for various purposes such as stimulant, tonic, and rejuvenator.Methods: The present study is conducted to evaluate the effect of conventionally prepared SMD on the hematological parameters in experimental animals, for providing scientific data base for its logical use in clinical practice. Acute toxicity tests were conducted to determine the LD50 of the drug. To find out the effect of chronic administration of SMD on hematological parameters it was administered chronically to the male Sprague-Dawley rats at a dose of 40mg/kg for 28 days.Results: In this experiment the TC, DC, various erythrocytic parameters, platelet parameters, ESR were determined. The results of the studies are given below. There is an (13.41%) increase in the number of white blood cell count of the male rat, the increase though not significant yet it was prominent (p=0.257). There is an (15.87%) increase in the absolute count of Neutrophils of the male rat, the increase though not significant yet it was prominent (p=0.371). There is an (12.29%) increase in the absolute count of Lymphocytes of the male rat, the increase though not significant yet it was prominent (p=0.388). There is a statistically significant (p=0.035) increase in the number of platelet count of the male rat (11.13% increase). There is a (2.03%) decrease in the platelet volume distribution width of the male rat, the decrease though not significant yet it was noticeable (p=0.094). There is a statistically insignificant (p=0.619) (10.0%) increase in Erythrocyte sedimentation rate in blood from the male rat.Conclusions: As SMD decreases and increases abnormally on the hematological parameters in body of treated rats, so it should not be administered chronically at a higher dose. Further studies should be done by reducing the administered dose.

scholarly journals Preclinical Acute Toxicology Study of Surfactant-Stabilized Ultrasound Contrast Agents in Adult Rats

2009 ◽  
Vol 29 (1) ◽  
pp. 32-39 ◽  
Author(s):  
Flemming Forsberg ◽  
Ji-Bin Liu ◽  
Mihir Patel ◽  
Liping Liu ◽  
Ling Lin ◽  
...  
Keyword(s):  
Contrast Agents ◽  
Clinical Signs ◽  
Blood Parameters ◽  
Ultrasound Contrast Agents ◽  
Dose Dependency ◽  
Sprague Dawley ◽  
Adult Rats ◽  
Toxicology Study ◽  
Ultrasound Contrast ◽  
Sprague Dawley Rats

Gas-filled microbubbles are used as contrast agents in diagnostic ultrasound imaging. A preclinical, acute toxicity study of 2 surfactant-stabilized ultrasound contrast agents (ST68 and ST44) was conducted. Subjects were 104 Sprague-Dawley rats (experimental doses, 0.1, 0.2, 0.8, and 1.0 mL/kg; control, 1.0 mL/kg saline) that were studied for 14 days after contrast; clinical signs, weight, blood, and urine were evaluated. Histopathology was performed following euthanasia. Of the 40 animals receiving ST44, 4 died prematurely and a dose dependency was demonstrated ( P = .011), whereas in the ST68 groups only 1 death occurred (no dose dependency; P = .48). Only the weight of rats injected with ST44 varied significantly ( P = .0003). This dependency was also found for 3 of 5 urine parameters and 4 of 36 blood parameters ( P < .05). For ST68, only 1 urine parameter showed significance ( P < .0001). Giant cell infiltration in the lungs was significantly higher than controls in the ST44 0.1 mL/kg and the ST68 0.8-1.0 mL/kg groups ( P < .01). It is concluded that the prudent choice for future nonrodent, toxicology studies and potentially for human clinical trials is ST68 (given the deaths in the ST44 groups).

scholarly journals Liquiritigenin Protects Rats from Carbon Tetrachloride Induced Hepatic Injury through PGC-1αPathway

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Yiping Zhang ◽  
Yuanqiao He ◽  
Hongbo Yu ◽  
Fuying Ma ◽  
Jianguo Wu ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Diseases ◽  
Critical Role ◽  
Inflammatory Cells ◽  
Antioxidant Enzyme Activities ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Elevated Expression ◽  
Hematoxylin And Eosin ◽  
Hepatocyte Death

The lack of effective treatment for liver cirrhosis and hepatocellular carcinomas imposes serious challenges to the healthcare system. Here, we investigated the efficacy and mechanism of liquiritigenin involved in preventing or retarding the progression of liver diseases in a rat model with chronic carbon tetrachloride (CCl4) exposure. Sprague Dawley rats were given CCl4 and lliquiritigenin alone or simultaneously for 8 weeks before liver was harvested to check histological changes by Hematoxylin and Eosin (H&E) staining, apoptosis by TUNEL assay, ROS by dihydroethidium staining, antioxidant enzyme activities and malondialdehyde using specific kits, and gene expression by quantitative real-time PCR and western blot. Chronic CCl4 exposure caused profound changes in liver histology with extensive hepatocyte death (necrosis and apoptosis), fat accumulation, and infiltration of inflammatory cells, accompanied by depressed activities of antioxidant enzymes, increased oxidative stress, elevated expression of inflammation and fibrotic genes, and downregulation of PGC-1α, ND1, and Bcl-x in rat liver. All these changes were abolished or alleviated by lliquiritigenin. The results demonstrated that liquiritigenin is effective in protecting liver from injury or treating chronic liver diseases. The modulation of PGC-1αand its downstream genes might play a critical role in relieving CCl4-induced hepatic pathogenesis by liquiritigenin.

Ultrastructural Investigation of Spontaneous Pituitary Adenomas in Aging Sprague-Dawley Rats

1982 ◽  
Vol 40 ◽  
pp. 216-217
Author(s):  
D. J. McComb ◽  
J. Beri ◽  
F. Zak ◽  
K. Kovacs
Keyword(s):  
Microscopic Study ◽  
Pituitary Adenomas ◽  
Wistar Rats ◽  
Microscopic Level ◽  
Sprague Dawley ◽  
Prolactin Cells ◽  
Light Microscopic Level ◽  
Ultrastructural Investigation ◽  
Sprague Dawley Rats ◽  
Long Evans

Investigation of the spontaneous pituitary adenomas in rat have been limited mainly to light microscopic study. Furth et al. (1973) described them as chromophobic, secreting prolactin. Kovacs et al. (1977) in an ul trastructural investigation of adenomas of old female Long-Evans rats, found that they were composed of prolactin cells. Berkvens et al. (1980) using immunocytochemistry at the light microscopic level, demonstrated that some spontaneous tumors of old Wistar rats could contain GH, TSH or ACTH as well as PRL.

Early Development of Drug-Induced Hepatic Necrosis

1971 ◽  
Vol 29 ◽  
pp. 576-577
Author(s):  
F. G. Zaki ◽  
E. Detzi ◽  
C. H. Keysser
Keyword(s):  
Early Development ◽  
Hepatic Necrosis ◽  
Screening Tests ◽  
Dense Matrix ◽  
Sprague Dawley ◽  
Electron Microscopic ◽  
Drug Induced ◽  
Hepatocellular Damage ◽  
Sprague Dawley Rats ◽  
Microscopic Studies

This study represents the first in a series of investigations carried out to elucidate the mechanism(s) of early hepatocellular damage induced by drugs and other related compounds. During screening tests of CNS-active compounds in rats, it has been found that daily oral administration of one of these compounds at a dose level of 40 mg. per kg. of body weight induced diffuse massive hepatic necrosis within 7 weeks in Charles River Sprague Dawley rats of both sexes. Partial hepatectomy enhanced the development of this peculiar type of necrosis (3 weeks instead of 7) while treatment with phenobarbital prior to the administration of the drug delayed the appearance of necrosis but did not reduce its severity.Electron microscopic studies revealed that early development of this liver injury (2 days after the administration of the drug) appeared in the form of small dark osmiophilic vesicles located around the bile canaliculi of all hepatocytes (Fig. 1). These structures differed from the regular microbodies or the pericanalicular multivesicular bodies. They first appeared regularly rounded with electron dense matrix bound with a single membrane. After one week on the drug, these vesicles appeared vacuolated and resembled autophagosomes which soon developed whorls of concentric lamellae or cisterns characteristic of lysosomes (Fig. 2). These lysosomes were found, later on, scattered all over the hepatocytes.

Ultrastructural investigation of spontaneous pituitary gonadotroph cell adenomas in aging Sprague-Dawley rats

1983 ◽  
Vol 41 ◽  
pp. 702-703
Author(s):  
D. J. McComb ◽  
J. Beri ◽  
F. Zak ◽  
K. Kovacs
Keyword(s):  
Electron Microscopy ◽  
Animal Model ◽  
Epoxy Resin ◽  
Immunoelectron Microscopy ◽  
Tumor Type ◽  
Gonadal Function ◽  
Sprague Dawley ◽  
Male And Female ◽  
Reticulin Fibers ◽  
Sprague Dawley Rats

Gonadotroph cell adenomas of the pituitary are infrequent in human patients and are not invariably associated with altered gonadal function. To date, no animal model of this tumor type exists. Herein, we describe spontaneous gonadotroph cell adenomas in old male and female Sprague-Dawley rats by histology, immunocytology and electron microscopy.The material consisted of the pituitaries of 27 male and 38 female Sprague Dawley rats, all 26 months of age or older, removed at routine autopsy. Sections of formal in-fixed, paraffin-embedded tissue were stained with hematoxylin-phloxine-saffron (HPS), the PAS method and the Gordon-Sweet technique for the demonstration of reticulin fibers. For immunostaining, sections were exposed to anti-rat β-LH, anti-ratβ-TSH, anti-rat PRL, anti-rat GH and anti-rat ACTH 1-39. For electron microscopy, tissue was fixed in 2.5% glutaraldehyde, postfixed in 1% OsO4 and embedded in epoxy-resin. Tissue fixed in 10% formalin, embedded in epoxy resin without osmification, was used for immunoelectron microscopy.

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