scholarly journals EXPERIMENTAL MODELS OF THE ATHEROSCLEROSIS ON RABBITS

2021 ◽  
Vol 28 (4) ◽  
pp. 78-87
Author(s):  
Aleksey M. Chaulin ◽  
Yulia V. Grigorieva ◽  
Galina N. Suvorova ◽  
Dmitry V. Duplyakov
Keyword(s):  
Lipid Metabolism ◽  
Plasma Cholesterol ◽  
Cholesterol Content ◽  
Genetic Mutation ◽  
Atherogenic Diet ◽  
Experimental Models ◽  
Normal Diet ◽  
Laboratory Animals ◽  
Therapeutic Effects ◽  
Transgenic Rabbits

Atherosclerosis is the main cause of cardiovascular diseases, which, despite a number of new advances in their diagnosis and treatment, still occupy a leading position. Experimental modeling of atherosclerosis in laboratory animals plays an important role in the study of the fundamental pathophysiological processes and pathology of atherosclerosis. Rabbits are among the most suitable animals for simulating atherosclerosis, as they are widely available, inexpensive to maintain, and easy to manipulate. The key advantage of rabbits over other animals is that their lipid metabolism is practically similar to that of humans. The aim of the study was to analyze literature data on experimental models of atherosclerosis in rabbits. The review shows that the history of the study of atherosclerosis by means of experimental models is very rich and originates from the works of the well-known Russian pathologists A.I. Ignatovsky, N.N. Anichkov, S.S. Khalatov (1908-1915), who developed a cholesterol model of the formation of atherosclerosis in rabbits. The principle of this model is to feed laboratory animals with food containing elevated levels of lipids and cholesterol. The composition of the cholesterol (atherogenic) diet may vary, determining the existence of modifications of this model. Most often, a diet with a cholesterol content of 0.3-0.5% is used, in cases where it is necessary to accelerate the development of atherosclerosis, a short-term use of a diet with a 1% cholesterol content is allowed. In addition to cholesterol, it is recommended to use vegetable oils (soybean, coconut or corn) in the atherogenic diet as they improve the absorption of cholesterol in the intestine. In 1980, Japanese researcher Y. Watanabe deduced a new model of atherosclerosis formation - on hereditarily determined hyperlipidemic rabbits Watanabe (WHHL-rabbits). WHHL rabbits contain a genetic mutation in the gene encoding low-density lipoprotein receptors, which results in these animals having high plasma cholesterol levels with a normal diet. Thanks to modern genetic technologies, various genetic models of atherosclerosis in rabbits have also been created: transgenic and “knocked out” rabbits. The main method for obtaining transgenic rabbits is pronuclear microinjection, which allows the introduction of a transgene (additional DNA fragment) into their genome. To date, using this technology, it has been possible to introduce more than a dozen genes responsible for lipid metabolism. The principle of creating knocked out rabbits consists in specific inactivation using genome editing technologies (ZFN, TALEN, CRISPR / Cas9) of a certain working gene. Experimental models of atherosclerosis in rabbits have not lost their significance and continue to be used to study the fundamental morphological (pathological) and pathological mechanisms underlying atherosclerosis, to search for new diagnostic biomarkers and potential targets for therapeutic effects, as well as to conduct preclinical trials of newly developed drugs.

DEFIBROTIDE DECREASES CHOLESTEROL CONTENT IN HYPERCHOLESTEROLEMIC RABBIT AORTA, WITH NO MODIFICATION OF PLASMA OR LIPOPROTEIN CHOLESTEROL

1987 ◽  
Author(s):  
R Pescador ◽  
R Porta ◽  
R Niada ◽  
M Mantovani ◽  
G Prino
Keyword(s):  
Foam Cell ◽  
Plasma Cholesterol ◽  
Rabbit Aorta ◽  
Cholesterol Content ◽  
Normal Diet ◽  
Plasma Lipoproteins ◽  
Vascular Lesions ◽  
Aortic Tissue ◽  
Perfused Heart ◽  
Lipoprotein Lipids

Defibrotide was shown to stimulate the production of endogenous PGI2 from rat and hamster aortic tissue, as well as the production of PGi2 frcm the coronary vascular bed in the platelet perfused heart model. This effect was only seen in presence of platelets. Durirg the infusion period with Defibrotide thromboxane release remained unaffected while platelet cAMP rised. Defibrotide, was also able to reduce the secretion of ATP from platelets as well as to deaggregate platelet cluTps. It has been postulated that long-term administration of stable PGI^ metabolites or analogues could be a more useful means of enhancing cholesterol and cholesteryl ester mobilization out of the arterial “ foam” cell during early stages of cardiovascular disease. These observations prompted us to administer Defibrotide i.v. to cholesterol fed rabbits to verify if it could cause a decrease in cholesterol content of aortas. Aorta cholesterol was evaluated by gas chromatography. Plasma or lipoprotein lipids were assayed by enzymatic kits from Boehringer Biochemia. Plasma lipoproteins were separated by density gradient ultracentrifugation. Platelet aggregation was carried out with ADP using an optical aggregometer to find out the effective aggregatory concentration fifty (EC). Histology of the rabbit hearts was performed by optical microscopy on heart sections coloured with hematoxylin-eosine. Defibrotide caused a decrease (-49%, P < 0.05, vs. cholesterol fed rabbits treated with placebo) in cholesterol content of aortas with no modification of total plasma cholesterol, triglyceride and phospholipid. The cholesterol, triglyceride, phospholipid and protein of plasma lipoproteins were not affected too. The EC of rabbits treated with Defibrotide was 50 normalized (-9%, N.S. vs. control animals fed the normal diet and treated with placebo; cholesterol fed animals treated with placebo: -32%, P< 0.05 vs. control animals fed the normal diet). Vascular lesions in the hearts of animals treated with Defibrotide had a lower rate (33%) in comparison to that (87%) of animals fed with cholesterol and treated with placebo. It is concluded that the ability of Defibrotide to stimulate vascular PGI2 formation and to reduce platelet sensitivity could be helpful in reducing the amount of cholesterol in the cardiovascular system in atherosclerotic prone situations.

Abstract 262: Cytochrome P450 1B1 is Critical for the Development of Atherosclerosis and Hypertension in ApoE Knockout Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Khuzema Ghafoor ◽  
Hafiz Usama Ghafoor ◽  
Brett L Jennings ◽  
Nayaab S Khan ◽  
Shyamala Thirunavukkarasu ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
T Lymphocytes ◽  
Lipid Analysis ◽  
Plasma Lipid ◽  
Atherogenic Diet ◽  
Experimental Models ◽  
Normal Diet ◽  
Ros Production ◽  
Collagen Deposition ◽  
Novel Target

We have reported that cytochrome P450 (CYP) 1B1 contributes to hypertension in various experimental models and promotes neointimal growth in injured carotid arteries. This study was conducted to determine the role of CYP1B1 in the development of atherosclerosis and its pathogenesis, including reactive oxygen species (ROS) production, inflammation, and hypertension caused by atherogenic diet (AD; TD02028). Eight weeks old male ApoE knockout ( ApoE -/- /Cyp1b1 +/+ ) and ApoE /CYP1B1 knockout ( ApoE -/- /Cyp1b1 -/- ) mice were fed a normal diet (ND) or AD for 12 weeks. A separate group of ApoE -/- /Cyp1b1 +/+ mice on AD, were injected twice weekly with the selective inhibitor of CYP1B1, 2,3',4,5'-tetramethoxystilbene (TMS) (300 μg/kg), or its vehicle DMSO (i.p.). Systolic blood pressure (SBP) was measured weekly by tail cuff. After 12 weeks, animals were sacrificed; blood was collected for lipid analysis and aorta for measurement of lesions by Oil red O, collagen deposition by Masson’s trichrome and ROS production by dihydroethidium staining, and infiltration of macrophages (F4/80) and T-lymphocytes (CD3) by immunohistochemistry. Plasma lipid levels, area of lipids and collagen deposition, ROS production (Table), infiltration of macrophages, and T lymphocytes in the aorta and SBP were increased in ApoE -/- /Cyp1b1 +/+ mice on AD vs. ND; these were minimized in mice on AD given TMS but not its vehicle, and in ApoE -/- /Cyp1b1 -/- mice on AD. These data suggest that the development of hypercholesterolemia by AD and associated pathogenesis including increase in SBP in ApoE -/- /Cyp1b1 +/+ mice depend on CYP1B1 and that it could serve as a novel target for treatment of atherosclerosis.

scholarly journals Transgenic Rabbit Models: Now and the Future

2020 ◽  
Vol 10 (21) ◽  
pp. 7416
Author(s):  
Fumikazu Matsuhisa ◽  
Shuji Kitajima ◽  
Kazutoshi Nishijima ◽  
Toshiaki Akiyoshi ◽  
Masatoshi Morimoto ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Genetically Modified ◽  
Embryonic Stem ◽  
Experimental Manipulation ◽  
Biomedical Science ◽  
Current Status ◽  
Laboratory Animals ◽  
Transgenic Rabbit ◽  
Research Fields ◽  
Transgenic Rabbits

Transgenic rabbits have contributed to the progress of biomedical science as human disease models because of their unique features, such as the lipid metabolism system similar to humans and medium body size that facilitates handling and experimental manipulation. In fact, many useful transgenic rabbits have been generated and used in research fields such as lipid metabolism and atherosclerosis, cardiac failure, immunology, and oncogenesis. However, there have been long-term problems, namely that the transgenic efficiency when using pronuclear microinjection is low compared with transgenic mice and production of knockout rabbits is impossible owing to the lack of embryonic stem cells for gene targeting in rabbits. Despite these limitations, the emergence of novel genome editing technology has changed the production of genetically modified animals including the rabbit. We are finally able to produce both transgenic and knockout rabbit models to analyze gain- and loss-of-functions of specific genes. It is expected that the use of genetically modified rabbits will extend to various research fields. In this review, we describe the unique features of rabbits as laboratory animals, the current status of their development and use, and future perspectives of transgenic rabbit models for human diseases.

PRECLINICAL STUDY OF THE VETERINARY DRUGS TOXICITY

1970 ◽  
pp. 61-64
Author(s):  
E. K. Rakhmatullin ◽  
O. D. Sklyarov
Keyword(s):  
Lethal Dose ◽  
Clinical Manifestations ◽  
Preclinical Study ◽  
Veterinary Drugs ◽  
Toxic Effects ◽  
Laboratory Animals ◽  
Therapeutic Effects ◽  
Significant Information ◽  
Important Indicator ◽  
Organ Systems

Preclinical study of the drugs toxicity was analysed it allows predicting the safety of veterinary drugs in laboratory animals. The fundamental normative instruments in the field of preclinical study of drugs for veterinary medicine and animal husbandry are Order of the Ministry of Agriculture of the Russian Federation dated 06.03.2018 N 101 and GOST 33044-2014 Principles of Good Laboratory Practice. An important indicator of the preclinical study of the veterinary drugs is the determination (calculation) of median lethal dose value (lethal dose for half of the animals tested) or concentration (LD50 or LC50). Existing methods for determining this indicator make it possible at the initial study stage to determine the degree and class the drug of toxicity. Studying the symptoms of intoxication in the analysis of pharmacological substances one obtains significant information about the nature of the action of the future drug. The clinical manifestations of intoxication with damage to various organ systems are presented. As criteria for assessing the toxic effects of veterinary drugs it is recommended to determine LD50, cumulation coefficient, latitude index of therapeutic effects, dose level of toxic effects in the experiment which allows predicting the nature and degree of toxic effects of the drug even at the stage of preclinical veterinary drugs study.

scholarly journals Targeted Therapies for Metabolic Myopathies Related to Glycogen Storage and Lipid Metabolism: a Systematic Review and Steps Towards a ‘Treatabolome’

2021 ◽  
pp. 1-18
Author(s):  
A. Manta ◽  
S. Spendiff ◽  
H. Lochmüller ◽  
R. Thompson
Keyword(s):  
Systematic Review ◽  
Lipid Metabolism ◽  
Genetic Defect ◽  
Genetic Mutation ◽  
Glycogen Storage ◽  
Carnitine Deficiency ◽  
Exercise Intolerance ◽  
Enzyme Replacement ◽  
Metabolic Myopathies ◽  
Published Evidence

Background: Metabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective treatments for some of these diseases are available, but while our understanding of the pathogenesis of metabolic myopathies related to glycogen storage, lipid metabolism and β-oxidation is well established, evidence linking treatments with the precise causative genetic defect is lacking. Objective: The objective of this study was to collate all published evidence on pharmacological therapies for the aforementioned metabolic myopathies and link this to the genetic mutation in a format amenable to databasing for further computational use in line with the principles of the “treatabolome” project. Methods: A systematic literature review was conducted to retrieve all levels of evidence examining the therapeutic efficacy of pharmacological treatments on metabolic myopathies related to glycogen storage and lipid metabolism. A key inclusion criterion was the availability of the genetic variant of the treated patients in order to link treatment outcome with the genetic defect. Results: Of the 1,085 articles initially identified, 268 full-text articles were assessed for eligibility, of which 87 were carried over into the final data extraction. The most studied metabolic myopathies were Pompe disease (45 articles), multiple acyl-CoA dehydrogenase deficiency related to mutations in the ETFDH gene (15 articles) and systemic primary carnitine deficiency (8 articles). The most studied therapeutic management strategies for these diseases were enzyme replacement therapy, riboflavin, and carnitine supplementation, respectively. Conclusions: This systematic review provides evidence for treatments of metabolic myopathies linked with the genetic defect in a computationally accessible format suitable for databasing in the treatabolome system, which will enable clinicians to acquire evidence on appropriate therapeutic options for their patient at the time of diagnosis.

Legumin from chickpea: hypolipidemic effect in the liver of hypercholesterolemic rats

2014 ◽  
Vol 44 (5) ◽  
pp. 378-388 ◽  
Author(s):  
Ana L. Amaral ◽  
Ederlan S. Ferreira ◽  
Valdir A. Neves ◽  
Aureluce Demonte
Keyword(s):  
Lipid Metabolism ◽  
Cholic Acid ◽  
Hdl Cholesterol ◽  
Normal Diet ◽  
Single Daily Dose ◽  
High Cholesterol Diet ◽  
Hypolipidemic Effect ◽  
Content Type ◽  
Daily Dose ◽  
11S Globulin

Purpose – This paper aims to determine the effects of 11S globulin isolated from Chickpea (Cicer arietinum L.) on lipid metabolism in animals subjected to a hypercholesterolemic and hyperlipidemic diet and compared to the drug simvastatin. Design/methodology/approach – Thirty-six male Wistar rats, kept in individual cages and under appropriate conditions, were separated into groups that were fed a normal diet (STD) containing casein as protein source and according to AIN-93G; a high-cholesterol diet (HC), normal diet plus 1 per cent cholesterol and 0.5 per cent cholic acid and 20 per cent coconut oil; HC diet plus the isolated 11S globulin (300 mg/kg/day); and HC diet plus the simvastatin (50 mg/kg/day), both dissolved in saline and administered by gavage for 28 days. After this time, the animals were killed. Findings – The results indicated that the addition of 1 per cent cholesterol and 0.5 per cent cholic acid induced hypercholesterolemia in the animals without interfering with their weight gain. Analyses of total cholesterol (TC), HDL-cholesterol (HDL-C) and triglycerides (TG) in the plasma, and TC and TG in the liver were made. The results show that the protein isolated from chickpea, and given as a single daily dose, did not affect the levels of plasma TC and its fractions, although decreasing the TG levels. Unlike the simvastatin, the chickpea protein significantly reduced TC and TG in the liver relative to HC group. Originality/value – A single daily dose of 11S globulin from chickpea contributed as only as additional 2.8 per cent of dietary protein intake. These findings demonstrate that 11S chickpea protein acts as a functional agent in the lipid metabolism in addition to its nutritional properties.

scholarly journals Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve

2016 ◽  
Vol 2 ◽  
pp. 205521731664170 ◽  
Author(s):  
Melissa M Gresle ◽  
Yaou Liu ◽  
Trevor J Kilpatrick ◽  
Dennis Kemper ◽  
Qi-Zhu Wu ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Axonal Regeneration ◽  
Antibody Therapy ◽  
Experimental Models ◽  
Therapeutic Effects ◽  
Axonal Loss ◽  
Nerve Crush ◽  
Acute Optic Neuritis ◽  
Injury Models

Background Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. Objective In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. Methods The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. Results In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. Conclusion These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.

scholarly journals Comparison of the therapeutic effects of tri-iodothyronine and methylprednisolone during early sepsis in laboratory animals

2012 ◽  
Vol 113 (06) ◽  
pp. 339-346
Author(s):  
F. Coskun ◽  
B. Saylam ◽  
B. Kulah ◽  
I. Dolapci ◽  
A. Sungur ◽  
...  
Keyword(s):  
Laboratory Animals ◽  
Therapeutic Effects ◽  
Early Sepsis

scholarly journals Miltefosine Affects Lipid Metabolism in Leishmania donovani Promastigotes

2007 ◽  
Vol 51 (4) ◽  
pp. 1425-1430 ◽  
Author(s):  
M. Rakotomanga ◽  
S. Blanc ◽  
K. Gaudin ◽  
P. Chaminade ◽  
P. M. Loiseau
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Leishmania Donovani ◽  
Cholesterol Content ◽  
Strong Reduction ◽  
Drug Pressure ◽  
Antileishmanial Drug ◽  
Partial Inactivation ◽  
Orally Active

ABSTRACT Miltefosine (hexadecylphosphocholine [HePC]) is the first orally active antileishmanial drug. Transient HePC treatment of Leishmania donovani promastigotes at 10 μM significantly reduced the phosphatidylcholine content and enhanced the phosphatidylethanolamine (PE) content in parasite membranes, suggesting a partial inactivation of PE-N-methyltransferase. Phospholipase D activity did not seem to be affected by HePC. In addition, the enhancement of the lysophosphatidylcholine content could be ascribed to phospholipase A2 activation. Moreover, transient HePC treatment had no effect on the fatty acid alkyl chain length or the fatty acid unsaturation rate. Concerning sterols, we found a strong reduction of the C24 alkylated sterol content, and the enhancement of the cholesterol content could be the result of the HePC condensation effect with sterols. Because some of the effects observed after transient HePC treatment were different from those previously observed in HePC-resistant parasites, it could be hypothesized that continuous in vitro drug pressure induces the mechanisms of regulation in Leishmania lipid metabolism.

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