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PubMed2006

Upregulation of metallothionein-I mRNA expression in a rodent model for amyotrophic lateral sclerosis.

Metallothionein (MT) mRNA expression was investigated in a rodent model (G93A SOD1 transgenic mouse) for a lethal motor neuron disease, amyotrophic lateral sclerosis (ALS). In 8-wk-old mice that did not yet exhibit motor paralysis, MT-I mRNA expression was already significantly upregulated in the region of the spinal cord responsible for motor paralysis. The expression of another isoform, MT-III, was not changed. In the cerebellum, which is not responsible for motor paralysis in ALS, neither the expression profiles of MT-I nor MT-III were altered. In 16-wk-old mice exhibiting motor paralysis, the expression of MT-I mRNA remained upregulated and the MT-III level tended to be elevated. Although no significant differences were found in the levels of both isoforms in the liver or kidney of 8-wk-old mice, the MT-I mRNA expression level was significantly upregulated in the kidney and liver of 16-wk-old mice. These results indicated that the MT-I isoform, but not the MT-III isoform, is associated with motor neuron death in ALS and suggested that the disease might be a systemic disorder to which the spinal cord is particularly susceptible.

Amyotrophic Lateral Sclerosis↗

PubMed1989

Effects of dantrolene sodium in rodent models of cardiac arrhythmia.

Dantrolene sodium has been compared with reference antiarrhythmic agents in rodent models of cardiac arrhythmia. In a coronary-artery-ligation model in rats, dantrolene sodium (3, 10 and 20 mg/kg i.v.) significantly decreased extrasystoles, episodes of ventricular tachyarrhythmia, and frequency, duration, and total episodes of ventricular fibrillation in a dose-dependent manner. In an electrically induced fibrillation model in rats, dantrolene sodium (10 and 20 mg/kg i.v.) significantly raised ventricular fibrillation threshold in a dose- and time-dependent manner. In contrast to its activity in these models, dantrolene sodium was not active in two chemically induced models involving automaticity. Aconitine-induced arrhythmias in rats and mice and ouabain-induced arrhythmias in guinea pigs were not suppressed by i.v. (10 or 20 mg/kg) or i.p. (100-3000 mg/kg) doses of the drug. These results show that the antiarrhythmic potential of dantrolene sodium, predicted by in vitro Class III and Class IV electrophysiological effects, is expressed in whole animal models.

Action Potentials↗

PubMed1995

Behavioral effects of neonatal cocaine exposure using a rodent model.

This study examined the effects of neonatal cocaine exposure on behavior using a rodent model. Rat pups were implanted with intragastric cannulas on postnatal day (PND) 4 and artificially reared (AR) from PND 4-10. The AR groups included two cocaine doses (20 mg/kg per day and 60 mg/kg per day) and an AR control. A sham surgery control group was also included that was reared naturally by its dam. Offspring from these neonatal treatment groups were examined for suckling performance (PND 13), passive avoidance learning (PND 23-24), activity (PND 18-21), or spontaneous alternation (PND 21). Neonatal cocaine exposure had no effect on suckling measures or passive avoidance learning. Activity was increased in the 60 mg/kg per day cocaine group relative to controls. In addition, spontaneous alternation was delayed in the 20 mg/kg per day cocaine-exposed females relative to all other groups. These data suggest that neonatal cocaine exposure may alter performance on some relatively simple tasks. More work is clearly warranted to look at the effects of neonatal cocaine exposure on more complex behaviors.

Animals↗

PubMed2006

Integrative strategies to identify candidate genes in rodent models of human alcoholism.

The search for genes underlying alcohol-related behaviours in rodent models of human alcoholism has been ongoing for many years with only limited success. Recently, new strategies that integrate several of the traditional approaches have provided new insights into the molecular mechanisms underlying ethanol's actions in the brain. We have used alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) genetic strains of mice in an integrative strategy combining high-throughput gene expression screening, genetic segregation analysis, and mapping to previously published quantitative trait loci to uncover candidate genes for the ethanol-preference phenotype. In our study, 2 genes, retinaldehyde binding protein 1 (Rlbp1) and syntaxin 12 (Stx12), were found to be strong candidates for ethanol preference. Such experimental approaches have the power and the potential to greatly speed up the laborious process of identifying candidate genes for the animal models of human alcoholism.

Alcoholism↗

PubMed1998

Spontaneous cholangiofibrosis in Long-Evans Cinnamon rats: a rodent model for Wilson's disease.

The Long-Evans Cinnamon (LEC) rat is a rodent model of Wilson's disease characterized by ceruloplasmin deficiency, hepatic copper accumulation, and hepatocellular injury. So far, the LEC rat appears to be the only strain in which cholangiofibrosis develops spontaneously. The aim of the study reported here was to characterize the time course of development and investigate the structural and ultrastructural features of cholangiofibrosis and their possible relationship to hepatic copper and iron content. The livers of 54 rats (22 males), ages 5 to 113 weeks, were examined by light microscopy and graded for statistical analysis, with respect to extent of replacement of liver tissue by cholangiofibrosis. The study was complemented by electron microscopy, and by measurements of copper and iron contents by atomic absorption spectroscopy. Cholangiofibrosis was present in LEC rats by 20 weeks of age. The hyperplastic biliary epithelial cells varied markedly in size and shape, ranging from flat to cuboidal or elongated. Epithelial cells did not exhibit characteristics of intestinal cells. Some basement membranes had splits, duplications, or multiplications. Cytoplasmic organelles within hyperplastic biliary cells appeared unremarkable in contrast to the characteristic mitochondrial abnormalities present in neighboring hepatocytes. There was a positive correlation between histologic grades of cholangiofibrosis and ages of the animals (r = 0.68, P < 0.001), but no significant correlation between histologic grade and hepatic copper or iron content. We conclude that cholangiofibrosis is the predominant pathologic response to chronic liver injury induced by excess copper in LEC rats. The pathogenic role of copper in the development of cholangiofibrosis requires clearer definition.

Adenosine Triphosphatases↗

PubMed1996

Lack of autoimmune serological reactions in rodent models of insulin dependent diabetes mellitus.

Spontaneous insulitis with insulin-dependent diabetes mellitus (IDDM) in rodent models, the BB rat and NOD mouse, has clarified the pathogenesis of and guided decisions on interventional therapy for human IDDM. However, the occurrence in such models of a standard marker of human IDDM, autoantibodies to beta islet cell constituents, has been controversial. Hence we assessed diabetes-prone rodents for the frequencies of raised levels of auto-antibodies to glutamic acid decarboxylase GAD (anti-GAD), insulin and heat shock protein 65 (HSP-65) in relation to levels in non-diabetes-prone animals and levels in human diabetic sera. Assays were performed sequentially at various ages of life. The immunoassays used for anti-GAD and anti-insulin were those validated for sensitivity and specificity for detection of the corresponding autoantibodies in human IDDM sera at international workshops. Positive controls included human IDDM sera with reactivity with GAD or insulin and, for mouse anti-GAD, the highly reactive monoclonal antibody, GAD-6. The results were that levels of autoantibodies in diabetes-prone BB rats or NOD mice to the "IDDM-relevant' autoantigens in our panel did not exceed levels in control rats or mice, and were much lower than levels in humans with IDDM. We conclude that the BB rat and NOD mouse represent a model, but not a facsimile, of human IDDM and that therapeutic successes in such models should be interpreted with caution in relation to interventional therapy for human IDDM.

Animals↗

PubMed1999

Rodent models of lymphocyte migration.

The ability of leukocytes to migrate out of blood into tissues enables them to perform their surveillance functions. Understanding the molecular mechanisms by which this migration is accomplished has the potential of unveiling new methods of regulating immune responses. The existing knowledge of rodent physiology and the recent development of knockout mice makes rodents attractive models for studying the mechanisms of leukocyte migration in vivo. This review considers the existing rodent models in light of the knowledge gained from them in lymphocyte migration, and in addition, shows the advantages and limitations of using rodent models in studying lymphocyte migration.

Animals↗

PubMed1996

Effects of ethanol in a putative rodent model of tardive dyskinesia.

The effects of acute challenge with ethanol were studied in a putative rodent model of tardive dyskinesia. Chronic administration of fluphenazine elicited vacuous chewing movements (VCMs) in the rat. Neuroleptic-induced VCMs were dose dependently suppressed by ethanol in a behaviorally specific fashion. Suppression by ethanol of neuroleptic-induced VCMs was reversed by pretreatment with the benzodiazepine inverse agonist Ro 15-4513 (2.5 mg/kg). These findings suggest that ethanol may acutely suppress neuroleptic-induced dyskinesias in humans via stimulation of GABAA receptors and are compatible with the previously reported clinical effects of alcohol consumption on the extrapyramidal system. Treatment strategies focussed on GABAergic stimulation deserve further investigation in the management of tardive dyskinesia.

Affinity Labels↗

PubMedDate not supplied

Rodent models of Alzheimer's disease: rat A beta infusion approaches to amyloid deposits.

The development of rodent models for Alzheimer's disease is a critical step for both understanding the disease and developing therapeutic drugs. Transgenic and knockout mouse models will elucidate some important aspects of the etiology of the disease and the development of pharmaceutical treatments. Here, we will focus on the advantages of nontransgenic models. In nontransgenic rat models, intraventricular infusion of A beta 1-40 (alone) generally results in diffuse deposition of A beta with very few focal plaque-like amyloid deposits after a 30-day intraventricular infusion. However, we have recently found that large numbers of scattered A beta immunoreactive plaque-like deposits can be produced in retired female Sprague-Dawley rat breeders using intraventricular infusion of A beta combined with neuropil injection of transforming growth factor beta 1(TGF beta). A beta that was not associated with the large deposits was often immunolocalized with neurons and cell processes. Immunogold electron microscopy demonstrated the presence of A beta in endosome/lysosomes of neuronal processes and glia and basal lamina. In some cases this labeling was clearly in lysosomes of degenerating neurites. This model allows one to introduce A beta and other plaque-associated factors without overexpression of potentially confounding APP domains. We conclude that A beta infusion models will be a useful complement to transgenic approaches to Alzheimer's pathology.

Alzheimer Disease↗

PubMed1989

Rodent models of alcoholism: a review.

Four criteria should be fulfilled when establishing an animal model of alcoholism. (1) The animal should voluntarily and selectively consume a solution of the drug to yield pharmacologically significant blood alcohol concentrations. When ethanol is consumed for several weeks under these conditions, (2) the animals should exhibit tolerance to the acute effects of the drug. Furthermore, (3) abrupt termination of drug administration should result in physical signs of drug withdrawal (e.g. audiogenic seizures). (4) Changes in endocrine and liver function would also be expected to occur following the chronic administration of alcohol, such effects being particularly pronounced if the diet of the animal is nutritionally deficient. A number of self-administration, operant conditioning and forced alcohol administration models are critically assessed. A detailed description of the models in which rodents are forced to consume increasing quantities of alcohol as part of a nutritionally enriched milk diet suggests that this method fulfils most of the above criteria.

Alcoholism↗

PubMedDate not supplied

Relevance of the rodent model to human aging studies.

Rodents have proven to be a useful general model for aging research. Although they are not necessarily appropriate for the study of such specific human age-associated diseases as atherosclerosis, rodents have provided the basis for important age-related findings in many diverse areas, including nutrition, behavior, immunology, physiology, oncology, biochemistry, and neurobiology. Contributions in these areas are briefly reviewed.

Aging↗

PubMed2004

General pharmacological profiles of bee venom and its water soluble fractions in rodent models.

Recently, the antinociceptive and anti-inflammatory efficacy of bee venom (BV, Apis mellifera) has been confirmed in rodent models of inflammation and arthritis. Interestingly, the antinociceptive and anti-inflammatory effect of whole BV can be reproduced by two water-soluble fractions of BV (>20 kDa:BVAF1 and<10 kDa: BVAF3). Based on these scientific findings, BV and its effective water-soluble fractions have been proposed as potential anti-inflammatory and antinociceptive pharmaceuticals. While BV's anti-inflammatory and antinociceptive properties have been well documented, there have been no careful studies of potential, side effects of BV and its fractions when administered in the therapeutic range (BV, 5 microgram/kg; BVAF1, 0.2 microgram/kg: BVAF3, 3 microgram/kg; subcutaneous or intradermal). Such information is critical for future clinical use of BV in humans. Because of this paucity of information, the present study was designed to determine the general pharmacological/physiological effects of BV and its fractions administration on the rodent central nervous, cardiovascular, respiratory and gastrointestinal system. Subcutaneous BV and its fractions treatment did not produce any significant effects on general physiological functions at the highest dose tested (200-fold and 100-fold doses higher than that used clinically, respectively) except writhing test. These results demonstrate that doses of BV or BV subfractions in the therapeutic range or higher can be used as safe antinociceptive and anti-inflammatory agents.

Analgesics↗

PubMed1993

The opiate antagonist naloxone suppresses a rodent model of tardive dyskinesia.

The effects of both opiate agonists and the opiate antagonist naloxone were examined in a rodent model of tardive dyskinesia (TD). Chronic (approximately 20 weeks) administration of fluphenazine resulted in the emergence of vacuous chewing mouth movements (VCMs), a response which may be a useful model for this disorder. Fluphenazine-induced VCMs were not affected by a variety of selective opiate agonists administered intracerebroventricularly, but were potently suppressed by subcutaneous administration of the opiate antagonist naloxone. These findings suggest that increased opiate transmission may contribute to the pathogenesis of TD. Further investigation of the role of opiate antagonists in treating this disorder are warranted.

Animals↗

PubMed1982

An analysis of piroxicam in rodent models of arthritis.

Piroxicam, a potent, long acting non-steroidal anti-inflammatory drug, was tested in several rodent models of arthritis to assess further the possible mechanisms underlying its anti-inflammatory action. Piroxicam inhibited rat adjuvant disease and its associated manifestations, which include erosion of bone and cartilage (as evidenced by X-ray examination), soft tissue swelling and disease-induced weight loss. Piroxicam also inhibited the edema, the total leukocyte infiltration and the mononuclear cell infiltration into the carrageenan-injected pleural cavity of the rat. The possible relationship of these effects to the clinical activity of piroxicam is discussed.

Animals↗

PubMed2005

Development and application of rodent models for type 2 diabetes.

The increasing worldwide incidence of diabetes in adults constitutes a global public health burden. It is predicted that by 2025, India, China and the United States will have the largest number of people with diabetes. According to the 2003 estimates of the International Diabetes Federation, the diabetes mellitus prevalence in the USA is 8.0% and approximately 90-95% of diabetic Americans have type 2 diabetes - about 16 million people. Type 2 diabetes is a complex, heterogeneous, polygenic disease characterized mainly by insulin resistance and pancreatic beta-cell dysfunction. Appropriate experimental models are essential tools for understanding the molecular basis, pathogenesis of the vascular and neural lesions, actions of therapeutic agents and genetic or environmental influences that increase the risks of type 2 diabetes. Among the animal models available, those developed in rodents have been studied most thoroughly for reasons such as short generation time, inherited hyperglycaemia and/or obesity in certain strains and economic considerations. In this article, we review the current status of most commonly used rodent diabetic models developed spontaneously, through means of genetic engineering or artificial manipulation. In addition to these models, the Psammomys obesus, rhesus monkeys and many other species are studied intensively and reviewed by Shafrir, Bailey and Flatt and Hansen.

Animals↗

PubMed2006

The effect of prenatal hypoxia on brain development: short- and long-term consequences demonstrated in rodent models.

Hypoxia (H) and hypoxia-ischemia (HI) are major causes of foetal brain damage with long-lasting behavioral implications. The effect of hypoxia has been widely studied in human and a variety of animal models. In the present review, we summarize the latest studies testing the behavioral outcomes following prenatal hypoxia/hypoxia-ischemia in rodent models. Delayed development of sensory and motor reflexes during the first postnatal month of rodent life was observed by various groups. Impairment of motor function, learning and memory was evident in the adult animals. Activation of the signaling leading to cell death was detected as early as three hours following H/HI. An increase in the counts of apoptotic cells appeared approximately three days after the insult and peaked about seven days later. Around 14-20 days following the H/HI, the amount of cell death observed in the tissue returned to its basal levels and cell loss was apparent in the brain tissue. The study of the molecular mechanism leading to brain damage in animal models following prenatal hypoxia adds valuable insight to our knowledge of the central events that account for the morphological and functional outcomes. This understanding provides the starting point for the development and improvement of efficient treatment and intervention strategies.

Animals↗

PubMed2007

Experimental rodent models of prostatitis: limitations and potential.

Prostatitis is a polyetiological inflammation of the prostate gland in men characterized by pelvic pain, irritative voiding symptoms, and sexual dysfunction. Histologically prostatitis is characterized by poly- and mononuclear cell infiltrates (neutrophils, lymphocytes, macrophages and plasma cells) in the stromal connective tissue around the acini or ducts. Prostatitis is an important worldwide health problem in men. The pathogenesis and diagnostic criteria for the condition are obscure, with the result that the development of management programs for this condition has been hindered. Animal model(s) might be useful in elucidating mechanisms involved in the molecular pathogenesis of chronic nonbacterial prostatitis and chronic pelvic pain syndrome. Given that prostatitis might have a multifactorial etiology, several animal models with unique features may prove helpful. This review examines a number of experimental rodent models of prostatitis and evaluates their advantages and limitations.

Animals↗

PubMed1993

The gerbil, hamster, and guinea pig as rodent models for hyperlipidemia.

The purpose of this study was to compare the effects of a hyperlipidemic diet on three different rodent models to evaluate them on how their responses simulate human serum lipid diseases. Forty hamsters, 40 gerbils, and 20 guinea pigs were given either a chow diet or a modified high-fat, high-cholesterol diet (HF/HC) for 7 days. Food was withheld from half of the animals on each diet for 12 hours prior to collecting the blood for analysis of total cholesterol and triglyceride concentration. In all species, HF/HC feeding resulted in at least a 370% increase in total cholesterol concentration. Withholding food significantly decreased total cholesterol concentration in hamsters and gerbils fed HF/HC but had no effect on animals fed chow diet. Triglyceride concentrations were increased by the HF/HC in the hamster and the gerbil. As with total cholesterol, triglyceride concentration was decreased after food was withheld in these two animal groups. We suggest that the guinea pig is the most appropriate model for studying hypercholesterolemia because of its moderate plasma cholesterol response and normal triglyceride response to a HF/HC. We also suggest that the hamster is a good model for studying hypertriglyceridemia since increased serum triglyceride concentrations can be easily maintained on a HF/HC.

Animals↗