Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Rodent models”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 721 records · Page 40Linked to original sources

Electrophysiology and pathology evaluation of the Yucatan pig as a non-rodent animal model for regulatory and mechanistic toxicology studies.

Six male and six female Yucatan pigs were utilized to investigate the feasibility of this species as a non-rodent model for routine regulatory and mechanistic toxicology studies. This study evaluated disease surveillance and computerized electrophysiology, along with possible gross and micropathology changes. Two pigs were used as sentinel animals to evaluate the microbiological status of the vendor upon arrival; the other pigs were maintained as biomonitors and to provide baseline clinical chemistry, urinalysis, pathology and electrophysiology data. The electrophysiology tests conducted included electrocardiography (ECG), electroretinography (ERG) and quantitative electroencephalography (qEEG), which achieved consistent baseline values with acceptable intrasubject variation. Tissue cholinesterase and histochemical staining were done to determine their suitability for testing cholinesterase compounds. Evaluation of the serum chemistry profile demonstrated increased CPK and LDH, which was likely associated with slight haemolysis or minor subclinical muscle stress during handling. There were no additional clinical chemistry changes or findings in haematology, urinalysis parameters or gross pathology. Micropathology found an absence of background lesions which would interfere with routine toxicology studies, except for a mild rhinitis. The aetiological agent was identified by electron microscopy as being consistent with inclusion body rhinitis of swine, previously unreported in miniature swine. This would most notably interfere with inhalation studies. The anatomical and physiological similarities of the Yucatan pig, along with its ability to accept the performance of electrophysiology tests allow this species to be considered as a suitable model for organ system testing in toxicology studies.

Animals↗

Contrast-enhanced dark lumen PET/CT and MR colonography in a rodent polyp model: initial results with histopathologic correlation.

OBJECTIVE: The objective of this study was to assess the feasibility of PET/CT for the detection of colorectal masses in a rodent polyp model in an intraindividual comparison with dark-lumen MR colonography. CONCLUSION: Detection of small tumors with PET/CT and MR colonography is possible in a rodent model. The technique thus warrants further evaluation in animal studies as well as in patients with suspected colorectal disease.

Animals↗

Review article: How useful are the rodent animal models of gastric adenocarcinoma?

Gastric cancer is the second most common cause of cancer-related mortality world-wide. In most cases, it develops via the pre-malignant stages of atrophic gastritis, intestinal metaplasia and dysplasia, following Helicobacter pylori infection of susceptible individuals. A number of rodent models have recently provided valuable insights into the host, bacterial and environmental factors involved in gastric carcinogenesis. Wild-type rodents do not develop gastric adenocarcinoma, but early studies showed that the disease could be induced in several rodent species by chemical carcinogens. More recently, it has been demonstrated that gastric adenocarcinoma can be induced in Mongolian gerbils by H. pylori infection and in C57BL/6 mice by long-term H. felis infection. These models have allowed the importance of Helicobacter virulence genes, host factors, such as gender, strain and immune response, and environmental factors, such as dietary salt, to be explored. A number of transgenic mice with alterations in various pathways, including the immune response, gastrin biosynthesis, parietal cell development, growth factors and tumour suppressors, have also provided models of various stages of gastric carcinogenesis. One model that has proved to be particularly valuable is the hypergastrinaemic INS-GAS mouse, in which gastric carcinoma develops spontaneously in old animals, but the process is greatly accelerated by Helicobacter infection.

Adenocarcinoma↗

Lessons from the Eker rat model: from cage to bedside.

Rodent models of human diseases serve a vital role in translating bench observations to bedside therapies. In vivo manipulation of these animals allows us to explore the biologic significance of the underlying molecular and biochemical pathways. The study of human cancers has been highly enriched by the observations made from numerous transgenic mouse models. Long before the techniques of genetic engineering were discovered, Dr. Reidar Eker described one of the earliest examples of an autosomal dominant model of renal tumors in a unique strain of rats. They were used in the 1980's by Alfred Knudson to validate the "two-hit" hypothesis and to study the multi-step process of carcinogenesis. Following the identification of the Tsc2 germline mutation in the Eker rat, it became the first rodent model of tuberous sclerosis and has since been exploited in many areas of tumor biology as illustrated in the content of this issue. The focus of our review is to highlight the contribution of the Eker rat towards understanding the Tsc2 signaling pathways in tumorigenesis and evaluating potential therapeutics in the pre-clinical setting.

Animals↗

Development of multiorgan pathology in the wpk rat model of polycystic kidney disease.

Rodent models of polycystic kidney disease (PKD) have provided valuable insight into the cellular changes associated with cystogenesis in humans. The present study characterizes the morphology of renal and extrarenal pathology of autosomal recessive PKD induced by the wpk gene in Wistar rats. In wpk(-/-) rats, proximal tubule and collecting duct cysts develop in utero and eventually consume the kidney. Increased apoptosis, mitosis, and extracellular tenascin deposition parallel cyst development. Extrarenal pathology occurs in the immune system (thymic and splenic hypoplasia) and central nervous system (CNS; hypoplasia to agenesis of the corpus callosum with severe hydrocephalus). Severity of hydrocephalus varied inversely with size of the corpus callosum. In wpk(-/-) rats, the corpus callosum exhibits relatively few axons that cross the midline. This CNS pathology is similar to that described in three human renal cystic syndromes: orofaciodigital, genitopatellar, and cerebrorenal-digital syndromes. Collecting duct and ventricular ependymal cilia appear morphologically normal. To determine if rodent background strain and the presence of modifier genes affect severity of the disease, we crossed the Wistar-wpk rat with Brown Norway (BN) and Long Evan (LE) rats and found the degree of renal and cerebral pathology was diminished as evidenced by lower kidney weight as a percent of body weight and serum urea nitrogen concentration in cystic rats on LE or BN strains as well as less prominent cranial enlargement. Crosses with BN rats allowed us to localize the wpk gene on chromosome 5 very close to the D5Rat73 marker. The wpk gene lies within a chromosomal region known to harbor a PKD modifier locus. In summary, the types of renal and cerebral pathology seen in the Wistar wpk rat are a unique combination seen only in this rodent model.

Agenesis of Corpus Callosum↗

Rodent doxapram model of panic: behavioral effects and c-Fos immunoreactivity in the amygdala.

BACKGROUND: Panic attacks, the hallmark of panic disorder, are often characterized by hyperventilation. Existing animal models of anxiety have not addressed the effects of the hyperventilation on anxiety-related behaviors. Doxapram is a respiratory stimulant that reliably evokes panic attacks in patients with panic disorder. We examined doxapram in four rodent models of anxiety and sought to identify brain regions involved in its behavioral effects. METHODS: The effects of doxapram were determined for cue and contextual fear conditioning, the open field test, and the social interaction test. The effect of doxapram on c-Fos-like immunoreactivity was examined in three brain regions. RESULTS: Doxapram at 4 mg/kg increased anxiety-related behaviors in all four anxiety models. An inverted U-shaped dose-response curve was identified for fear conditioning to cue. Doxapram induced c-Fos-like immunoreactivity in the central nucleus of the amygdala but not the lateral nucleus or the nucleus tractus solitarius. CONCLUSIONS: Doxapram enhanced anxiety-related behaviors in four animal models of anxiety that involve conditioning or spontaneous avoidance. The effect of doxapram may result from activation of neurons in the amygdala. Doxapram, by inducing hyperventilation, may be a useful adjunct to existing animal anxiety models for improving validity for panic anxiety.

Amygdala↗

[Importance of Helicobacter pylori in the pathogenesis of gastric cancer. Experimental models in rodents].

UNLABELLED: We found that the seroprevalence in Cancer Institute of H. pylori infection was significantly more frequent in gastric cancer than in age- and gender-matched controls. This study suggested an epidemiological link between H. pylori infection and gastric cancer. H. pylori exhibits a complex system of enzymes which serve a range of functions. Toxic effects are produced by urease (UR), phospholipase (PL) and alcohol dehydrogenase (ADH). We embarked on an exploration of the enzyme activities of H. pylori infected patients using a TLC-autoradioluminography. This method has a wide dynamic range and could offer an analytical technique for studying a radioactive compound and its enzymes in H. pylori infected mucosa. Biopsies samples taken from 21 gastric cancer patients and 95 controls were studied. Although high activity of UR indicates well the presence of H. pylori impairment, activities of ADH and PL reflects more the chronicity of mucosal damage in both groups. Clearly, the enzyme profile showed in our study reflects the "physiological" adaptations behind chronic injured mucosal changes but its relation to gastric cancer and H. pylori needs further study. There is an urgent need to understand the carcinogenesis process using animal models. We performed previous study for to explore the effect of H. pylori infection on N- methyl-N-nitrosourea-induced (MNU) gastric carcinogenesis in mice C57BL/6 mice were administered broth culture of H. pylori and given MNU in drinking water. In terms of the incidence of neoplasms development was increase in the MNU group pre-infected with H. pylori. That findings showed that C57BL/6 mice-infected model is well suited for investigating the bacteria promoter effect in the gastric carcinogenesis. Finally another rodent model study (still in process) showed rapid development of hyperplastic gastritis with gastric erosions in H. pylori-infected MTH1 knockout mice. We sought to further evaluate MTH1 knockout mice as potential test animal for carcinogenesis. CONCLUSION: It is suggested that H. pylori infection is an important risk factor for the development of gastric cancer. The possibility that this organism acts etiologically, exerting its effect over long period of time, is biologically plausible. However, the role of H. pylori per se in that process is still a matter of discussion. The various enzymes of H. pylori discussed in this paper support colonization, and are perhaps important for epithelial damage, they could contribute to the stimulation and modulation of the chronic inflammatory response, but its relation to gastric cancer and H. pylori needs further study. Finally H. pylori in C57BL/6 and knockout mice showed excellent colonization at two months and six months after infection there was adenomatous, hyperplastic and ulcerative changes. Those findings showed that both mice-infected models are well suited for investigating the bacteria promoter effect in the gastric carcinogenesis.

Adenocarcinoma↗

Rodent obesity models: an overview.

Animal obesity models differ widely in type and extent of obesity. They are either based on environmental factors (eg. high fat diet induced obesity), spontaneous mutants (i.e. ob/ob mice), genetically engineered animals (eg. mice with melanocortin receptor subtype-4 gene disruption (knock-out)) or mechanical intervention (eg. chemical lesion of the ventromedial hypothalamus). This article reviews available rodent models to study obesity and attempts to highlight the greatest utility for each model.

Animals↗

Antidepressant treatment and rodent aggressive behaviour.

This review examines two 'ethologically relevant' rodent models, the resident-intruder and social hierarchy paradigms, that are sensitive to chronic antidepressant treatment (including repeated electroconvulsive shock). These models of rodent social and agonistic behaviour demonstrate that acute and chronic treatment with antidepressant drugs (regardless of their acute pharmacological activity) induce diametrically opposite changes in rodent aggressive behaviour. The common ability of chronic antidepressant treatment to increase rodent aggression (which in turn results in increased hierarchical status in closed social groups) most likely reflects the increased assertiveness and associated externalization of emotions (indicative of increased extrapunitive aggression) expressed during recovery from depressive illness. Finally, findings that relate observed behavioural changes to underlying neurochemical changes are briefly reviewed in terms of adaptive mechanisms in the rodent central nervous system induced by antidepressants, and also with respect to suicide ideation and panicogenic responses observed in some patients at the onset of treatment with selective serotonin reuptake inhibitors for affective disorders.

Aggression↗

Differential regulation of the cynomolgus, human, and rat acyl-CoA oxidase promoters by PPARalpha.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of transcription factors and is recognized as the molecular target of the hypolipidemic fibrate drugs. Fibrates promote lipid catabolism by inducing genes involved in fatty acid beta-oxidation. In rodents this is accompanied by peroxisome proliferation, and after chronic dosing hepatocarcinoma, whereas epidemiological studies suggest these adverse events are lacking in humans. Rodents such as rats and mice appear particularly sensitive to PPARalpha-induced peroxisome proliferation while humans are resistant. These findings question the utility of rodent models for safety monitoring of experimental PPARalpha agonists and highlight the need for additional preclinical models that display greater physiological relevance for human response. Thus we have focused on elucidating the molecular mechanism of species-dependent peroxisome proliferation by understanding the PPARalpha-dependent regulation of the acyl-CoA oxidase (AOX) promoter, the rate-limiting step of peroxisomal beta-oxidation. We have chosen the cynomolgus monkey as a model that is modestly responsive to peroxisome proliferation and functionally characterized it against the highly responsive rat and non-responsive human species. We report the identification of a putative peroxisome proliferator response element (PPRE) within the 2.3 kb proximal promoter of the cynomolgus monkey AOX gene. Characterization of these promoters using a series of constitutively active, PPARalpha constructs demonstrate that the PPREs within the proximal cynomolgus and human AOX promoters are non-responsive to PPARalpha whereas the rat PPRE is highly responsive. These findings were verified in vivo using a small molecule PPARalpha agonist. Taken together, we demonstrate concordant regulation of the AOX promoter by PPARalpha in cynomolgus monkeys and humans and suggest that this model is superior to rodent models with respect to preclinical evaluation of PPARalpha agonists.

Acyl-CoA Oxidase↗

Bub1 up-regulation and hyperphosphorylation promote malignant transformation in SV40 tag-induced transgenic mouse models.

Rodents do not naturally develop prostate cancer. Currently, most widely used genetically engineered mouse prostate cancer models use SV40 T/tag oncogene. To understand the mechanism underlying prostate cancer development in transgenic and knock-in SV40 Tag mouse models, we did cDNA microarray analyses, comparing gene expression profiles of prostate cancer tissues from early-, late-, and advance-stage androgen-independent prostate cancers. Of the 67 genes that were up-regulated by > or = 10-fold, 40 are known to be required for chromosome stability. In particular, the spindle checkpoint component Bub1 was persistently up-regulated from early to advanced androgen-independent prostate cancer lesions. Significantly, Bub1, which is required for accurate chromosome segregation during mitosis, has recently been reported to bind SV40 Tag. Consistent with a spindle checkpoint defect, flow cytometry experiments indicate that advanced androgen-independent prostate cancer tumors exhibit aneuploidy, along with up-regulation of levels of both Bub1 mRNA and Bub1 protein or hyperphosphorylation. Importantly, up-regulation and hyperphosphorylation of Bub1 were also observed in established human prostate cancer cell lines and in clinical studies. Furthermore, analysis of human prostate cancer lines showed impaired spindle checkpoint function and endoreduplication following exposure to spindle toxins. Small interfering RNA-mediated repression of Bub1 in the human prostate cancer line PC-3 restrained cell proliferation, an effect mimicked by inhibition of mitogen-activated protein kinase, an upstream activator of Bub1. Thus, by perturbing Bub1 function, our observations suggest a new mechanism whereby the SV40 Tag oncoprotein promotes chromosomal instability and aneuploidy in transgenic mouse prostate cancer models. Whereas the exact details of this mechanism remain unclear, our novel findings raise the possibility of exploiting Bub1 as a new therapeutic target in the treatment of prostate cancer, the most common cancer in adult men in North America.

Animals↗

Plasticity of directional place fields in a model of rodent CA3.

We propose a computational model of the CA3 region of the rat hippocampus that is able to reproduce the available experimental data concerning the dependence of directional selectivity of the place cell discharge on the environment and on the spatial task. The main feature of our model is a continuous, unsupervised Hebbian learning dynamics of recurrent connections, which is driven by the neuronal activities imposed upon the network by the environment-dependent external input. In our simulations, the environment and the movements of the rat are chosen to mimic those commonly observed in neurophysiological experiments. The environment is represented as local views that depend on both the position and the heading direction of the rat. We hypothesize that place cells are intrinsically directional, that is, they respond to local views. We show that the synaptic dynamics in the recurrent neural network rapidly modify the discharge correlates of the place cells: Cells tend to become omnidirectional place cells in open fields, while their directionality tends to get stronger in radial-arm mazes. We also find that the synaptic learning mechanisms account for other properties of place cell activity, such as an increase in the place cell peak firing rates as well as clustering of place fields during exploration. Our model makes several experimental predictions that can be tested using current techniques.

Animals↗

Diabetes mellitus: stress, neurochemistry and behavior.

Neurochemical alterations in several rodent models of insulin-dependent diabetes are compared and their relevance to behavioral and physiological pathology in the clinical disorder is discussed. In the majority of rodent models, reductions in metabolism of norepinephrine (NE), dopamine (DA) and serotonin (5HT) in the central nervous system (CNS) have been reported. While there are two reports of increased 5HT turnover in CSF or post-mortem brains of diabetic humans experiencing severe ketoacidosis, these patients were receiving insulin therapy. Insulin appears to have effects on monoamines opposite to that of chronic hyperglycemia. Both in rodent models and in clinical populations, there is widespread evidence of enhanced hormonal and behavioral responsiveness to stress. There are findings in rodent models indicating that hormonal responses to stress are related to CNS monoamine activity. The mechanisms responsible for both hormonal and CNS alterations in diabetes, as well as their involvement in behavioral pathology, can best be investigated further using animal models.

Animals↗

Laboratory evaluation of the ict malaria P.f./P.v. immunochromatographic test for detecting the panmalarial antigen using a rodent malaria model.

We evaluated the ICT Malaria P.f./P.v. immunochromatographic test for the detection of the panmalarial antigen (PMA) using a rodent malaria model. Mice were infected with Plasmodium berghei by mosquito bite, and blood was examined by microscopy and the ICT test. Treatment with artemether was started when the parasite density exceeded 70,000/microL. The ICT PMA band appeared when the parasite density was more than 2,000/microL, but it continued to be positive after the parasitemia became negative in response to the drug treatment. When all the test results were divided into increasing phase (IP) and declining phase (DP), the sensitivity in the DP was significantly higher than that in the IP, suggesting that the reactivity of the ICT PMA is significantly influenced by persistent and accumulated PMA after drug treatment and longer duration of infection in the DP. Recognizing that the patient population in a clinical situation would be a mixture of individuals in the IP and DP, it should be emphasized that the individual history of recent fever, duration of illness, and drug treatment must be considered carefully for the interpretation of the ICT results.

Animals↗

Intratumoral injection of an adenovirus expressing interleukin 2 induces regression and immunity in a murine breast cancer model.

Rodent tumor cells engineered to secrete cytokines such as interleukin 2 (IL-2) or IL-4 are rejected by syngeneic recipients due to an enhanced antitumor host immune response. An adenovirus vector (AdCAIL-2) containing the human IL-2 gene has been constructed and shown to direct secretion of high levels of human IL-2 in infected tumor cells. AdCAIL-2 induces regression of tumors in a transgenic mouse model of mammary adenocarcinoma following intratumoral injection. Elimination of existing tumors in this way results in immunity against a second challenge with tumor cells. These findings suggest that adenovirus vectors expressing cytokines may form the basis for highly effective immunotherapies of human cancers.

Adenocarcinoma↗

Miniaturization: an overview of biotechnologies for monitoring the physiology and pathophysiology of rodent animal models.

Recent advances in bioengineering technologies have made it possible to collect high-quality reproducible data quantitatively in a wide range of laboratory animal species, including rodents. Several of these technologies are incorporated into a plan called Miniaturization, which aims to design, develop, and maintain rodent animal models to study the pathophysiology and therapy of human diseases. Laser Doppler flowmetry, digital sonomicrometry, bioelectrical impedance, and microdialysis are some of the most widely used methods under the plan because they cause minimal pain and distress, reduce the number of animals used in biomedical research, and allow chronic, nonterminal assessment of physiological parameters in rodents. An overview of each of these technologies and their major applications in rodents used for biomedical research is provided.

Animals↗

Marked alterations in circulating inflammatory cells during cardiomyopathy development in a magnesium-deficient rat model.

Rodents fed on a Mg-deficient (Mg-D) diet develop cardiomyopathic lesions, as well as other types of cardiovascular dysfunction. In the rat, inflammatory cell infiltration of the myocardium begins to occur by week 1, and the lesions develop extensively in the third and fourth weeks on the Mg-D diet. Although the aetiologic mechanisms of Mg-D cardiomyopathy are unknown, we have previously reported that once plasma Mg is markedly reduced, one of the earliest molecular markers of the pathophysiological process is elevation of plasma substance P, calcitonin gene-related peptide and prostaglandin E2, followed by histamine and the inflammatory cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha). In order to evaluate the potential role of specific circulating inflammatory cell subpopulations in the mechanisms underlying pathophysiological changes observed in Mg-deficiency-induced cardiomyopathy, we analysed these cells by flow cytochemistry. Leucocyte subpopulation pools increased progressively in the Mg-D rats. Elevated circulating levels of neutrophils and lymphocytes appeared to contribute to both the acute (week 1-2) and chronic phases (week 3-4) of the inflammatory responses; monocytes, eosinophils, basophils and large unstained cells which are lymphoid in stained smears, on the other hand, increased significantly in the third and fourth weeks and thus contributed to the chronic inflammatory phase. Changes in the circulating leucocyte subpopulations paralleled the chronological progression of the cardiomyopathic lesions, particularly in weeks 3 and 4. Since a pronounced neutrophilia preceded leucocyte infiltration and deposition within the myocardial tissue, modifications of the microvascular barrier may be a prerequisite for cardiomyopathy in this model of neurogenic inflammation.

Acute Disease↗

Evaluation of gas-filled microparticles and sonoporation as gene delivery system: feasibility study in rodent tumor models.

PURPOSE: To evaluate the feasibility of gene delivery mediated with diagnostic ultrasound and plasmid DNA (pDNA) encapsulated in gas-filled microparticles (GFMP) in rodent tumor models. MATERIALS AND METHODS: This study was performed according to a protocol approved by the regional animal research committee. The model plasmid UT651 (pUT651) that contained the Escherichia coli LacZ gene for beta-galactosidase was used to demonstrate the feasibility of ultrasound-mediated gene delivery in CC531 liver tumors in rats. In preliminary experiments, a single injection of pUT651-containing GFMP was administered intraarterially (n=4) or intravenously (n=6) with simultaneous sonication (color Doppler mode, maximum mechanical index) of the GFMP passing through the capillaries of the tumors. All animals were sacrificed 2-5 days later, and liver tumors were examined for beta-galactosidase expression histochemically. Subsequently, potential medical usefulness of this delivery system was tested in nude mice bearing Capan-1 tumors (adenocarcinoma of the human pancreas) by using the plasmid RC/CMV-p16 (pRC/CMV-p16), which contains tumor suppressor gene p16. The tumor suppressor gene p16 is deleted in Capan-1 cells. Twenty-five tumor-bearing mice were classified into five groups (four to six mice per group, one treatment group, four control groups) at random. All mice were treated once weekly for 5 weeks with intravenous infusion of p16-containing GFMP or control substances with simultaneous tumor sonication with color Doppler mode ultrasound and maximum mechanical index or without ultrasound treatment. The therapeutic effect of p16 was measured as an increase in tumor volume doubling time. Data were analyzed with analysis of variance. Results were considered significant at the 5% critical level (P < .05). RESULTS: A clear expression of pDNA was found in tumors in rats treated with a combination of pUT651-containing GFMP and ultrasound; relevant controls showed a significantly lower expression of marker gene. The controlled ultrasound-triggered release of pRC/CMV-p16 from GFMP leads to a strong tumor growth inhibition, which is significant (P < .002), compared with that in controls. CONCLUSION: A combination of GFMP and ultrasound provides an effective approach for nonviral gene therapy-based cancer treatment.

Animals↗