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PubMed1999

[Mechanisms of rejection in guinea pig (GP)-to-rat liver xenotransplantation: improvement of recoloration of GP liver graft and effects of perfluorochemical (FC43) in GP-to-rat liver xenotransplantation].

The impaired reperfusion after revascularization has not allowed guinea pig (GP)-to-rat liver xenograft model to be widely used for xenotransplant research. This study was designed to clarify mechanisms responsible for the impaired recoloration, and to examine effects of FC43 emulsion, an anti-complement agent. 1) Mechanisms responsible for the impaired recoloration: GP allogeneic and xenogeneic liver grafts flushed with 4 degrees C lactated Ringer's (LR) solution were poorly perfused around the porta hepatis, whereas those flushed with 15 degrees C LR solution were immediately recolored, this being confirmed by portal venography. The recoloration was also ameliorated by reduction of ischemic time. Even recolored GP xenografts, turned uneven dark gray however, and enlarged around 5 min after revascularization. Histological and immunohistological findings of GP livers 1 h after xenografting were characteristic of sinusoidal congestion and hepatocytes necrosis, and the livers had remarkable C3 deposits on sinusoids and central veins, IgM deposits faintly stained on some small vessels but no detectable deposits of IgG. 2) Effects of FC43. Administration with of either a single dose of 10 microliters/g or repeated doses of 5 microliters/g of FC43 resulted in significant prolongation of xenograft survivals compared with controls (8.06 +/- 1.45, 9.45 +/- 3.64 vs. 4.23 +/- 0.89 h; p < 0.02), thereby sustaining almost normal gross appearances until abdominal closures. Thus, the onset of hyperacute rejection (HAR) was postponed by FC43 administration; however, all rats died within 14 h. No deposit of C3 was detected in GP xenografts of FC43 groups, while deposits of granulocytes and macrophages (M phi) were observed from 1 and 3 h after revascularization, respectively. In conclusion, the impaired recoloration in this model may be due to physiological defects during the initial stage of revascularization, which is followed by the immunological responses that probably involved M phi and granulocytes. The present study indicates that discordant GP liver xenotransplantation is feasible as a useful rodent model for either exploration of mechanisms of immunological responses or examination of the immunosuppressive effects of pharmacological agents.

Animals↗
PubMed2006

Analysis of lesion development during acute inflammation and remission in a rat model of experimental autoimmune encephalomyelitis by visualization of macrophage infiltration, demyelination and blood-brain barrier damage.

In vivo tracking of macrophage migration is feasible by labeling cells with ultra-small particles of iron oxide (USPIO). It is demonstrated that it is possible to monitor distinct patterns of macrophage migration during the early states of inflammation in a rodent model of chronic relapsing experimental autoimmune encephalomyelitis (EAE). As previous MRI studies showed that EAE inflammation processes are clearly linked to macrophage infiltration in the brain, a longitudinal protocol for macrophage visualization was designed, where USPIOs were injected repeatedly during the acute phase of the disease, the remitting phase and the first relapse. In addition to USPIO-enhanced MRI, blood-brain barrier (BBB) damage, magnetization transfer ratios (MTRs) and neurological impairment were assessed as classical markers for central nervous system (CNS) inflammation and tissue damage. During the acute phase, animals showed severe paralysis of the hind paws, intense accumulation of macrophages in brain tissue and some diffuse patterns of BBB disruption. While USPIO-accumulation completely disappeared after the acute phase, residual damage of the BBB remained detectable in some lesions during the remitting phase. During the first relapse, the accumulation of USPIO-loaded cells was less pronounced but still detectable. The time course of MTR, which is used as a marker for myelin loss, was linked to the infiltration of macrophages during the acute phase.

Acute Disease↗
PubMed1990

Effects of hematopoietic growth factors following myeloablation in a primate model.

The complex effects of hematopoietic growth factors (granulocyte and granulocyte-macrophage colony-stimulating factors and interleukin 3 and interleukin 1 beta) following myeloablation in juvenile male cynomolgus monkeys was studied. Since the effects of a given cytokine in vivo do not necessarily reflect the in vitro situation, and since cytokines are frequently species specific, extrapolation from rodent models to man may be fraught with inaccuracies. A primate model, therefore, was developed which has provided useful preclinical information on hematopoietic responses, dose response relationships and toxicities associated with administration of recombinant hematopoietic growth factors. This information has direct application to human trials.

Alkylating Agents↗
PubMed1992

The effect of immunosuppression on the development of cerebral oedema in an experimental model of intracerebral haemorrhage: whole body and regional irradiation.

The oedema which forms around an intracerebral haemorrhage has a complex aetiology. The immune response may have a role in its formation. There is clinical and experimental evidence that circulating leucocytes and platelets may mediate oedema formation. Global depletion of circulating leucocytes and platelets by whole body irradiation in a rodent model of intracerebral haemorrhage was found to confer protection against both ischaemia and oedema formation. This was not a direct effect of irradiation of the brain. The possible mechanisms for this protection are discussed.

Animals↗
PubMed2004

Potential role of IGF-I in hypoxia tolerance using a rat hypoxic-ischemic model: activation of hypoxia-inducible factor 1alpha.

Hypoxia preconditioning and subsequent tolerance to hypoxia-ischemia damage is a well-known phenomenon and has significant implications in clinical medicine. In this investigation, we tested the hypothesis that the transcriptional activation of IGF-I is one of the underlying mechanisms for hypoxia-induced neuroprotection. In a rodent model of hypoxia-ischemia, hypoxia preconditioning improved neuronal survival as demonstrated by decreased hypoxia-ischemia-induced neuronal apoptosis. To study the role of IGF-I in hypoxia tolerance, we used in situ hybridization to examine IGF-I mRNA distribution on adjacent tissue sections. In cerebral cortex and hippocampus, hypoxia preconditioning resulted in an increase in neuronal IGF-I mRNA levels with or without hypoxia-ischemia. To test its direct effects, we added IGF-I to primary neuronal culture under varying oxygen concentrations. As oxygen concentration decreased, neuronal survival also decreased, which could be reversed by IGF-I, especially at the lowest oxygen concentration. Interestingly, IGF-I treatment resulted in an activation of hypoxia-inducible factor 1alpha (HIF-1alpha), a master transcription factor for hypoxia-induced metabolic adaptation. To evaluate whether IGF-I transcriptional activation correlates with HIF-1alpha activity, we studied the time course of HIF-1alpha DNA binding activity in the same rat model of hypoxia-ischemia. After hypoxia-ischemia, there was an increase in HIF-1alpha DNA binding activity in cortical tissues, with the highest increase around 24 h. Like IGF-I mRNA levels, hypoxia preconditioning increased HIF-1alpha DNA binding activity alone or with subsequent hypoxia ischemia. Overall, our results suggest that IGF-I transcriptional activation is one of the metabolic adaptive responses to hypoxia, which is likely mediated by a direct activation of HIF-1alpha.

Adaptation, Physiological↗
PubMed2006

Of mice and men: more neurobiology in dementia.

PURPOSE OF REVIEW: An increasing number of genetically modified mouse models are designed and used in the field of Alzheimer disease research. This review aims to offer a general view of the existing transgenic mouse lines and to discuss their relevance and limitations. RECENT FINDINGS: Potential therapeutic targets have been identified in rodent models of Alzheimer disease. Although important steps towards obtaining a safe vaccine to prevent amyloid plaque formation have been made, further evaluations and the use of intermediate models are considered a necessity. SUMMARY: More than 18 million people worldwide are suffering from Alzheimer disease, the most common dementing disorder in humans. Transgenic lines have been created in order to understand the underlying mechanisms of Alzheimer disease and to find a cure. None of the available models completely recapitulates the characteristics of human pathology, but they provide valuable information on different pathogenic pathways involved. New therapeutic approaches and improvement of current strategies can be obtained from the use of Alzheimer animal models.

Alzheimer Disease↗
PubMed2003

Effects of endotoxin exposure on cationic amino acid transporter function in ovine peripheral blood mononuclear cells.

Rodent models of sepsis differ from clinical human disease in that humans make substantially less whole-body nitric oxide and have different cellular responses to endotoxin. Sheep, when exposed to endotoxin, behave in a manner more similar to humans. Many studies of rodent peripheral blood mononuclear cells (PBMCs) exposed to endotoxin demonstrate increased cationic amino acid transporter function (particularly through the y+ transporter) to supply arginine substrate to upregulated nitric oxide synthase. Whether this is true in sheep is not known. We have studied cationic amino acid transport in sheep PBMCs stimulated with endotoxin, using labelled lysine. PBMCs stimulated both in vitro and in vivo show an initial reduction in total and y+ lysine transport (after 1-2 h exposure to endotoxin): a previously undescribed effect of endotoxin. In in vitro activated cells, the reduction in y+ transport was prevented by the lipoxygenase inhibitor, nordihydroguaretic acid (NDGA), and the phospholipase inhibitor 4-bromophenacyl bromide (4-BPAB), but not cyclohexamide or a number of other inhibitors of intracellular second-messenger pathways. In contrast after 14 h incubation, the expected increase in total and y+ lysine transport was seen. The increase in y+ transport could be prevented by cyclohexamide, dexamethasone, ibuprofen, the protein kinase C inhibitor sphingosine, NDGA and 4-BPAB. These results suggest that in response to endotoxin exposure there is an initial decrease in y+ activity mediated by a lipoxygenase product, followed by a substantial increase in y+ activity mediated by the products of either cyclo-oxygenase or lipoxygenase. Cyclo-oxygenase and/or lipoxygenase inhibition might be useful in reducing arginine transport, and hence nitric oxide production, in these cells.

Amino Acid Transport System y+↗
PubMed2004

Minireview: developmental regulation of thyrotropin receptor gene expression in the fetal and newborn thyroid.

The TSH receptor plays a pivotal role in thyroid gland growth, function, and differentiation in the mature animal, but only recently has its role in the fetus and neonate been examined. Observational studies comparing the developmental regulation of TSH receptor gene expression, with thyroid morphology, and thyroid-specific gene expression in the rodent model, are reviewed in the context of older literature. Together, these data strongly suggest that the TSH receptor is essential for terminal thyroid maturation and growth but is not involved in early thyroid organogenesis or migration. Consistent with the aforementioned studies in rodents, babies with a loss of function mutation of the TSH receptor as well as babies born to mothers with potent TSH receptor-blocking antibodies have hypothyroidism and hypoplastic, but normally located, thyroid glands. Because the TSH receptor is probably not expressed in human fetuses before 10-12 wk gestation when thyroid organogenesis and migration are complete, these data provide strong evidence that human chorionic gonadotropin, which peaks in the first trimester of human pregnancy, could not play a role in fetal thyroid development. Similarly, these data imply strongly that maternal TSH receptor antibodies, when present in high titer, are of major importance in influencing fetal thyroid function only after mid-pregnancy when, by analogy with rodents, increased TSH receptor expression is likely to occur.

Animals↗
PubMedDate not supplied

Behavioural models for the characterisation of established and innovative antidepressant agents.

To improve the management of depressive states, it is essential to develop preclinical behavioural models for the characterisation of both conventional and new antidepressant agents. This need is illustrated in this article with two very different classes of antidepressant agents, serotonin and/or noradrenaline reuptake inhibitors (SNRIs) and neurokinin NK1 receptor antagonists. Their effects are evaluated in rodent models of (i) the detection of potential antidepressant activity via marble-burying behaviour in mice; (ii) drug discrimination procedures in rats (mechanistic); and (iii) the evaluation of potential activity on co-morbid symptoms, such as anxiety, via the social recognition test in rats and gerbils. It is concluded that behavioural assays offer a palette of techniques for the characterisation of clinically active antidepressants as well as for innovative (acting on new targets) or improved (multi-target) antidepressants. Nevertheless, for antidepressants of the future, as for established antidepressants, feedback from clinical trials are awaited to confirm the predictive value of these models.

Animals↗
PubMed2003

A novel model for prenatal brain damage. II. Long-term deficits in hippocampal cell number and hippocampal-dependent behavior following neonatal GABAA receptor activation.

Premature infants are at especially high risk for asphyxia, seizures, and other conditions that cause hypoxia-ischemia. These events result in abnormal brain pathology and behavioral deficits that persist throughout adolescence and into adulthood. Current rodent models of human infant hypoxic-ischemic brain damage have focused on exogenous glutamate receptor agonist exposure in the postnatal day 7 rat. While this model is considered analogous to the newborn human, no adequate models for preterm infant brain damage have been developed. Recent work from our lab has proposed a potential model for preterm infant brain damage in which neonatal rats are treated with exogenous muscimol, the selective gamma-aminobutyric acid(A) (GABA(A)) receptor agonist, on postnatal days 0 and 1. In the companion paper to this one (Exp. Neurol., in press), we report fewer neurons in the hippocampal formation on postnatal day 7 (6 days after treatment), but the persistence of these anatomical deficits, and potential resultant behavioral dysfunctions, were not investigated. In the current experiment, we documented that muscimol exposure on postnatal days 0 and 1 leads to fewer neurons in the male and female rat hippocampus (CA1, CA2/3, and dentate gyrus) on postnatal day 21. Also, neonatal muscimol exposed males and females displayed deficits on hippocampal-dependent learning tasks such as a preweanling version of the Morris water maze task and the open field task. We conclude that exposure to exogenous GABA(A) receptor activation over the first 2 days of postnatal life, a model for preterm infant hypoxic injury, produces anatomical and behavioral deficits observed into adolescence.

Animals↗
PubMed2001

[The use of mutagenic and transgenic mice for the study of aging mechanisms and age pathology].

Increased interest is emerging for using mouse models to assess the genetics of aging and age-related diseases, cancer including. Despite this demand, relatively little information is available on relations between aging and spontaneous tumor development in transgenic and null mutant mice. Analysis of various transgenic and knockout rodent models which characterized by shortening or extension of the life span gives an unique possibility to evaluate the role of involved in aging genes in mechanisms of carcinogenesis. Only few models represent examples of life span extension. Ames dwarf mutant mice, p66-/- knocked out mice, aMUPA and MGMT, transgenic mice live longer than wild-type strains. The incidence of spontaneous tumors in these mice was usually similar to those in controls, whereas the latent period of tumor development was increased. Practically all models of accelerated aging show the increased tumor incidence and shortening of tumor latency. This phenomenon has been observed both in animals which display phenotype more resemble to the natural aging and in animals showed only partial features of normal aging process. These observations are in agreement with the data on the positive correlation between tumor incidence and the rate of its age-related increase, and the aging rate in a population.

Age Factors↗
PubMed1992

Calcium, vitamin D, and colon cancer.

Calcium contributes to the progression of epithelial cells through all phases of the proliferative cycle and into stages of cell differentiation; intracellular concentrations of calcium that are required for cell renewal, however, are lower than those required for epithelial-cell differentiation. These effects of calcium are modulated by interactions with 1,25-dihydroxy-vitamin D3, phosphate, and fatty acids, all of which are partly dependent on dietary intake. In rodent models, increased dietary calcium inhibited hyperproliferation of colon epithelial cells induced by increased levels of fatty acids or bile acids present in the colon. When carcinogens induced hyperproliferation of colon epithelial cells the hyperproliferation was decreased by added dietary calcium, and in several animal models the occurrence of carcinogen-induced carcinomas of the colon decreased with increased dietary calcium. A nutritional stress diet, designed to represent human Western dietary intake of calcium, phosphate, vitamin D, and fat, produced hyperproliferation and hyperplasia in the colons of rodents; these effects were reduced by increasing dietary levels of calcium. Decreased levels of ornithine decarboxylase also were reported in human and rodent colon mucosa exposed to increasing levels of calcium. In human subjects at increased risk for familial colon cancer, hyperproliferation of colon epithelial cells was reduced after oral dietary supplementation with calcium. In epidemiological studies, several investigators reported inverse correlations between levels of dietary calcium intake and the incidence of colon cancer. Extrapolation of the data have suggested a protective effect of total calcium intakes above 1500 to 1800 mg/day.

1,2-Dimethylhydrazine↗
PubMed2006

Neuromodulation with levetiracetam and vagus nerve stimulation in experimental animal models of epilepsy.

Epilepsy is a neurological disorder consisting of recurrent seizures, resulting from excessive, uncontrolled electrical activity in the brain. Epilepsy treatment is successful in the majority of the cases; however; still one third of the epilepsy patients are refractory to treatment. Besides the ongoing research on the efficacy of antiepileptic treatments in suppressing seizures (anti-seizure effect), we want to seek for therapies that can lead to plastic, neuromodulatory changes in the epileptic network. Neuropharmacological therapy with levetiracetam (LEV) and vagus nerve stimulation (VNS) are two novel treatments for refractory epilepsy. LEV acts rapidly on seizures in both animal models and humans. In addition, preclinical studies suggest that LEV may have antiepileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression. VNS as well can have an immediate effect on seizures in epilepsy models and patients with, in addition, a cumulative effect after prolonged treatment. Studies in man are hampered by the heterogeneity of patient populations and the difficulty to study therapy-related effects in a systematic way. Therefore, investigation was performed utilizing two rodent models mimicking epilepsy in humans. Genetic absence epilepsy rats from Strasbourg (GAERS) have inborn absence epilepsy and Fast rats have a genetically determined sensitivity for electrical amygdala kindling, which is an excellent model of temporal lobe epilepsy. Our findings support the hypothesis that treatment with LEV and VNS can be considered as neuromodulatory: changes are induced in central nervous system function or organization as a result of influencing and initiating neurophysiological signals.

Animals↗
PubMed2003

Preclinical models for chemoprevention of colon cancer.

Colon cancer is the second leading cause of cancer incidence and death in the USA in 2002. Specific genetic defects have been identified which cause hereditary colon cancers in humans. In addition, a number of intestinal luminal risk factors for colon cancer have been described. This information has been exploited to develop experimental cell and rodent models which recapitulate features of human colon cancer. In this chapter, we will discuss the strengths and limitations of these models to further our understanding of basic mechanisms of colon carcinogenesis and to develop strategies for colon cancer chemoprevention.

Animals↗
PubMed2005

A new animal model of hyperoxaluria and nephrolithiasis in rats with small bowel resection.

An association between small bowel resection and stone disease has been noted, which is primarily due to increased gut oxalate absorption and resulting excretion by the kidney. In order to better understand the factors affecting both oxalate absorption and renal excretion, and the resulting renal lesions, we have developed a rodent model of small bowel resection and hyperoxaluria. Using this model, we have studied the renal histology in animals with hyperoxaluria over time spans from 2 weeks to 7 months. The initial lesion appears to be crystal formation along the brush border of the proximal tubule, with eventual crystal deposition in collecting ducts and papillary interstitium, and eventual tubule obstruction, interstitial inflammation and fibrosis. Crystal formation appears to dissociate from urinary supersaturation. We hypothesize that oxalate transporters in the proximal tubule may increase local saturations, leading to crystal formation at this site initially. Further studies are required to better characterize the causes and consequences of hyperoxaluria in this animal model.

Animals↗
PubMed1992

Mechanisms of triglyceride-lowering effect of an HMG-CoA reductase inhibitor in a hypertriglyceridemic animal model, the Zucker obese rat.

Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase have been approved for treatment of hypercholesterolemia in humans. This class of therapeutic agents, in addition to lowering plasma cholesterol, reduces plasma triglyceride levels. We have investigated the mechanism of triglyceride-lowering effect of lovastatin in the hypertriglyceridemic state by using a rodent model of hypertriglyceridemia and obesity, the Zucker obese (fa/fa) rat. Lovastatin treatment (4 mg/kg), as compared to placebo, caused a 338% reduction in plasma triglyceride (146 +/- 5 vs. 494 +/- 76 mg/dl), a 58% decrease in total cholesterol (99 +/- 13 vs. 156 +/- 18 mg/dl), and a 67% reduction in high density lipoprotein (HDL)-cholesterol (69 +/- 8 vs. 115 +/- 15 mg/dl). The fall seen in plasma triglyceride was due to a decrease in hepatic secretion of very low density lipoproteins (VLDL), determined after blocking the clearance of triglyceride-rich lipoproteins with Triton WR-1339. Lovastatin treatment did not affect either the activities of hepatic lipogenic enzymes, glucose-6-phosphate dehydrogenase, or malic enzyme, or the activities of the lipolytic enzymes of adipose tissue, lipoprotein lipase, or liver, hepatic triglyceride lipase. Supplementation of mevalonolactone in the diet partially reversed the changes in plasma triglyceride (265 +/- 37 vs. 146 +/- 5 mg/dl), but not in total or HDL-cholesterol. These data demonstrate that, in the hypertriglyceridemic Zucker rat model, HMG-CoA reductase inhibitors reduce the rate of secretion of VLDL and this effect can be partially reversed by administration of mevalonolactone.

Adipose Tissue↗
PubMed2004

In vivo bioluminescent imaging of virus-mediated gene transfer and transduced cell transplantation in the intervertebral disc.

STUDY DESIGN: Work presented here used a small animal model to demonstrate the feasibility and usefulness of in vivo bioluminescent imaging to studying degenerative disc disease. OBJECTIVES: To determine the utility of in vivo bioluminescent imaging to monitor the temporal and spatial expression of genetically modified cells within the intervertebral disc of a rodent model. SUMMARY OF THE BACKGROUND DATA: Noninvasive imaging of genetically engineered cells in the spine has the advantage of allowing events to be tracked without killing the animal and can be used to follow the time course of a particular therapy. Results are presented on the use of Sprague-Dawley rats in experimental studies in which the luciferase reporter gene was delivered to the lumbar intervertebral disc through adenovirus-mediated or cell-based transfer techniques to demonstrate the feasibility to monitor gene expression noninvasively over time. METHODS: Tissue culture, disc surgery, and in vivo bioluminescent imaging were used. The intervertebral disc of the rat was either injected in situ with an adenovirus containing the luciferase reporter gene or implanted with fat, bone marrow or intervertebral disc cells transduced ex vivo and contained in a bioresorbable carrier. Results were assessed with in vivo bioluminescent imaging at several time points. CONCLUSION: Data from 11 animals were obtained with imaging up to 14 days. To our knowledge, this is the first description of in vivo bioluminescence imaging to study spinal conditions. We have characterized the relative expression of three cell types transduced with the Ad-luc virus by ex vivo transfection followed by cell implantation in the rat spine and compared them to one another and to direct infection of Ad-luc adenovirus in situ. Our results demonstrate the feasibility of tracing genetically altered cells in the spine. This technique has the potential to be used to noninvasively track the fate and expression of therapeutic genes within the spine of small animals used in disc research.

Adenoviridae↗
PubMed1984

The sensitivity of rainbow trout and other fish to carcinogens.

Systematic design of replacement chemicals with reduced toxicities will require knowledge of mechanisms of action of parent compounds, especially in species which occupy the environment of most likely exposure. For aquatic systems, the rainbow trout has proven a valuable model for studying mechanisms of carcinogenicity. By comparison, small aquarium species show great potential as in situ field monitors of aquatic contamination by toxic chemicals but are less developed for mechanism studies. Fish species, especially rainbow trout, have also proven useful alternatives to traditional rodent models for comparative studies on mechanisms of action of nonaquatic carcinogens. These kinds of comparative studies form an essential basis for extrapolation of animal studies to man. Carcinogenicity testing of individual compounds and their replacements can provide only limited information on the expected impact of such chemicals on natural populations, since these populations are unavoidably exposed to potent modulators of the carcinogenic response. Hence any program which aims at redesign of commercial chemicals with reduced toxicities must have as a prior aim the full understanding of the mechanisms of joint carcinogen-inhibitor-promotor interactions. Because of their high sensitivity, low cost per individual, and low background tumor incidences, fish models such as the rainbow trout may be the only vertebrate models in which it is economically practical to initiate such complex studies.

Aflatoxin B1↗