Rodent model of reproductive tract leiomyomata: characterization and use in preclinical therapeutic studies.
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Animals↗
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The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson's disease.
Overactivity in the subthalamic nucleus (STN) is believed to contribute to the pathophysiology of Parkinson's disease. It is hypothesized that dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by using in vivo extracellular single unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway (a model of Parkinson's disease). As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal conditions and were decreased by the nonselective dopamine receptor agonists apomorphine and L-3, 4-dihydroxyphenylalanine (L-DOPA). STN firing rates were also decreased by the D2 receptor agonist quinpirole when administered after the D1 receptor agonist (+/-)- 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393). Results of the present study challenge the prediction that dopaminergic agonists reduce STN activity predominantly through actions at striatal dopamine D2 receptors. Firing rates of STN neurons were not altered by selective stimulation of D2 receptors and were increased by selective stimulation of D1 receptors. Moreover, there was a striking difference between the responses of the STN to D1/D2 receptor stimulation in the lesioned and intact rat; apomorphine inhibited STN firing in the lesioned rat and increased STN firing in the intact rat. These findings support the premise that therapeutic efficacy in the treatment of Parkinson's disease is associated with a decrease in the activity of the STN, but challenge assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity of the STN in both the intact and dopamine-depleted states.
Animals↗
BCH-2763, a novel potent parenteral thrombin inhibitor, is an effective antithrombotic agent in rodent models of arterial and venous thrombosis--comparisons with heparin, r-hirudin, hirulog, inogatran and argatroban.
Current clinical use of heparin as an antithrombotic agent is limited by suboptimal efficacy and safety considerations. Thrombin's central role in thrombosis makes it an attractive target to develop more effective and safer antithrombotic agents. BCH-2763 is a novel, potent (Ki: 0.11 nM), low molecular weight (1.51 kDa), bivalent direct thrombin inhibitor. The antithrombotic efficacy of BCH-2763 in vivo following i.v. bolus plus infusion in rats was compared in arterial and venous thrombosis models with two other bivalent direct thrombin inhibitors, r-hirudin and hirulog, with two catalytic site-directed thrombin inhibitors, inogatran and argatroban, and with heparin. In vivo efficacy was related to inhibition in vitro of fibrin clot formation, thrombin-induced aggregation of rat or human washed platelets and activity of free and plasma clot-bound thrombin. All the direct thrombin inhibitors were effective on both arterial and venous thrombosis at markedly lower fold aPTT increases than heparin. The antithrombotic doses of all inhibitors against venous thrombosis were less than against arterial thrombosis. The rank order of potency based on doses (mg/kg/h) required for full efficacy against arterial thrombosis was BCH-2763 (1.2) > inogatran (1.5) > r-hirudin (1.8) > hirulog (3.3) > argatroban (> 3.0); heparin required a markedly higher dose (5.7). In venous thrombosis the doses required for full efficacy were substantially lower for the bivalent (BCH-2763: 0.12; r-hirudin: 0.12; hirulog: 0.18) than for the catalytic site-directed (inogatran: 0.48; argatroban: 0.90) thrombin inhibitors; the dose required for heparin was 0.19. All the direct thrombin inhibitors caused similar shifts in aPTT at doses required to inhibit arterial thrombosis, but BCH-2763 inhibited venous thrombosis at lower aPTT fold increases. In vivo antithrombotic efficacy of direct thrombin inhibitors correlated with their inhibitory activity in vitro against fibrin clot formation and platelet aggregation. In contrast to heparin, all the direct thrombin inhibitors inhibited plasma clot-bound thrombin, but the relative IC50s did not correlate with their antithrombotic efficacy. In summary, direct thrombin inhibitors are more effective than heparin in inhibiting arterial and venous thrombosis in rats with less aPTT increases. BCH-2763 is effective at lower doses than the other direct thrombin inhibitors and for venous thrombosis at a smaller aPTT increase. BCH-2763 may offer an improved therapeutic index in the treatment of thromboembolic complications over heparin and other direct thrombin inhibitors.
Animals↗
Short- and long-term functional vs morphometrical salivary effects of irradiation in a rodent model.
BACKGROUND: Irradiation-induced salivary damage which results in severe xerostomia is a well known entity. However, the underlying mechanism of this phenomenon is still considered enigmatic. MATERIALS AND METHODS: We used one of the most studied models, male Wistar rats, and irradiated them to the head and neck region with both a low dose [2.5 Gy] and a high dose [15 Gy] of irradiation. Then we evaluated salivary gland function, weight and morphology of both parotid and submandibular glands in the same animals. Examinations were obtained for the short-term [3 days], long-term [40 days] and extended-term [90 days] time points. RESULTS: We found that irradiation with 15 Gy, but not 2.5 Gy, profoundly affected all salivary parameters evaluated, the parotid gland to a greater extent. At 40 days post- 15 Gy irradiation, parotid acini tissue was reduced by 35% [p < 0.01], being replaced by fibrovascular stromal tissue. This reduction was accompanied by parotid weight and function reduction of 27% [p < 0.05] and 58% [p < 0.01], respectively. At ninety days post-15 Gy irradiation, the parotid and submandibular functions were reduced by 84% [p < 0.01] and 62% [p < 0.01] respectively, while the gland weights were reduced by 62% [p < 0.01] and 39% [p < 0.01], respectively. CONCLUSION: The accumulated data demonstrate the time and dose dependent effects of irradiation on both parotid and submandibular glands. The effects were more profound for the parotid gland and a partial correlation between salivary hypofunction and parenchymal destruction was demonstrated.
Animals↗
Characterization of a rodent model in which to investigate the molecular and cellular mechanisms underlying the pathophysiology of L-dopa-induced dyskinesia.
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Animals↗
Assessing growth and response to therapy in murine tumor models.
Rodent models provide an important means of assessing antitumor activity vs toxicity for new cancer therapies. Tumors are often grown subcutaneously on the flank or back of animals, allowing accurate serial determination of tumor volume with calipers by measuring the tumors in three dimensions. The advantages of assessing tumor volume in subcutaneous tumors must be balanced against the potential artifacts induced by growth of tumor cells in subcutaneous tissue. Various orthotopic models have been developed. However, they are more labor-intensive and generally do not allow accurate assessment of tumor growth and/or response unless investigators have access to small animal cross-sectional imaging. Use of small-animal magnetic resonance imaging (MRI) allows one to assess the growth and response of intracavitary tumors, but the cost and labor-intensive nature of MRI limits its use in drug testing. Another approach to intracavitary solid tumor models is the intravenous injection of tumor cells, which can produce lung, liver, or bone metastases (depending on the cell line used), whereas direct injection of tumor cells into the femur or tibia of mice can cause local growth in bone. Progression of both lung metastases and bone lesions can be assessed by small-animal analog X-ray techniques that are more easily available and less labor-intensive to use, and are proving useful for selected therapeutic and biological studies.
Animals↗
Alopecia areata - animal models.
Several rodent models with spontaneous and induced alopecia areata (AA), a nonscarring inflammatory hair loss disease with suspected autoimmune elements, have been identified. Of these, the C3H/HeJ mouse and DEBR rat have been most extensively used in examining AA development. Flow cytometry and micro array characterization, manipulation of inflammatory cells by in vivo cell depletion or cell receptor blockade, lymph node cell transfer between affected and unaffected rodents, and the recent use of transgenic knockout mice have given important insights into the development of AA. From our current understanding of rodent models, the development of AA relies upon a general genetic susceptibility where major susceptibility genes may be supplemented by minor disease severity modifying genes. However, the actual onset of AA, its duration, extent, and persistence in individual rodents may be modified by epigenetic factors. Rodent AA seems to be fundamentally, but not exclusively, Th1 cell mediated. Onset of disease may be dependent on several factors including the break down of the putative anagen stage hair follicle immune privilege, appropriate antigen presentation with costimulation of lymphocytes, presence of autoreactive lymphocytes, and a deficiency of functional immune system regulatory cells. Rodents have already been used in examining a variety of current AA treatments and developing new therapies with some success. With a greater understanding of AA disease mechanisms through rodent model research, improved and more specific treatment interventions may be defined.
Alopecia Areata↗
Quantitative assessment of directed hind limb scratching behavior as a rodent itch model.
Hind limb scratching is used increasingly as an itch model in rodents. Scratching is usually quantified as the number of scratching bouts over a 60 min period. Since the antipruritic effect of scratching should depend on the total time of skin contact, then the duration of scratching bouts and within-bout scratching frequency may also be important factors. Therefore, we measured these parameters during episodes of scratching directed toward the site (nape of neck) of intradermal injection of serotonin in Sprague-Dawley rats. Serotonin elicited significantly more scratching bouts than saline. There was a biphasic pattern of scratching over time, with peaks at 10-20 and 40-50 min. Although cumulative bout duration (2-min intervals) had a similar biphasic distribution, the mean individual bout duration (2.1 s) did not change significantly over time. Within-bout scratching frequency remained constant over time at 8 Hz. The number of scratching bouts was suppressed in a dose dependent manner by naltrexone (3 and 5 mg/kg), while the individual bout duration and the within-bout frequency were not significantly different compared with serotonin-evoked scratching without naltrexone. These results validate the total number of scratching bouts as an indicator of the magnitude of itch-related scratching.
Animals↗
The chemotherapy of rodent malaria. LX. The importance of formulation in evaluating the blood schizontocidal activity of some endoperoxide antimalarials.
The activities of artemisinin (QHS) and a number of its semi-synthetic analogues, as well as Fenozan B07 (B07), a synthetic 1,2,4-trioxane, and arteflene (ATF), a synthetic surrogate of yingzhaosu, were compared in mice infected with drug-sensitive Plasmodium berghei or chloroquine-resistant P. yoelii ssp. NS. The studies were stimulated by the observation that B07, in certain aqueous preparations, appears to be equipotent by the subcutaneous (sc) or oral (po) routes in the rodent model but not in a simian model. In the rodent model, B07 was found to undergo rapid alteration (with a half-life of <24h) in an aqueous stock solution prepared using dimethyl sulphoxide (DMSO) to pre-dissolve the drug. Therefore, for all later experiments with aqueous preparations, the test material was newly formulated each day. In a carboxymethylcellulose formulation used as a 'standard suspending vehicle' (SSV), B07 and dihydroartemisinin (DIHYD) were found to be, respectively, one sixth and one 10th as active po as when the drugs were pre-dissolved in DMSO and then diluted with water. ATF in DMSO given po was less than one 20th as active as when used sc in the rodent model, and this drug in SSV was almost inactive po. The relatively low oral activity of these three compounds (especially DIHYD and ATF) may be attributable to extensive first-pass metabolism in the mouse. Oral beta-artemether (AM) and beta-arteether (AE) were highly active when used in SSV. ATF has been found to have low activity in simian models and clinical trials because of its poor absolute bio-availability. In in-vivo studies of the blood schizontocidal action of anti-malarials, in rodent malaria models, the data collected on the structure-activity relationships (SAR) of the drugs must be viewed critically when selecting specific compounds from a chemical series for further development. A study of the influence of drug formulation on the activity of other, novel antimalarials is crucial to the evaluation of the drugs, and merits high priority.
Administration, Oral↗
Susceptibility of nonhuman primates to carcinogens of human relevance.
Nonhuman primates are a valuable experimental model for the evaluation of human carcinogenic risk but have not been widely used for various reasons, such as high cost and lack of availability. The present review discusses the findings from a long-term carcinogenesis study in nonhuman primates that was carried out under contract by the National Cancer Institute from 1961 to 1997. Among the classes of compounds investigated were model rodent carcinogens, food additives, food and environmental contaminants, heterocyclic amines, N-nitroso compounds, and antineoplastic and immunosuppressives. Of the model rodent carcinogens tested, only urethane was carcinogenic in monkeys. Long-term administration of saccharin or cyclamate did not result in toxicity or carcinogenicity in nonhuman primates, which is commonly seen in rodent models. Similar to rodent models and suspected in the human population, the fungal toxins, aflatoxin B1 and sterimatocystin, induced malignant liver tumors in monkeys. Relatively few animals administered DDT developed malignant tumors, however, hepatic and CNS toxicity was commonly observed. Hepatocellular carcinoma developed in a majority of monkeys administered the heterocyclic amine, IQ but not the structurally similar MeIQx. Resultant toxicity and carcinogenicity from N-nitroso compounds was variable. While diethylnitrosamine proved to be the most potent hepatocarcinogen tested, no malignant tumors were seen in animals administered N-methyl-N-nitro-N-nitrosoquanidine. Susceptibility of nonhuman primates to chemotherapeutic agents was also variable. Only procarbazine and N-methyl-N-nitrosourea were highly carcinogenic, whereas few tumors were seen as a result of cyclophosphamide, Adriamycin, melphalan, or azathioprine.
Animals↗
Use of rodents as models for the study of "normal aging": conceptual and practical issues.
Certain guidelines may exist for selecting and using rodent models for aging research. These are based, however, on only operational criteria because we presently lack good biomarkers for (or even a suitable definition of) normal aging. Longevity and disease characteristics of the experimental population are the most important of the operational criteria for choosing a particular rodent model. These factors, in turn, are influenced by genetics and by environmental factors, including diet, housing, and physical activity.
Aging↗
Dark lumen magnetic resonance colonography in a rodent polyp model: initial experience and demonstration of feasibility.
PURPOSE: We sought to assess dark lumen magnetic resonance (MR) colonography for the detection of colon polyps in a rodent model with histology as the gold standard. MATERIAL AND METHODS: Fourteen male Wistar rats were subjected to carcinogenic N-methyl-N'-nitro-N-nitrosoguanidine at the age of 4 months to induce colon neoplasms. MR imaging was performed after a time interval of 1 year. Preparation and data acquisition was performed with the animals under full anesthesia. After a body-warm saline enema images were acquired on a clinical 1.5-T whole-body MR system using a standard extremity coil. Plain and contrast-enhanced (0.3 mmol/kg; Gd-DOTA; Dotarem, Guerbet, France) 3-dimensional T1-weighted gradient recall echo images were acquired. Two radiologists analyzed the MR data sets in consensus for lesion depiction. Contrast uptake in colonic wall and polyps was quantitatively assessed by signal-to-noise ratio and contrast-to-noise ratio measurements and compared using a Wilcoxon-Mann-Whitney U test with statistical significance at a P value < 0.05. Finally, all animals were killed, and the MR imaging results were compared with pathologic findings. Sensitivity and specificity were calculated. RESULTS: By pathology, a total of 15 polyps were found in 9 of 14 rats. MR colonography detected 13 of 15 polyps measuring between 4 and 11 mm (mean 7 +/- 0.6 mm) in 8 of 9 animals, resulting in a sensitivity and specificity of 0.87 and 1.0, respectively. Compared with the precontrast data, all polyps showed a statistically significant increase in signal-to-noise ratio (78.2 +/- 6.3 to 167.4 +/- 17.7) and contrast-to-noise ratio (45.4 +/- 5.2 to 124.6 +/- 11.2). CONCLUSION: MR colonography with a dark colon lumen and a bright, contrast-enhanced colon wall appears well suited for the detection of colonic lesions in a rodent model.
Animals↗
Relationships between sequestration, antigenic variation and chronic parasitism in Plasmodium chabaudi chabaudi--a rodent malaria model.
We describe here a rodent malaria model using cloned lines of Plasmodium chabaudi chabaudi in inbred CBA/Ca mice that exhibits both clonal antigenic variation in late stage-specific surface antigens, and deep vascular schizogony in the liver. We show that both these features are modulated by the spleen, and that surface antigen expression is crucially involved in the sequestering phenotype. Surface antigens are variant in chronic infection, and host protective immune responses can distinguish between these variants. Splenectomy abolishes this difference. The acute infection with non-sequestering cloned lines is kinetically indistinguishable from sequestering clones, but parasites unable to express variant sequestration-associated antigen do not form a chronic recrudescing infection. Another clone, able to re-express this antigen in the presence of the spleen, undergoes typical chronic recrudescence. In this model, the biological significance of sequestration-associated variant antigen seems to enable the establishment of chronic infection in the presence of a primed spleen.
Animals↗
Islet amyloid polypeptide (IAPP) transgenic rodents as models for type 2 diabetes.
Blood glucose concentrations are maintained by insulin secreted from beta-cells located in the islets of Langerhans. There are approximately 2000 beta-cells per islet, and approximately one million islets of Langerhans scattered throughout the pancreas. The islet in type 2 diabetes mellitus (T2D) has deficient beta-cell mass due to increased beta-cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). Accumulating evidence implicates toxic IAPP oligomers in the mediation of beta-cell apoptosis in T2D. Humans, monkeys, and cats express an amyloidogenic toxic form of IAPP and spontaneously develop diabetes characterized by islet amyloid deposits. However, longitudinal studies of islet pathology in humans are impossible, and studies in nonhuman primates and cats are costly and impractical. Rodent IAPP is not amyloidogenic, thus commonly used rodent models of diabetes do not recapitulate islet pathology in humans. To investigate the diabetogenic role of human IAPP (h-IAPP), several mouse models and, more recently, a rat model transgenic for h-IAPP have been developed. Studies in these models have revealed that the toxic effect of h-IAPP on beta-cell apoptosis demonstrates a threshold-dependent effect. Specifically, increasing h-IAPP transgene expression by breeding or induction of insulin resistance leads to increased beta-cell apoptosis and diabetes. These transgenic rodent models for h-IAPP provide an opportunity to elucidate the mechanisms responsible for h-IAPP-induced beta-cell apoptosis further and to test novel approaches to the prevention and treatment of T2D.
Amyloid↗
Preliminary report of a new rodent separation model of depression.
Phodopus sungorus, the Siberian dwarf hamster, exhibits an unusual set of behavioral changes when the members of a male-female pair bond are separated. Quantification of these behaviors reveals a significant increase in body weight, decrease in social interactions, and decrease in exploratory behaviors, predominantly in separated males. Preliminary data on antidepressant treatments to reverse the separation syndrome, and on neurochemical changes during the separation period, are presented. Separation of pair-bonded Siberian dwarf hamsters may provide a new animal model for depression, incorporating the practical advantages of a rodent model with the conceptual advantages of a naturalistic life event precipitant.
Animals↗
Broad sensitivity of rodent arrhythmia models to class I, II, III, and IV antiarrhythmic agents.
To determine specificity of rodent models of arrhythmia for different Vaughan Williams classes of antiarrhythmic drugs, we tested 17 drugs from the four classes in one in vitro and four in vivo models. In the mouse chloroform-induced ventricular fibrillation model and in the guinea pig ouabain-induced arrhythmia model, drugs of classes I (amefalone, aprindine, lidocaine, mexiletine, phenytoin, procainamide, or quinidine), II (metoprolol or propranolol), and IV (bepridil) were active. Class III drugs (bretylium, clofilium, or melperone did not suppress ouabain arrhythmias, but were active in the mouse chloroform model. In the rat coronary artery ligation model, disopyramide (class I), amefalone and melperone significantly (P less than 0.05) reduced the number of extrasystoles. Propranolol, sotalol, and verapamil (class IV) were less effective. In the rat coronary artery ligation/reperfusion model, all four classes of antiarrhythmic agents were active in vitro (isolated heart) and in vivo (anesthetized rat). Thus, one model of automaticity, the guinea pig ouabain model, detected class I, II, and IV drugs, whereas another automaticity model, the mouse chloroform model, also detected class III agents. The model of reentry induced by ischemia plus reperfusion (rat coronary artery ligation reperfusion) can be recommended as a screen for new antiarrhythmic agents based on its sensitivity to all four classes of antiarrhythmic drugs. The Vaughan Williams class of an antiarrhythmic agent must be determined, however, by additional mechanism studies.
Animals↗
The role of contortrostatin, a snake venom disintegrin, in the inhibition of tumor progression and prolongation of survival in a rodent glioma model.
OBJECT: Malignant gliomas are not curable because of diffuse brain invasion. The tumor cells invade the surrounding brain tissue without a clear tumor-brain demarcation line, making complete resection impossible. Therapy aimed at inhibition of invasion is crucial not only for prevention of tumor spread, but also for selectively blocking migrating cells that may be more resistant to chemotherapy and radiation. Recently, investigations have shown that the snake venom disintegrin contortrostatin specifically binds to certain integrins on the surface of glioma cells and thereby inhibits their interaction with the extracellular matrix (ECM), resulting in a blockage of cell motility and invasiveness. To translate these in vitro findings into clinical settings, the authors examined the effect of contortrostatin on glioma progression in a rodent model. METHODS: Athymic mice were intracranially or subcutaneously injected with U87 glioma cells, and the effect of intratumorally administered contortrostatin on tumor progression and animal survival was then studied. In addition, the authors evaluated the pharmacological safety of contortrostatin use in the brains of tumor-free animals. CONCLUSIONS: The results demonstrate that contortrostatin is able to inhibit tumor growth and angiogenesis and to prolong survival in a rodent glioma model. Moreover, contortrostatin appears to be well tolerated by the animal and lacks obvious neurotoxic side effects. Thus, contortrostatin may have potential as a novel therapeutic agent for the treatment of malignant gliomas.
Animals↗
An in vitro model of rodent nongenotoxic hepatocarcinogenesis.
An in vitro model of liver in which rat hepatocytes are maintained as cocultures with nonparenchymal epithelial cells (NPC) derived from liver has been developed and characterized with respect to maintenance of hepatocyte viability and differentiated function. The system was then evaluated as a model for studying peroxisome proliferator-induced rodent liver nongenotoxic carcinogenesis. Within the coculture model, hepatocyte viability and morphology were maintained for 1 month or more within a system that is both easily accessible for microscopic examination and is free of any additives that may lead to artifacts. Even after 1 month or more, hepatocyte cocultures retained expression of the constitutive liver marker albumin. In addition, they maintained the ability to show induction of the peroxisome proliferator-inducible enzymes peroxisomal bifunctional enzyme (PBE) and cytochrome P450IVA1 in response to the peroxisome proliferator nafenopin. After 4 weeks, NPC cocultures showed a six- and a fourfold induction of PBE and cytochrome P450IVA1 expression, respectively, which compared well with the three- and fivefold induction seen in freshly isolated cells. This was paralleled by an increase in the cytoplasmic volume fraction of peroxisomes averaging eightfold. Interestingly, great heterogeneity was exhibited between adjacent hepatocytes in terms of the degree of peroxisome proliferation, a finding reflected by immunocytochemical staining which indicated heterogeneity in the level of expression of the peroxisome proliferator-inducible enzymes. Other cell lines representing different tissue types, morphologies, and species were also examined for their ability to support hepatocyte survival but were found to be ineffective, with the exception of a bovine corneal endothelial cell line. This line supported hepatocyte survival and maintenance of differentiated function but to a lesser extent than that observed with NPC. Ultrastructural examination of NPC cocultures revealed extensive interhepatocyte junctional complexes and interdigitation of adjacent membranes together with the presence of bile canalicular structures. There were no junctional complexes between the hepatocytes and the supporting feeder cells with any contact being limited to a close association of the hepatocytes with the extracellular matrix presumably produced by the NPC. The data demonstrate that hepatocytes maintained in vitro within an NPC coculture system retain differentiated function and the ability to respond to the peroxisome proliferator class of nongenotoxic carcinogens. Cocultures will provide us with a model system for the study of changes in hepatocyte growth regulation during rodent liver nongenotoxic carcinogenesis.
3-Hydroxyacyl CoA Dehydrogenases↗