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PubMed1982

Cardiovascular complications.

This report summarizes the current state of knowledge concerning the cardiovascular system in various animal models of diabetes and presents their major strengths and weaknesses for studying the important research questions in the field. Nonhuman primates have many desirable features for studies on the macrovascular and cardiac complications of the disease as well as risk factor alterations, but their availability, cost, and maintenance present practical disadvantages. The spontaneous rodent models of diabetes currently are not considered very useful for cardiovascular research, but they have not been well characterized with respect to most aspects of their cardiovascular system. Alloxan-diabetic rabbits offer some promise for examining the effects of diabetes on atherogenesis, lipoprotein metabolism, and cardiomyopathy, but additional research is required to validate their usefulness. Insufficient data are available on canine and swine models of diabetes to judge their merits for cardiovascular research. The Task Force recommends: (1) additional longterm investigations to determine the extent and severity of cardiovascular complications in the well-characterized rodent models and in diabetic rodents with multiple risk factor abnormalities; (2) further studies on the macrovascular disease and lipoprotein abnormalities of the alloxan-diabetic rabbit and the development of rabbit colonies with spontaneous diabetes; (3) increased emphasis on such potentially important but neglected areas of research in diabetic animals as the intramyocardial circulation, adventitial blood vessels, blood pressure, platelet function, blood coagulation, blood rheology, and autonomic nervous function; (4) long-term studies on the influence of control of hyperglycemia and of insulin therapy on cardiovascular complications in diabetic animals; and (5) encouragement of use of diabetic nonhuman primates for cardiovascular research and institution of measures to increase their supply and availability by expanding current colonies, screening newly imported animals for diabetes, and establishing a visiting scientist's program allowing investigators to study diabetic primates at resource centers.

Animals↗
PubMed1992

Multiple oncogenes and tumor suppressor genes are structurally and functionally intact during hepatocarcinogenesis in hepatitis B virus transgenic mice.

In the current study we sought to elucidate the molecular mechanisms which might contribute to hepatocarcinogenesis in a hepatitis B virus (HBV) envelope transgenic mouse model in which chronic hepatocellular injury and inflammation lead to regenerative hyperplasia and eventually to the development of chromosomal abnormalities and hepatocellular carcinoma (HCC), thereby reiterating many of the pathophysiological events that occur prior to the development of HCC in chronic HBV infection in humans. We have previously demonstrated that HBV envelope gene expression is decreased in regenerating hepatocytes and preneoplastic nodules early in the disease process and that expression of alpha-fetoprotein and the multidrug transporter gene mdr-III is activated in the tumors that develop in this model, but not prior to tumor development. In the current study, we examined the structure and expression of a large panel of dominant acting oncogenes and tumor suppressor genes in the liver at all stages of the disease process in order to determine the extent to which they contribute to hepatocarcinogenesis in these transgenic mice. To our surprise, no changes were observed in the structure or function of any of these genes, many of which are commonly activated in other rodent models of hepatocarcinogenesis but rarely activated in human HCC. These findings suggest that the HBV transgenic mouse model is different from most other rodent models of hepatocarcinogenesis and that it may relate more closely to the events involved in HBV-induced human hepatocarcinogenesis, where generalized chromosomal abnormalities are common, while structural and functional changes in most of the commonly studied positive-acting oncogenes examined herein are not. Since p53 and RB mutations have recently been reported to be late events in human hepatocarcinogenesis, the structural integrity of the RB locus and the absence of p53 mutations in the HBV transgenic mouse model suggest that they may represent a relatively early stage of hepatocellular tumorigenesis and that further manipulation of this model is warranted in order to more fully reproduce the molecular-genetic events that characterize HBV-induced HCC in humans.

Animals↗
PubMed1998

Global primary blast injury: a rat model.

Blast wave injury from bombs cause a unique but poorly understood spectrum of injuries. Previous blast wave models involved high energy explosives detonated in an open field without the sophisticated monitoring of laboratory equipment. We characterized a rodent model that produces a global blast injury in a safe laboratory environment. Male rats, prospectively randomized to four groups of ten, were anesthetized and subjected to a blast at 2.0 cm, 2.5 cm, or 3.5 cm from the blast nozzle. The control group received no blast. Intensity of the blast (80-120 psi peak pressure, 1-2 msec duration) was controlled by varying the distance of the blast wave generator to the rat. The rats were monitored for three hours following the blast and then euthanized. Bradycardia was an immediate but transient response to blast injury. Mean arterial pressure was bimodal with severe hypotension occurring immediately after the blast and, again, two to three hours later. The characteristic injuries from a blast wave, such as pulmonary hemorrhage with increased lung weight, intestinal serosal hemorrhage, and hemoperitoneum, were found in the rats subjected to the blast pressure wave. In conclusion, our rodent model accurately reproduces the clinical spectrum of injuries seen in blast victims and will provide a powerful tool for studying the pathophysiology and potential treatments of bomb blast victims.

Analysis of Variance↗
PubMed2003

Microsurgical intraluminal middle cerebral artery occlusion model in rodents.

OBJECTIVES: Focal brain ischemia induced in rodents by occlusion of the middle cerebral artery (MCA) is a widely used paradigm of human brain infarct. The objective of this study is to compare the effectiveness and reproducibility of MCA filament occlusion model in rats and mice. MATERIALS AND METHODS: A total of 140 rodents (69 rats and 71 mice) were operated. Ninety-five animals were subjected to MCA occlusion; the surgical procedure consisted of introducing an uncoated surgical nylon monofilament into the cervical common carotid artery (CCA) and advancing it intracranially to permanently block blood flow into the right MCA. Forty-five sham-occluded rodents underwent CCA ligation. Surgical success, autopsy confirmed success and mortality rate were evaluated. Effective MCA occlusion was confirmed by the evidence of motor neurological deficit, by histopathology, immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction (RT-PCR). IHC was performed in a randomly selected number of animals to detect the protein product of monocyte chemoattractant protein-1. The brain tissue in mice was examined by RT-PCR for the expression of macrophage inflammatory protein-1 alpha mRNA. RESULTS: Surgical success rate was 89% in the rats, significantly lower than that in the mice (100%, P < 0.05). Autopsy confirmed success rate in the rats, 60%, was also significantly different from that in the mice (92.5%, P < 0.001). The operative mortality rate was 4.3% in the rats and 15% in the mice. CONCLUSION: The present study demonstrates that the microsurgical filament occlusion of the MCA can be more successfully performed in mice. The lower rate of success in rats seems to be as a result of the architecture of the carotid canal in this animal. No previous reports, using a considerable number of animals, have compared the feasibility of intraluminal model in the rat with that in the mouse.

Animals↗
PubMed1994

Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents.

This study investigated behavioural effects of very potent 5-HT reuptake inhibitors after acute treatment (cianopramine and citalopram), as well as after chronic treatment (cianopramine), in two behavioural models of anxiety: 1) the light/dark choice procedure in mice and 2) the elevated plus-maze test in rats. In addition, the responses of mice to novelty in a free exploration paradigm were assessed after acute administration of both drugs. A single injection of cianopramine or citalopram increased neophobic reactions in the free exploration test. Furthermore, these drugs increased the avoidance reaction to a brightly illuminated chamber in the light/dark choice procedure as well as to open arms in the elevated plus-maze test. In contrast, after chronic treatment (10 mg/kg IP, once daily for 21 days) of cianopramine, anxiogenic-like effects were no longer produced in the light/dark choice paradigm whereas in the elevated plus-maze test, anxiolytic-like effects appeared. These results shed more light on the 5-HT hypothesis of anxiety, insofar as the increased availability of 5-HT resulting here from reuptake inhibition seems to initially result in an increased emotional reactivity which, however, subsequently disappears during chronic treatment.

Animals↗
PubMed2002

Neuroleptic-like profile of the cannabinoid agonist, HU 210, on rodent behavioural models.

(1) The present study was performed to assess the effects exerted by the cannabinoid (CB) agonist, (-)11-hydroxy-delta8-tetrahydrocannabinol-dymethylheptyl (HU 210; 12.5-50 microg/kg ip), on rodent behavioural tests involving dopamine (DA) transmission; in comparison, the DA D2 antagonist, S(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxy-benzamide hydrochloride ((-)eticlopride; 50 microg/kg sc), was used. (2) In rats, HU 210, at all doses, potently antagonized penile erection (PE) and stretching-yawning (SY) typically elicited by the DA D2/D3 agonists, 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine (B-HT 920) and +/-7-hydroxy-N,N-di-n-propylaminotetralin hydrobromide (7-OH-DPAT) both at 100 pg/kg ip. (3) In nonreserpinized mice, HU 210 impaired motor ability assessed by means of a motor test battery, and B-HT 920 (1 mg/kg ip) worsened the phenomenon. (4) In reserpinized mice, HU 210 at 50 microg/kg counteracted the amelioration exerted by B-HT 920 (1 mg/kg ip) on reserpine-induced akinesia. (5) As all these effects were similarly displayed by (-)eticlopride (50 microg/kg sc), our data suggest a neuroleptic-like profile of acute HU 210 in animal behavioural tests.

Animals↗
PubMed2000

Investigations of the metabolites of the trypanocidal drug melarsoprol.

BACKGROUND: Melarsoprol remains the first-choice drug for trypanosomiasis (human African sleeping sickness). To contribute to the sparse pharmacologic data and to better understand the cause of the frequent serious adverse reactions, we investigated the metabolism of this 50-year-old organoarsenic compound. RESULTS: The half-life of melarsoprol determined by HPLC was <1 hour compared with 35 hours determined by bioassay and atomic absorption spectroscopy, indicating the existence of active metabolites. One metabolite, melarsen oxide, was identified by ultraviolet HPLC after incubation of melarsoprol with microsomes. The maximum plasma concentration of melarsenoxide was reached 15 minutes after administration; the clearance was 21.5 mL/min/kg and the half-life of free melarsen oxide was 3.9 hours. Either melarsen oxide or a yet-undiscovered active metabolite is irreversibly bound to proteins, as shown by ultrafiltration, precipitation experiments, and atomic absorption spectroscopy. Because of the poor pharmaceutical properties of melarsoprol, the therapeutic potential of melarsen oxide was investigated. In a rodent model of acute infection, 20 of 20 mice were cured (0.1 to 1 mg/kg intravenously or 2.2 mg/kg intraperitoneally). In a rodent model of central nervous system infection, five of six mice survived for more than 180 days (5 mg/kg intravenously), indicating a sufficient melarsen oxide penetration across the blood-brain barrier. CONCLUSION: The prospects for the future of trypanosomiasis treatment are deplorable. Investigations on the improvement of the use of the old drugs are therefore required. The results of this study may build a basis for further research on the cause of severe adverse reactions.

Adult↗
PubMed2003

Changes of metabotropic glutamate receptor subtype 1a in diffuse brain injury with secondary brain insults and the effects of 2-methyl-4-carboxyphenylglycine.

OBJECTIVE: To observe the changes of metabotropic glutamate receptor 1a in rat brain in a rodent model of diffuse head injury with secondary insults and the effects of 2-methyl-4-carboxyphenylglycine (MCPG). METHODS: Based on Marmarous rodent model of diffuse brain injury (DBI), hypotension was made by blood withdrawal as secondary brain insults (SBI). 105 male SD rats were randomized into A and B groups. The changes of mGluR(1a) in cerebral cortex were studied by immunohistochemistry and the effect of MCPG by HE. Each group was divided into different subgroups at different time after injury. RESULTS: Compared with that of sham group, the number of mGluR(1a) positive neuron increased by 12.9+/-3.2 (P<0.05) 1 day after injury in the injured cerebral cortex in DBI group. However, in DBI and SBI group there was a more significant increase in the number of mGluR(1a) positive neuron at 4 hours after injury (15.6+/-3.0, P<0.05) and then the number of mGluR(1a) positive neuron gradually decreased. Administration of MCPG reduced total cortical necrotic neurons counts on the 7th day after injury (5.21+/-2.52, P<0.05). CONCLUSIONS: Brain injury can increase the gene expression of mGluR(1a) and the role of mGluR(1a) may be a key factor in the aggravation of head injury with SBI, and that MCPG may have therapeutic potential in head injury.

Analysis of Variance↗
PubMed1989

Induction of hepatocellular carcinoma in nonhuman primates by chemical carcinogens.

Several compounds were evaluated in nonhuman primates for their potential to induce neoplasms, especially hepatocellular carcinoma (HCC). The compounds can be classified into three groups: food contaminants, model rodent carcinogens, and nitrosamines. All three compounds in the food contaminants group, namely, aflatoxin B1, sterigmatocystin, and methylazoxymethanol acetate, induced HCC. None of the model rodent carcinogens tested consistently induced HCC in rhesus and cynomolgus monkeys. Three of four nitrosamines evaluated induced HCC in rhesus and cynomolgus monkeys. One nitrosamine, diethylnitrosamine, is a predictable and potent inducer of HCC and is useful for establishment of a nonhuman primate model for numerous oncologic studies.

2-Acetylaminofluorene↗
PubMed1998

Repair of nasal defects using collagen gels containing insulin-like growth factor 1.

OBJECTIVE: Facial osseous defects are a common and challenging problem for the otolaryngologist-head and neck surgeon. Current methods of repair including synthetic grafts, cadaveric material, and autologous tissue have drawbacks of foreign body reactions, infectious agent transmission, and the morbidity of a second surgical site. In the effort to develop an ideal technique for osseous reconstruction, a critical-size facial defect has previously been developed in the Sprague-Dawley rat. This model exhibits less than 10% healing by surface area over 6 months. A novel approach to osseous reconstruction is attempted using this model with type I collagen gel augmented with insulin-like growth factor 1 (IGF-1). STUDY DESIGN: Randomized controlled trial using a rodent model. METHODS: Twelve adult male Sprague-Dawley rats underwent a surgical procedure to produce a critical-size nasal defect by removing the nasal bones with a cutting burr. Six animals were repaired with 300 microg of type I collagen gel. Six animals were repaired with 300 microg of type I collagen gel augmented with 3.0 microg of IGF-1. Thirty days later, the animals were examined after necropsy. Precise planimetry, radiodensitometric analysis, and histologic sectioning were performed. RESULTS: All animals had complete coverage of this defect with a thin layer of bone. Radiodensitometric analysis indicated that there was a statistically significant (P < .037) increase in bone density in the collagen plus IGF-1 group compared with that of collagen only. In addition, histologic evaluation revealed increased bone density and thickness in the IGF-1 group. CONCLUSION: Type I collagen gel augmented with IGF-1 results in a significant increase in healing of a nasal critical-size defect in a rodent model.

Absorptiometry, Photon↗
PubMed2005

Functional abnormalities in isolated arteries from Goto-Kakizaki and streptozotocin-treated diabetic rat models.

Several different rat models have been developed for both type 1 and type 2 diabetes with the aim of displaying specific traits of diabetes. For example, a review on nephropathy associated with type 2 diabetes included 16 different rodent models ; new models are still being developed. The large number of different models developed for different traits makes it difficult to choose the right model for a given study. It is often a problem that the models are not sufficiently characterized, which makes it easy to misinterpret data or even come to the wrong conclusions. In this brief review, we will concentrate on the functional responses obtained in vitro from mesenteric arteries and aortic segments from rat models of diabetes. Since it is beyond the scope of this review to overview all different rodent models of diabetes, we will focus on two commonly used models of diabetes, namely the streptozotocin (STZ)-induced type 1 diabetic rat model and the inbred type 2 diabetic Goto-Kakizaki (GK)-rat model.

Animals↗
PubMed2002

The neurobiology of social recognition, approach, and avoidance.

Rodent models of social behavior provide powerful experimental tools for elucidating the molecular, cellular, and neurobiological mechanisms regulating social behavior. Here I discuss several rodent models that have been particularly useful in understanding the neurobiology of the discrimination of social verses nonsocial stimuli, affiliative behavior, and social avoidance. The oxytocin knockout mouse model has been useful for understanding how, in the context of social recognition, the brain may process social stimuli differently from nonsocial stimuli. Vole species that are either highly social and monogamous or solitary and promiscuous have provided a model for investigating the brain mechanisms involved in promoting social interactions. Comparative studies in these species strongly implicate the neuropeptides oxytocin and vasopressin in the regulation of affiliative behavior as well as social attachment. A conditioned defeat model in hamsters may provide a useful model to understand how adverse social experiences may facilitate social avoidance. These models have yielded valuable insights into the regulation of social behaviors, and the findings of these studies may prove useful in understanding the neural mechanisms that underlie individual differences in human personality traits.

Animals↗
PubMed1998

Microvascular hemodynamics and in vivo evidence for the role of intercellular adhesion molecule-1 in the sequestration of infected red blood cells in a mouse model of lethal malaria.

The cytoadherence of infected red blood cells (IRBCs) to the vascular endothelium is the major cause of IRBC sequestration and vessel blockage in the cerebral form of human malaria. Among the rodent models of malaria, Plasmodium yoelii 17XL-infected mice show many similarities with the human cerebral malaria caused by P. falciparum. In both, the sequestration of IRBCs in the brain vessels is secondary to the cytoadherence of IRBCs to the vascular endothelium. Similar to P. falciparum infection in the human but in contrast to P. berghei ANKA infection in mice, P. yoelii 17XL results in little, if any, accumulation of monocytes in the brain. In vivo microcirculatory studies reported here were designed to further understand the hemodynamic aspects and mechanisms underlying cytoadherence of IRBCs in the P. yoelii model using the easily accessible cremaster muscle vasculature. The results show significant decreases in arteriovenous red blood cell velocities (Vrbc) and wall shear rates in the microcirculation of P. yoelii-infected mice, with a maximal decrease occurring in small-diameter postcapillary venules, the main sites of cytoadherence. This reflects contributions from IRBC cytoadherence as well as from increased rigidity of parasitized red blood cells. No cytoadherence is observed in arterioles of the infected mice despite decreased wall shear rates, indicating that endothelial receptors for cytoadherence are restricted to venules. Infusion of a monoclonal antibody (MAb) against the intercellular adhesion molecule-1 (ICAM-1) resulted in significant increases in both arteriolar and venular Vrbc and wall shear rates, accompanied by detachment of adhered IRBCs at some venular sites. The peripheral blood smears taken after the MAb infusion showed a distinct increase in the percentage of schizonts, again indicating detachment and/or prevention of cytoadherence. An MAb against the vascular cell adhesion molecule-1 (VCAM-1) as well as an irrelevant control antibody had no effect on these parameters. These results provide the first in vivo microcirculatory evidence indicating involvement of ICAM-1, but not of VCAM-1, in the sequestration of IRBCs in a rodent model of cerebral malaria.

Animals↗
PubMed1988

Comparative biology of test species.

This paper assesses the capacity of animal models to predict human response to carcinogenic agents with consideration for the heterogeneity of humans. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. Conventional rodent models are usually highly inbred and valued for their ability to display characteristic homogeneity. Current practice assumes that the homogeneity of response to toxic agents, including carcinogens, in the rodent model will be representative of humans. The issue then becomes, To which of the broad spectrum of human responses are specific animal models likely to be related? This paper examines the extent of human heterogeneity over a broad range of biochemical characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, beta-glucuronidase activity, debrisoquine hydroxylation, DNA-adduct formation) with emphasis on those biochemical characteristics that affect responses to carcinogens. Examples are presented to compare the heterogeneity of selected animal models for these biochemical characteristics as they relate to the spectrum of human responses noted above. The paper presents a theoretical perspective for determining to which part of the human population response spectrum common animal models are most likely to be extrapolated.

Animals↗
PubMed1984

Adherence of Candida species to human epidermal corneocytes and buccal mucosal cells: correlation with cutaneous pathogenicity.

Adherence of microorganisms to epidermal corneocytes may be a prerequisite for cutaneous colonization and infection. Six species of Candida were assayed in vitro for adherence to human epidermal corneocytes and buccal mucosal cells, and compared to previous studies of pathogenicity in a rodent model of cutaneous candidiasis. C. albicans and C. stellatoidea exhibited marked adherence to both epithelial cell types over time, and were cutaneous pathogens in the rodent model. The remaining species showed little or no adherence, and were nonpathogenic to skin. Adherence to corneocytes was not inhibited by ethylenediamine tetraacetic acid, mannan polysaccharide, or concanavalin A lectin. Fresh human serum, but not heat-inactivated serum, inhibited C. albicans adherence by 50%, and was associated with the deposition of complement components, C3 and factor B on blastospores. Adherence to epithelial corneocytes and mucosal cells is a property of pathogenic species of Candida, and may participate in cutaneous colonization and infection mechanisms. Adherence was time-dependent, and did not require divalent cations. Cell wall mannan may participate in the "adhesin" complex. Mannan activation of serum complement and deposition of C3 and factor B on blastospores may provide a protective action by inhibiting Candida adherence to corneocytes.

Candida↗
PubMed2006

Proinflammatory cytokines in granulomas associated with murine cysticercosis are not the cause of seizures.

Neurocysticercosis is a parasitic infection of the human central nervous system caused by the cestode Taenia solium. The most common clinical manifestations of neurocysticercosis are seizures. Taenia crassiceps cysticercosis in mice has been used as an experimental model for T. solium cysticercosis. Granulomas surrounding murine cysticerci have striking immunopathological resemblance to human neurocysticercosis; early stage granulomas were able to induce seizures in a rodent model. To assess the role of proinflammatory cytokines in early stage granulomas, we isolated RNA from murine cysticercal granulomas and checked for cytokine expression by reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ribonuclease (RNase) protection assays. Cytokine expression was compared with histological stages. Interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist, and tumor necrosis factor (TNF-alpha) were the major cytokines detected in all granulomas. Signals for IL-12, IL-18, and IL-6 RNA were not consistently detected and, when detected, were barely demonstrable. Expression of migration inhibitory factor (MIF), IL-6, IL-1alpha, TNF-alpha, and IL-18 was not significantly different between early and late-stage granulomas. Expression of IL-1beta, IL-1 receptor antagonist, and IL-12 p40 were higher in late, compared with early, stages. Thus, we demonstrated a broad range of cytokines in these granulomas. However, we did not document preferential expression of any proinflammatory cytokines in early stage granulomas. Thus, proinflammatory cytokines are not responsible for the seizures in the rodent model of neurocysticercosis.

Animals↗
PubMed2004

Prevention of breast cancer by recapitulation of pregnancy hormone levels.

At the present time, the only approved method of breast cancer prevention is use of the selective estrogen receptor modulator (SERM) tamoxifen. Many breast cancers are driven to grow by estrogen, and tamoxifen exploits this by blocking estrogen action at the estrogen receptor. A counter-intuitive and controversial approach to breast cancer prevention is administration of estrogen and progestin at an early age to achieve pregnancy levels. This approach is supported by the fact that breast cancer incidence is halved by early (< or = 20 years of age) full-term pregnancy. Moreover, it has been demonstrated in rodent models that mimicking the hormonal milieu can effectively prevent carcinogen-induced mammary cancer. In this issue of Breast Cancer Research Rajkumar and colleagues use the rodent model to further define the timing and type of hormonal therapy that is effective in preventing mammary carcinogenesis. Clearly, application of this approach in humans may be difficult, but the potential benefit is intriguing.

Animals↗
PubMed1997

Preliminary evaluation of primaquine activity on rodent malaria model after transdermal administration.

The aim of this preliminary study was to investigate the potential use of the transdermal route for primaquine administration in the treatment of malaria. Thus the activity of this drug on asexual blood forms of two rodent malaria parasites (P. v. petteri and P. y. nigeriensis) was evaluated following a single TTS patch application. Sustained plasma concentration values were observed for about 60 hours. The results obtained from a prepatency test showed that primaquine was more active towards P. v. petteri than P. y. nigeriensis. This preliminary study showed that the transdermal route for primaquine administration may be a promising strategy for improving the treatment of malaria in both causal prophylactic and prevention of relapses infection.

Administration, Cutaneous↗