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PubMed1996

Effect of age in rodent models of focal and forebrain ischemia.

BACKGROUND AND PURPOSE: The majority of animal experiments examining the nature and treatment of stroke have used relatively young animals ranging in age from 2 to 6 months. However, significant morphological, neurochemical, and behavioral changes occur with aging in rodents particularly during the first 24 months of age. This study examines the effect of age in two models of transient ischemia a forebrain and a focal model in male Wistar rats. METHODS: We induced forebrain ischemia of 12 minutes duration by bilateral carotid artery occlusion with controlled hypotension at a mean blood pressure of 45 mm Hg and using an intraluminal filament technique, induced focal middle cerebral artery occlusion of 100 minutes duration at a mean blood pressure of 60 mm Hg. Physiological parameters were monitored and maintained within normal limits. On day 7 after ischemia, the rats were perfusion-fixed and the brains removed for quantitative histopathology. RESULTS: After forebrain ischemia, older rats showed significantly less CA1 neuronal necrosis than the younger group (P < .003), whereas both striatal and neocortical injury were significantly greater in the older group (P < .05). Among animals subjected to focal ischemia, the volume of infarcted tissue and the number of necrotic neurons in the area adjacent to the infarction were both greater in older rats (P < .05). CONCLUSIONS: This study emphasizes the importance of age in models of forebrain and focal ischemia. The interaction between age-related changes in morphology, neurochemistry, and behavior on the ischemic cascade complicates the interpretation of mechanistic data, and pharmacological effects observed in younger animals may not necessarily translate to an older population.

Aging↗
PubMed1996

Altered c-fos expression in the parabrachial nucleus in a rodent model of CFA-induced peripheral inflammation.

Increases in the expression of immediate early genes have been shown to occur in the lumbar spinal cord dorsal horn after peripheral inflammation. Given that the pontine parabrachial nucleus has been implicated in nociceptive as well as antinociceptive processes and is reciprocally connected with the spinal cord dorsal horn, it seems likely that peripheral inflammation will cause alterations in immediate early gene expression in this nucleus. To test this hypothesis we examined cFos-like immunoreactivity in a rodent complete Freund's adjuvant-induced peripheral inflammatory model of persistent nociception. Unilateral hind paw injections of complete Freund's adjuvant produced inflammation, hyperalgesia of the affected limb, and alterations in open field behaviors. Immunocytochemical analysis demonstrated a bilateral increase in cFos-like immunoreactivity in the lateral and Kolliker-Fuse subdivisions of the parabrachial nucleus at 6 and 24 hours postinjection and an ipsilateral decrease below basal levels in the Kolliker-Fuse subdivision at 96 hours postinjection when compared to saline controls. Taken together, these results suggest that select parabrachial neurons are activated by noxious somatic inflammation. These active parabrachial neurons are likely to participate in ascending nociceptive and/or descending antinociceptive pathways.

Animals↗
PubMed1991

Laboratory rodent models for the tapeworm-stage of Taenia saginata and other related taeniid species.

Attempts were carried out to establish alternative definitive host systems for Taenia saginata, T. crassiceps, T. hydatigena, Echinococcus multilocularis and E. granulosus, in rodents. Following oral inoculation of cysticerci or protoscoleces, the tapeworm-stage development and sexual maturation of the 5 taeniid species in the intestine of a golden hamster (GH) and Mongolian gerbil (MG), both treated with prednisolone, were examined. Sexually mature T. saginata tapeworms were recovered from MG pretreated with prednisolone. The life cycles of E. multilocularis can be completed in MG and T. crassiceps in both MG and GH. T. hydatigena and E. granulosus developed to a certain extent at the tapeworm stage in MG pretreated with prednisolone. Potential use of rodents as an alternative definitive host for taeniid species is discussed.

Animals↗
PubMed1993

Rodent models for targeted oncogenesis of the prostate gland.

Currently, prostate cancer ranks as the most frequent non-skin malignancy detected in males. Yet, of the major human cancers, it remains one of the least understood in terms of its molecular and genetic basis. Research on prostate cancer has been limited by the paucity of tissues available for study. Much of the tissue obtained through surgery for localized prostate cancer will be required for pathological staging and grading. The more aggressive forms of prostate cancer are usually detected subsequent to metastatic involvement at which point there is little reason to surgically remove the prostate tumor(s). A final complication is the propensity of prostate cancer to metastasize to the bone, a site extremely difficult to obtain suitable biopsies for study. Further hindering research efforts on prostate cancer is the lack of suitable animal models for study. In contrast to its frequent occurrence in humans, prostate cancer is a rare event in most other mammalian species, particularly laboratory rodents. Therefore, in order to make this disease more amenable for study, there is a growing effort to identify or develop a means to target oncogenesis to the prostate gland of rodents. As will be reviewed here, this goal is being approached with the use of 3 different methods; one that takes advantage of the unique androgenic hormone requirement for prostate growth to exaggerate the effects of carcinogens at that site and two methods (recombinant retrovirus transduction prior to organ reconstitution and transgenic targeting) that allow direct genetic manipulation of cells in the prostate gland leading to the development of prostatic malignancy.

Animals↗
PubMed2003

Ultrasound measurement of aortic diameters in rodent models of aneurysm disease.

BACKGROUND: This investigation was undertaken to evaluate transabdominal ultrasound (US) measurements of aortic diameters in rats and mice as a complementary method to video microscopy (VM), the current standard for assessing the diameter of rodent aortas. METHODS: Aortic diameters were measured in 64 rats (n = 132 sets) and 12 mice (n = 36 sets) following experimental induction of aortic aneurysms. Diameters were measured at the renal vein, midinfrarenal aorta, and aortic bifurcation. RESULTS: In the rat, anteroposterior (AP) US measurements were closely correlated with transverse VM measurements, with correlation coefficients ranging from 0.66 to 0.77 (P < 0.0001) for axial US images and 0.58 to 0.63 (P < 0.0001) for sagittal US images. In the mouse, significant correlation coefficients were 0.57 (P < 0.001) near the renal vein and 0.44 (P = 0.007) at the midinfrarenal aorta. Aortic diameters increased significantly with increasing animal age and weight (R = 0.40, P = 0.003 at the renal vein, R = 0.29, P = 0.04 in the midinfrarenal aorta, and R = 0.39, P = 0.004 at the aortic bifurcation), suggesting that weight matched rodents must be used to define aortic dimensions in treatment groups as opposed to repeated comparisons with baseline measurements in a growing rat. CONCLUSION: Noninvasive aortic US measurements throughout the course of a rodent study of aneurysmal disease provide a practical alternative to VM for the repeated determinations of aortic diameters.

Animals↗
PubMed1998

Aged-rodent models of long-term growth hormone therapy: lack of deleterious effect on longevity.

Studies were carried out to examine the effects of long-term recombinant human growth hormone (GH) therapy on longevity in rodents. In the first study, 150 18-month-old female F344 rats were divided into three groups of 50 rats per group: Group 1, solvent vehicle; Group 2, 10 microg GH/kg body weight three times per week; Group 3, 50 microg GH/kg body weight three times per week. GH and solvent vehicle therapies were started at 18 months of age and continued until all the animals died spontaneously. Serum insulin-like growth factor (IGF)-I was measured at 18 and 29 months of age and on 3-month-old rats. Serum IGF-I level decreased between 3 and 29 months of age. GH therapy reversed the decrease in a dose-dependent manner, with the 50 microg GH dose returning the serum IGF-I level to that of 3-month-old animals. However, statistical analysis revealed no significant effect of GH therapy on median life span, 10th percentile life span, or maximum life span. Similar observations on longevity were made on aged F344 male rats and on aged Balb/c mice, even when the dose of GH was increased to 1.0 mg/kg body weight two times per week. The main pathologic lesions in control animals were nephropathy, cardiomyopathy, leukemia, and testicular interstitial cell tumor; the prevalence of these lesions was not significantly altered by GH therapy. We conclude that long-term low-dose GH therapy that includes doses in the range that is given to humans in clinical trials in GH deficiency and to revert age-related physiologic declines has no overt deleterious effects on longevity and pathology in aged rodents.

Aging↗
PubMed2006

Effect of artesunate and artemether against Clonorchis sinensis and Opisthorchis viverrini in rodent models.

Food-borne trematodiasis is an emerging public health problem and there is a need to develop novel treatment options. We examined the in vivo efficacy of single oral doses of artesunate and artemether administered to rodents experimentally infected with either Clonorchis sinensis or Opisthorchis viverrini. Rats infected with adult C. sinensis were administered artesunate or artemether at doses of 75, 150 or 300 mg/kg. Hamsters infected with adult O. viverrini were administered artesunate or artemether at doses of 200, 400 or 600 mg/kg. Treatment efficacy was assessed according to reductions in worm burden compared with infected but untreated control animals. Worm burden reductions of 98.6-100% were found in C. sinensis-infected rats after a single dose of artesunate and artemether at 150 mg/kg. Administration of artesunate and artemether at a dose of 400mg/kg to O. viverrini-infected hamsters resulted in worm burden reductions of 77.6% and 65.5%, respectively. However, both drugs showed toxic effects when administered to O. viverrini-infected hamsters at a dose > or =400mg/kg. Our study demonstrates that artesunate and artemether possess excellent clonorchicidal activities in vivo. These findings provide a foundation for subsequent clinical trials. More laboratory investigations are warranted to investigate further the opisthorchicidal properties of the artemisinins.

Animals↗
PubMed2006

[NEMOes, a new method to evaluate early atherosclerosis in rodent model].

We recently established new en face method for optimal observation of endothelial surface(NEMOes) that enabled us to obtain clear images of the entire endothelial surface, including at arterial bifurcations, and to quantitate the number of cells of interest in the rodent endothelium. Using this method, we found that not only advanced glycosylation endproducts, but also glucose spike induced a significant increase in the number of macrophages adhering to the endothelium. NEMOes may be a promising tool for understanding the pathophysiology of atherosclerosis.

Animals↗
PubMed1996

DNA vaccines against malaria: immunogenicity and protection in a rodent model.

Since the first demonstration of the technology a few years ago, DNA vaccines have emerged as a promising method of vaccination. In a variety of experimental systems, DNA vaccines have been shown not only to induce potent immune responses, but also to offer many advantages in terms of ease of construction, testing, and production. In this article we summarize the progress achieved in development of DNA vaccines that can protect mice from infection by the rodent malaria parasite Plasmodium yoelii, describe initial studies of immunogenicity of a malaria DNA vaccine in a primate model, and outline the strategies being employed to design the next generation of malaria DNA vaccines.

Animals↗
PubMed1995

Rodent model of systemic mammary tumor disease by surgical removal of the spontaneously metastasizing SMT2A mammary carcinoma: inhibitory effect of the stable prostacyclin analogue cicaprost on occult metastasis.

Cicaprost, a stable prostacyclin analogue, has been shown to be anti-metastatically active in a series of metastasizing rodent tumors. Start of treatment with cicaprost immediately before tumor implantation was a characteristic feature of our previous investigations. We have reported that in rats bearing mammary-fat-pad-implanted SMT2A mammary carcinoma, cicaprost treatment starting before tumor implantation led to a strong decrease in the number of lung metastases. In order to determine the effect on occult tumor metastasis, the present study examined the effect of starting treatment when tumor metastasis is already present. Cicaprost in daily oral doses of 0.1 mg/kg given from day 10 to day 32 reduced the number of lung metastases by about 75% compared with the control, whereas surgical removal of palpable primary tumors on day 5 or day 10 failed to influence lung metastasis. Using different treatment schedules, a pronounced reduction of the number of lung metastases was achieved by administration of cicaprost until the end of the experiment (from day 5 to day 35), whereas short-term treatments (from day 5 to day 15 or to day 25) were without significant effect. In rats whose SMT2A tumors were surgically removed 10 days after tumor implantation, there was a strong decrease of lung metastases by cicaprost given from day 20 to day 36. In addition to its inhibitory potential in animals with advanced tumor disease, cicaprost showed anti-metastatic action when used in peri-operative treatment of animals whose primary tumors had been removed. In conclusion, the present results demonstrate that cicaprost exhibits strong anti-metastatic activity in the SMT2A rat mammary-carcinoma model with treatment started when occult tumor metastases are already present. Results also indicate that direct effects on tumor cells may contribute to the anti-metastatic action of cicaprost in spontaneously metastasizing tumors.

Adipose Tissue↗
PubMed1998

Cardiac arrhythmia induction after exposure to residual oil fly ash particles in a rodent model of pulmonary hypertension.

Recent epidemiological studies have reported a positive association between exposure to ambient concentrations of particulate matter (PM) and the incidence of cardiopulmonary-related morbidity and mortality. The present study examined the effects of fugitive residual oil fly ash (ROFA) PM on cardiac arrhythmia induction in healthy and cardiopulmonary-compromised rodents. Male Sprague-Dawley rats were implanted with radiotelemetry transmitters capable of monitoring the electrocardiogram and were subjected to one of two treatment regimens. Rats in the first treatment regimen (n = 16) served as normal control animals whereas rats in the second treatment regimen (n = 16) were injected with monocrotaline (MCT, 60 mg/kg, ip) to induce pulmonary vascular inflammation and hypertension and served as a model of cardiopulmonary disease. Rats within each treatment regimen were equally divided into four dose groups (0.0, 0.25, 1.0, 2.5 mg ROFA), instilled intratracheally, and monitored for 96 h. In the animals in the first treatment regimen, ROFA instillation caused dose-related increases in the incidence and duration of serious arrhythmic events that appeared to be associated with impaired atrioventricular conduction and myocardial hypoxia. There were no lethalities in the normal animals following ROFA instillation. The frequency and severity of arrhythmias were greatly exacerbated in the MCT-treated animals in the second treatment regimen and were accompanied by one, three, and two deaths in the low-, medium-, and high-dose groups, respectively. The results of the present study demonstrate substantial cardiac effects in normal and compromised rats after exposure to ROFA PM and implicate both conductive and hypoxemic arrhythmogenic mechanisms in the observed cardiac-related lethalities. These results support previous epidemiological studies that suggest a link between preexisting cardiopulmonary disease and potentiation of adverse health effects following exposure to anthropogenic particulates.

Animals↗
PubMed1995

Onchocerca volvulus larval antigen, OvB20, induces partial protection in a rodent model of onchocerciasis.

OvB20 is an antigen of Onchocerca volvulus preferentially recognized by sera from cattle vaccinated with irradiated infective larvae of Onchocerca lienalis. Antibodies raised against the recombinant protein were used to characterize the expression of the native protein in different developmental stages of O. volvulus and the rodent filaria Acanthocheilonema viteae. In O. volvulus, antibodies reacted to a polypeptide of 42 kDa in microfilariae and with proteins of 52 and 65 kDa in third-stage larvae. No products were detected in adult stages. Immunogold electron microscopy localized the native protein to discrete patches of the hypodermis and cuticle of infective larvae. Characterization of a homologous protein in A. viteae confirmed the stage-specific expression in infective larvae of the 65-kDa protein, which was secreted during in vitro culture. Vaccination of rodents against A. viteae with a B20-maltose-binding-protein fusion protein resulted in a 49 to 60% reduction in adult worm recoveries with a corresponding 97% reduction in microfilaremia.

Animals↗
PubMed2001

Immunotoxicity risks associated with land-treatment of petrochemical wastes revealed using an in situ rodent model.

Land-treatment of petrochemical wastes is a widely used method to dispose of hazardous and non-hazardous waste by biodegradation. However, no comprehensive assessment of the impact of such disposal techniques on terrestrial ecosystems has been conducted. Despite the presence of suspected immunotoxicants in the soil, wild rodents frequently reside on these waste sites after closure or abandonment. We explored the seasonal sensitivity of the immune system of the hispid cotton rat (Sigmodon hispidus) to in situ exposures on sites land-treated with petrochemical wastes. Animals were monitored on five contaminated land-treatment sites and five ecologically matched-reference sites in Oklahoma, USA, over two seasons (summer and winter). Most hematological parameters were not adversely affected by land-treatment; however, platelet counts were 26% greater in cotton rats from land-treatment sites compared to reference sites in winter. Significant treatment-related differences were observed in total serum protein concentrations, organ mass and organ cellularity, but these differences were not consistent across the five land-treatment units. Lymphoproliferative responses of cotton rat splenocytes stimulated in vitro were elevated for a T-cell mitogen and depressed for a B-cell mitogen in animals from land-treatment compared to reference sites. The ability of splenocytes to proliferate in response to interleukin-2 receptor-binding was not influenced by treatment. Total yields of peritoneal cells, yield of peritoneal macrophages, and yield of peritoneal lymphocytes were influenced to varying degrees by land-treatment. Functionally, in vitro metabolic activity of peritoneal macrophages was 114% greater in cotton rats from land-treatment sites compared to reference sites during summer. These results indicate that petrochemical wastes applied to soils on these five land-treatment sites had variable immunomodulatory effects in resident cotton rats. Immune alterations for some assays were indicative of enhancement on some land-treatment sites while suppressive on other land-treatment sites, which could have been a function of type and concentration of immunotoxicants present on each site and highlights the uniqueness of each land-treatment site.

Animals↗
PubMed2005

Dopaminergic reinnervation of the globus pallidus by fetal nigral grafts in the rodent model of Parkinson's disease.

The current neural transplantation strategy for Parkinson's disease (PD) involves the dopaminergic reinnervation of the striatum (STR). Although up to 85% reinnervation of the STR has been attained by neural transplantation, functional recovery in animal models and transplanted patients is incomplete. This limitation may be due to an incomplete restoration of the dopaminergic input to other basal ganglia structures such as the external segment of the globus pallidus (GPe, homologue of the rodent GP), which normally receives dopaminergic input from the substantia nigra (SN). As part of our investigation into a multiple grafting strategy for PD, we have explored the effects of dopaminergic grafts in the GP of rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this experiment, lesioned rats received either 300,000 fetal ventral mesencephalic (FVM) cells or a sham injection into the GP. Functional assessment consisted of rotational behavior at 3 and 6 weeks posttransplantation. A fluorogold tracer study was conducted to rule out any behavioral improvement due to striatal outgrowth of the GP graft. Sections were stained for glial fibrillary acidic protein (GFAP) to assess the degree of trauma in the GP by the graft in comparison to the sham injection. Immunohistochemistry for tyrosine hydroxylase (TH) was performed after transplantation to assess graft survival. Animals with GP grafts demonstrated a significant improvement in rotational behavior at 3 and 6 weeks posttransplantation (p < 0.05) while sham control animals did not improve. All animals receiving FVM cells showed TH-immunoreactive grafts in the GP posttransplantation. TH-positive neurons in the GP showed no double labeling with an intrastriatal injection of fluorogold, indicating that behavioral improvement was not due to striatal innervation by the GP graft. These observations suggest that functional recovery was the result of dopaminergic reinnervation of the GP and that this nucleus may be a potential target for neural transplantation in clinical PD.

Animals↗
PubMed2001

Early insulin release effectively improves glucose tolerance: studies in two rodent models of type 2 diabetes mellitus.

AIM: Islet dysfunction, characterized by the loss of an acute insulin secretory response (AIR) to glucose is a well-established pathology of type 2 diabetes mellitus. Using oral insulin secreting agents with very different pharmacodynamic profiles, the present study was undertaken to test the hypothesis that, within the setting of an underlying insulin resistance, changes in the insulin response profile can differentially affect glycaemic control. METHOD: The mildly insulin resistant high-fat fed Sprague Dawley (HF) rat and the very insulin resistant Zucker fatty (fa/fa) rat, chronically fitted with indwelling jugular cannula were subjected to an oral glucose load. Compounds were administered 5 min before the oral glucose load. Nateglinide (Nateg) was administered to elicit only an early insulin secretory response and glipizide (Glip) to elicit a later but greater insulin secretory response. Acetaminophen was used as a marker to assess for potential effects of these compounds on gastric emptying rates. RESULTS: Nateg rapidly increased early insulin release (from -5 to 0) while the effects on total insulin release were similar to those in the controls and glucose excursions were eliminated in both diabetic models with no evidence of sustained hypoglycaemia. Conversely, Glip did not affect early insulin release but increased total insulin release (- 15 to 120 min), but only after the oral glucose load. Glip partially curbed glucose excursions in the mildly insulin resistant HF rodent and was totally ineffective in the very insulin resistant Zucker rat. The differential effects could not be attributed to effects on gastric emptying rates. CONCLUSION: These data support the importance of early insulin release in type 2 diabetes mellitus and indicate that, independent of the level of insulin resistance, stimulating insulin release early and briefly provides for more effective and tighter glycaemic control than increasing insulin exposure to a greater magnitude later.

Animals↗
PubMed1995

The fate of human glial cells following transplantation in normal rodents and rodent models of neurodegenerative disease.

Investigations on xenografting in the brain have previously focused on the anatomical and functional integration of the transplanted neurons. More recently, astrocytes are being implicated as having complex functions following transplantation, and are being investigated to determine their role(s) in transplantation. The present study was undertaken to investigate the migration of human astrocytes following transplantation of thalamic, striatal, and mesencephalic tissue into the rodent striatum. Human donor fetuses (9-16 weeks in gestation) obtained through elective and spontaneous abortions were utilized in this study. Following transplantation, donor astrocytes were labeled with an antiserum directed against human glial fibrillary acidic protein. Our results demonstrate that astrocytic elements from all three tissue types are capable of incorporating into the host brain, and have a tendency to follow white matter tracts (such as the corpus callosum, internal capsule, and fiber bundles in the striatum). Human astrocytes, originating from the striatum and thalamus exhibited extensive migration, while migration was more limited in animals with ventral mesencephalon transplants. Ventral mesencephalon transplanted animal demonstrated positive astrocytes within the transplant, with processes (very few cell bodies) extending into white matter of adjacent host striatum. Astrocytes demonstrating immature morphology were observed with all transplant types, but were most prevalent in the striatal transplanted animals. The extent of astrocyte migration and the morphologies observed in this study reflect regional differences of the developing human brain. These results confirm and extend previous investigations on glial cell migration following transplantation in the brain.

Animals↗
PubMed2004

Oncogenic transformation of human cells: shortcomings of rodent model systems.

Long-standing difficulties in the in vitro transformation of human cells have been overcome. Using telomerase, several successful oncogene-mediated transformations of human cells have been reported and the following cellular requirements for human cell transformation have been proposed: the maintenance of telomere sequences, the inactivation of Rb and p53 pathways, the perturbation of protein phosphatase 2A (PP2A) and the expression of activated Ras. Even when all of these requirements are fulfilled, however, the transformed phenotypes of human cells seem to be much less malignant than those of rodent cells meeting the same requirements. This suggests the existence of undefined cell-autonomous mechanisms that render human cells resistant to malignant transformation.

Animals↗
PubMed2000

Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models.

BACKGROUND: There is a paucity of information about events that follow immediately after tumor cells are triggered to initiate the process of angiogenesis (the formation of new blood vessels). Such information is relevant to the issue of when micrometastases vascularize and has implications for the accessibility of micrometastases to various treatments. In this study, we attempted to monitor events at the initiation of angiogenesis at the earliest possible stage of tumor growth in vivo. METHODS: Two different rodent mammary tumor cell lines, R3230Ac from the Fischer 344 rat and 4T1 from the BALB/c mouse, were stably transfected with a gene that encodes an enhanced version of green fluorescence protein (GFP). GFP-labeled R3230Ac or 4T1 cells (about 20-50 cells) were implanted into dorsal skinfold window chambers of Fischer 344 rats or BALB/c mice, respectively. Tumor angiogenesis was then monitored serially and noninvasively for up to 4 weeks. RESULTS: Clear evidence of modification of the host vasculature was observed when tumor mass reached approximately 60-80 cells, and functional new blood vessels were seen when tumor mass reached roughly 100-300 cells. Individual tumor cells exhibited a chemotaxis-like growth pattern toward the pre-existing host vasculature. When ex-flk1 (a soluble, truncated vascular endothelial cell growth factor receptor protein known to be antiangiogenic) was injected with the tumor cells, the initial angiogenic and tumor growth activities were inhibited considerably, indicating that angiogenesis inhibitors may halt tumor growth even before the onset of angiogenesis. CONCLUSION: Angiogenesis induced by tumor cells after implantation in the host begins at a very early stage, i.e., when the tumor mass contains roughly 100-300 cells. Identification of chemotactic signals that initiate tumor cell migration toward the existing vasculature may provide valuable targets for preventing tumor progression and/or metastases.

Animals↗