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PubMed2004

Combined bone morphogenetic protein-2 and -7 gene transfer enhances osteoblastic differentiation and spine fusion in a rodent model.

UNLABELLED: To enhance the osteogenic activity of BMP, combination BMP2 and BMP7 gene transfer was performed. This approach led to a significant increase in osteoblastic differentiation of mesenchymal precursors compared with single BMP gene transfer in vitro. When tested in 78 rats, combination gene transfer enhanced mechanically stable spine fusion and bone formation rate versus single BMP gene transfer. INTRODUCTION: Although clinical bone morphogenetic protein (BMP) therapy is effective, required doses are very high. Previous studies have suggested that the co-expression of two different BMP genes can result in the production of heterodimeric BMPs that may be more potent than homodimers. In this study, combined BMP2 and BMP7 gene transfer was performed to test whether this approach improves osteoblastic differentiation and bone formation compared with single BMP gene transfer. MATERIALS AND METHODS: A producer cell (A549) was co-transfected with adenovirus vectors encoding BMP2 (AdBMP2) and BMP7 (AdBMP7) or, as controls, each vector alone, AdNull (with no transgene) or no virus. Supernatants were compared for their ability to stimulate osteoblastic differentiation of C2C12 myoblasts and MC3T3-E1 pre-osteoblasts. In a rat posterolateral spine fusion model, co-administration of AdBMP2 and AdBMP7 was compared with treatment with each vector alone, AdNull or no virus in 78 rats. The spines were assessed 8 weeks after surgery for radiographic and mechanical fusion, bone formation, and mineralization. RESULTS: BMP2 and BMP7 were co-precipitated from supernatants of cells co-transfected with AdBMP2 and AdBMP7, indicating the presence of BMP2/7 heterodimer. Supernatants of co-transfected cells containing relatively low doses (7-140 ng/ml) of BMPs induced osteocalcin expression and alkaline phosphatase activity in both C2C12 and MC3T3-E1 cells, that were up to 6- and 40-fold higher, respectively, than levels induced by maximal doses (200-1000 ng/ml) of either BMP2 or BMP7 alone. In the spine fusion model, co-administration of AdBMP2 and AdBMP7 resulted in a significantly greater number of mechanically stable fusions and also 2-fold higher mineralization rate and bone volume in the fusion mass versus single BMP gene transfer (p < 0.02, all comparisons). CONCLUSION: Combined BMP2 and BMP7 gene transfer is significantly more effective in inducing osteoblastic differentiation and spine fusion than individual BMP gene transfer.

3T3 Cells↗
PubMed2004

Rodent models of experimental autoimmune uveitis.

The model of experimental autoimmune uveitis (EAU) in mice and in rats is described. EAU targets immunologically privileged retinal antigens and serves as a model of autoimmune uveitis in humans as well as a model for autoimmunity in a more general sense. EAU is a well-characterized, robust, and reproducible model that is easily followed and quantitated. It is inducible with synthetic peptides derived from retinal autoantigens in commonly available strains of rats and mice. The ability to induce EAU in various gene-manipulated, including HLA-transgenic, mouse strains makes the EAU model suitable for the study of basic mechanisms as well as in clinically relevant interventions.

Adoptive Transfer↗
PubMed1998

Diet-induced loss of cyclic ovarian function at normal body weight in a rodent model for bulimia nervosa.

A bulimic rat model was used to test whether type and frequency of food intake mimicking that in human bulimia nervosa could disrupt oestrous cyclicity, induce an effect on glycoprotein (LH) structure, or affect both processes and if so, to determine whether any such effects were acute, or persisted after return to normal eating patterns. Voluntary hyperphagia was induced by offering female rats a varied and palatable choice of human food items--the 'cafeteria diet'. There were four groups: control (normal chow), obese (continuous cafeteria diet), post-obese (cafeteria diet, then fasted to reduce weight to that of controls) and binge (cafeteria alternated with normal diet every few days). Animals were maintained on these diets for 60 days (phase I). They were then given a GnRH challenge on day 2 of dioestrus of the cycle. Twenty-four hours later, half of the animals in each group were killed for assessment of effects on their reproductive organs. The remaining animals were returned to normal diets and kept for a further 40 days, when the GnRH challenge was repeated and the animals were killed 24 h later (phase II). All animals on the cafeteria diet in phase I exhibited significant disruption of oestrous cyclicity irrespective of body weight. LH released in response to the first GnRH challenge showed a prolonged half-life, and/or increased rate of secretion in the obese and post-obese groups but in the binge group the secretory/clearance properties resembled those of control animals. After the second GnRH challenge at the end of phase II, however, the LH of the binge group appeared to have different secretory or clearance characteristics, whereas that of the previously obese animals had returned to normal. These data show ovarian cyclicity was disrupted by hyperphagia and irregular eating, even at normal body weight. Relating ovarian function to pituitary output in terms of LH, the effects of the continuous cafeteria diet did not appear to persist in the animals that returned to normal diets, but in the binge group the effect, presumably of the diet manipulation, was manifested after return to a normal eating pattern. This finding suggests that irregular eating habits may exert a direct (and acute) effect on the ovary, but that effects on the pituitary (and LH glycoforms) take longer to be expressed, explaining many features of bulimia nervosa.

Analysis of Variance↗
PubMed2006

An in vivo rodent model for identifying and characterizing acaricides.

Evaluation of candidate acaricides in livestock or companion animals is expensive, time-consuming, and usually requires large quantities of test material. To identify promising substances at the earliest possible stage of the development process, robust and predictive surrogate animal models, capable of rapidly characterizing potency with minimal compound requirements, are necessary. The objective of this study was to generate an in vivo surrogate animal bioassay capable of rapidly and accurately predicting the topical activity of acaricides emerging from in vitro acaricide bioassays. The rat acaricide test (RAT) requires adult rats, Rattus norvegicus (Berkenhout, 1769), a flexible tick containment device fastened to their dorso-thoracic region, and the nymphal stage of the lone star tick, Amblyomma americanum (L.). The feeding kinetics of A. americanum nymphs on rats was assessed, and compound efficacies were determined by measuring tick survivorship and engorgement weight on acaricide-treated animals. Results from this bioassay demonstrated efficacy with fipronil, ivermectin, permethrin, and chlorpyrifos, and dose-response relationships for each acaricide were determined. The rank order of potencies was fipronil > ivermectin > chlorpyrifos = permethrin for nymphal mortality and fipronil > ivermectin > chlorpyrifos > permethrin for inhibition of nymphal engorgement. The activity of permethrin against nymphs in the RAT was positively correlated with potency values for technical and commercial permethrin formulations against adult A. americanum infestations on cattle. The RAT proved to be an economical, rapid surrogate animal bioassay that together with the in vitro acaricide bioassay can be used for the rapid identification, characterization, and prioritization of candidate acaricides.

Animals↗
PubMed2005

Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease.

The umbilical cord contains an inexhaustible, noncontroversial source of stem cells for therapy. In the U.S., stem cells found in the umbilical cord are routinely placed into bio-hazardous waste after birth. Here, stem cells derived from human umbilical cord Wharton's Jelly, called umbilical cord matrix stem (UCMS) cells, are characterized. UCMS cells have several properties that make them of interest as a source of cells for therapeutic use. For example, they 1) can be isolated in large numbers, 2) are negative for CD34 and CD45, 3) grow robustly and can be frozen/thawed, 4) can be clonally expanded, and 5) can easily be engineered to express exogenous proteins. UCMS cells have genetic and surface markers of mesenchymal stem cells (positive for CD10, CD13, CD29, CD44, and CD90 and negative for CD14, CD33, CD56, CD31, CD34, CD45, and HLA-DR) and appear to be stable in terms of their surface marker expression in early passage (passages 4-8). Unlike traditional mesenchymal stem cells derived from adult bone marrow stromal cells, small populations of UCMS cells express endoglin (SH2, CD105) and CD49e at passage 8. UCMS cells express growth factors and angiogenic factors, suggesting that they may be used to treat neurodegenerative disease. To test the therapeutic value of UCMS cells, undifferentiated human UCMS cells were transplanted into the brains of hemiparkinsonian rats that were not immune-suppressed. UCMS cells ameliorated apomorphine-induced rotations in the pilot test. UCMS cells transplanted into normal rats did not produce brain tumors, rotational behavior, or a frank host immune rejection response. In summary, the umbilical cord matrix appears to be a rich, noncontroversial, and inexhaustible source of primitive mesenchymal stem cells.

Animals↗
PubMed2006

Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease.

Progressive photoreceptor degeneration resulting from genetic and other factors is a leading and largely untreatable cause of blindness worldwide. The object of this study was to find a cell type that is effective in slowing the progress of such degeneration in an animal model of human retinal disease, is safe, and could be generated in sufficient numbers for clinical application. We have compared efficacy of four human-derived cell types in preserving photoreceptor integrity and visual functions after injection into the subretinal space of the Royal College of Surgeons rat early in the progress of degeneration. Umbilical tissue-derived cells, placenta-derived cells, and mesenchymal stem cells were studied; dermal fibroblasts served as cell controls. At various ages up to 100 days, electroretinogram responses, spatial acuity, and luminance threshold were measured. Both umbilical-derived and mesenchymal cells significantly reduced the degree of functional deterioration in each test. The effect of placental cells was not much better than controls. Umbilical tissue-derived cells gave large areas of photoreceptor rescue; mesenchymal stem cells gave only localized rescue. Fibroblasts gave sham levels of rescue. Donor cells were confined to the subretinal space. There was no evidence of cell differentiation into neurons, of tumor formation or other untoward pathology. Since the umbilical tissue-derived cells demonstrated the best photoreceptor rescue and, unlike mesenchymal stem cells, were capable of sustained population doublings without karyotypic changes, it is proposed that they may provide utility as a cell source for the treatment of retinal degenerative diseases such as retinitis pigmentosa.

Animals↗
PubMed2006

Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson disease.

The derivation of dopamine neurons is one of the best examples of the clinical potential of embryonic stem (ES) cells, but the long-term function of the grafted neurons has not been established. Here, we show that, after transplantation into an animal model, neurons derived from mouse ES cells survived for over 32 weeks, maintained midbrain markers, and had sustained behavioral effects. Microdialysis in grafted animals showed that dopamine (DA) release was induced by depolarization and pharmacological stimulants. Positron emission tomography measured the expression of presynaptic dopamine transporters in the graft and also showed that the number of postsynaptic DA D(2) receptors was normalized in the host striatum. These data suggest that ES cell-derived neurons show DA release and reuptake and stimulate appropriate postsynaptic responses for long periods after implantation. This work supports continued interest in ES cells as a source of functional DA neurons.

Animals↗
PubMed2006

Concomitant immunity in a rodent model of filariasis: the infection of Meriones unguiculatus with Acanthocheilonema viteae.

In an attempt to study the occurrence of concomitant immunity in filarial infections, jirds (Meriones unguiculatus) were experimentally infected with Acanthocheilonema viteae, and patent animals were superinfected with a defined dose of A. viteae stage 3 larvae (L3). Infected animals harbored significantly less worms deriving from the superinfection than the control group (P < 0.05, 56.2%, and 63.4% protection), as shown by analysis of female worms 6 wk after superinfection on the basis of their developmental status and their length. This protection was not due to contact with L3 antigens because a significant reduction of worm burdens deriving of a superinfection was also observed after subcutaneous implantation of a single female worm (P < 0.05, 40.2% and 64.9% protection). The induced protective responses target L3 and restrict their migration because an established infection resulted in a reduction of L3 recovery (95.6% and 94.3%, P < 0.001) from tissues of jirds at day 5 after superinfection. Other data show that L3 from a superinfection are trapped within eosinophil-rich granulomas, which is likely to create unfavorable conditions for the worms and to lead to later death. Taken together, established A. viteae-infections partially protect hosts against homologous superinfection by an immune-mediated mechanism and, thus, regulate the population density of the parasites within the host by concomitant immunity.

Animals↗
PubMed2006

Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes.

Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic beta-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic beta-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA(1c), and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2-3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive beta-cells in islets, leading to the normalization of beta-cell mass and beta-cell-to-alpha-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.

Animals↗
PubMed2005

Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy.

Diabetes leads to vascular leakage, glial dysfunction, and neuronal apoptosis within the retina. The goal of the studies reported here was to determine the role that retinal microglial cells play in diabetic retinopathy and assess whether minocycline can decrease microglial activation and alleviate retinal complications. Immunohistochemical analyses showed that retinal microglia are activated early in diabetes. Furthermore, mRNAs for interleukin-1beta and tumor necrosis factor-alpha, proinflammatory mediators known to be released from microglia, are also increased in the retina early in the course of diabetes. Using an in vitro bioassay, we demonstrated that cytokine-activated microglia release cytotoxins that kill retinal neurons. Furthermore, we showed that neuronal apoptosis is increased in the diabetic retina, as measured by caspase-3 activity. Minocycline represses diabetes-induced inflammatory cytokine production, reduces the release of cytotoxins from activated microglia, and significantly reduces measurable caspase-3 activity within the retina. These results indicate that inhibiting microglial activity may be an important strategy in the treatment of diabetic retinopathy and that drugs such as minocycline hold promise in delaying or preventing the loss of vision associated with this disease.

Animals↗
PubMed1994

A rodent model for hemoglobin switching utilizing high performance liquid chromatography.

It has long been recognized that a treatment for beta hemoglobin chain anomalies could result if a way to reverse the Hb F to Hb A switch in humans were found. Studies of hemoglobin switching have been hampered by the fact that small animals normally used in the laboratory do not have a true Hb F. However, several small animal models which take advantage of a switch in minor beta chain proportions in certain strains of inbred mice and rats have been proposed and used. The use of these models has suffered from what, until now, could be considered technically demanding, time-consuming methodologies. In this study we report an effective, rapid and technically streamlined model of hemoglobin switching utilizing Fisher 344 rats and high performance liquid chromatography with a weakly cationic column.

Age Factors↗
PubMed1990

Mechanisms of alcohol intoxication in a rodent model: blunted alcohol-opposing reaction in "alcohol-sensitive" rats.

In this paper we describe new data and review some studies on the mechanisms of alcohol-induced motor impairment in rats. Habituation to handling did not affect the naive behavioural differences between the alcohol sensitive and alcohol insensitive rat lines. Nor was there any effect on the differential sensitivities of the lines to the motor impairing and hypnotic effects of alcohol. Peripheral mechanisms may be involved in the differential behaviours of these lines, as the plasma corticosterone response was much weaker in the alcohol sensitive animals, suggesting a limited capacity to react to stress and alcohol. A similar blunted response to acute ethanol exposure was found in the uptake of the benzodiazepine antagonist [3H]Ro 15-1788 in vivo by the cerebellum of alcohol sensitive rats. The finding that these rat lines do not have any general differences in their brain inhibitory GABAergic receptors was extended to the spinal cord inhibitory glycinergic receptors, which showed only a modest line difference in their dissociation constant. The apparent localisation of the two main receptor differences (high-affinity [3H]muscimol binding and diazepam sensitivity of [3H]Ro 15-4513 binding) to the cerebellar granule layer suggests a genetic modification in the granule cells of alcohol-sensitive rats. In conclusion, our studies on acute intoxication by moderate alcohol doses show that several central nervous and peripheral factors may be involved in this behaviour. As many of these factors mitigate the effects of alcohol, alcohol antagonistic treatments should be aimed at activating and supporting multiple adaptive phenomena.

Adrenal Glands↗
PubMed1999

Bornavirus immunopathogenesis in rodents: models for human neurological diseases.

Although the question of human BDV infection remains to be resolved, burgeoning interest in this unique pathogen has provided tools for exploring the pharmacology and neurochemistry of neuropsychiatric disorders potentially linked to BDV infection. Two animal models have been established based on BDV infection of adult or neonatal Lewis rats. Analysis of these models is already yielding insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior.

Animals↗
PubMed1997

Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke.

Several lines of evidence indicate that the extent of ischemic injury is not defined immediately after arterial occlusion, but that infarction expands over time. Episodes of spreading depression have been linked to this secondary increase in infarct volume. Tissue bordering the infarction fails to repolarize following spreading depression and is incorporated into the lesion. The result is that ischemic infarctions expand stepwise after each episode of spreading depression. Another line of evidence has demonstrated that gap junction blockers effectively inhibit spreading depression. These observations suggest that traffic of potentially harmful cytosolic messengers between ischemic cells and surrounding nonischemic cells might cause amplification of injury in focal stroke. It is therefore conceivable that minimizing gap junction permeability might reduce final infarct volume. To test this hypothesis, the authors pretreated rats with the gap junction blocker, octanol, before occluding the middle cerebral artery and compared the sizes of the ischemic lesions to those in rats that received the vehicle, dimethyl sulfoxide, prior to arterial occlusion. Histopathological analysis was performed 24 hours later. The 12 octanol-treated animals showed a significantly decreased mean infarction volume (80 +/- 16 mm3) compared with the nine control rats (148 +/- 9 mm3). In a separate set of experiments, the frequency of experimentally induced waves of spreading depression was evaluated after octanol treatment. Octanol pretreatment resulted in complete inhibition in two of nine animals, transient inhibition in five, and no inhibition in two. The results indicate that gap junction inhibitors, when not limited by toxicity, have significant therapeutic potential in the treatment of acute stroke.

Animals↗
PubMed2000

Rodent model for long-term maintenance and development of the viable cysticerci of Taenia saginata asiatica.

Although oncospheres of Taenia saginata asiatica can develop into cysticerci in immunodeficiency, immunosuppressed, and normal mice, no detailed information on the development features of these cysticerci from SCID mice is available. In the present study, the tumor-like cyst was found in the subcutaneous tissues of each of 10 SCID mice after 38-244 days inoculation with 39,000 oncospheres of T. s. asiatica. These cysts weighed 2.0-9.6 gm and were 1.5-4.3 cm in diameter. The number of cysticerci were collected from these cysts ranged from 125 to 1,794 and the cysticercus recovery rate from 0.3% to 4.6%. All cysticerci were viable with a diameter of 1-6 mm and 9 abnormal ones each with 2 evaginated protoscoleces were also found. The mean length and width of scolex, protoscolex, and bladder were 477 x 558, 756 x 727, and 1,586 x 1,615 microns, respectively. The diameters of suckers and rostellum were 220 microns and 70 microns, respectively. All cysticerci had two rows of rostellar hooks. These findings suggest that the SCID mouse model can be employed as a tool for long-term maintenance of the biological materials for advanced studies of immunodiagnosis, vaccine development, and evaluation of cestocidal drugs which would be most benefit for the good health of the livestocks.

Animals↗
PubMed2004

Neuroprotective effects of encapsulated CNTF-producing cells in a rodent model of Huntington's disease are dependent on the proximity of the implant to the lesioned striatum.

Huntington's disease (HD) is a devastating genetic disorder with no effective treatments for preventing or lessening the underlying neuronal degeneration. Intracerebral delivery of CNTF in animal models of HD has shown considerable promise as a means of protecting striatal neurons that would otherwise be destined to die. The present study examines whether the neuroprotective effects of CNTF require that the delivery be immediately proximal to the lesion site or whether protective effects can be exerted when the delivery site is more distal to the site of injury. Encapsulated CNTF-producing cells were implanted into the lateral ventricle either ipsilateral or contralateral to an intrastriatal quinolinic acid (QA) injection. A robust neuroprotective effect was observed only in those animals receiving CNTF implants ipsilateral to the QA injection. In these animals, the loss of striatal ChAT and GAD activity as well as the behavioral impairments that resulted from QA were completely prevented. In contrast, no neurochemical or behavioral benefits were produced by implants of CNTF-producing cells in the contralateral ventricle. These data continue to support the use of cellular delivery of CNTF for HD but caution that delivery directly to the striatum may be needed if any clinical benefits are to be seen.

Animals↗
PubMed2001

Lethal hepatitis after gene transfer of IL-4 in the liver is independent of immune responses and dependent on apoptosis of hepatocytes: a rodent model of IL-4-induced hepatitis.

The putative role of IL-4 in human and animal models of hepatitis has not yet been directly determined. We now report that direct expression of IL-4 in the liver of rats or mice using recombinant adenoviruses coding for rat or mouse IL-4 (AdrIL-4 and AdmIL-4, respectively) results in a lethal, dose-dependent hepatitis. The hepatitis induced by IL-4 was characterized by hepatocyte apoptosis and a massive monocyte/macrophage infiltrate. IL-4-induced hepatitis was independent of T cell-mediated immune responses. Hepatitis occurred even after gene transfer of IL-4 into nude rats, CD8-depleted rats, cyclosporine A-treated rats, or recombinase-activating gene 2(-/-) immunodeficient mice. Peripheral depletion of leukocytes using high doses of cyclophosphamide, and/or the specific depletion of liver macrophages with liposome-encapsulated dichloromethylene diphosphonate in rats did not block lethal IL-4-induced hepatitis. Direct transduction of hepatocytes with adenoviruses was not essential, since injection of AdrIL-4 into the hind limb induced an identical hepatitis. Finally, primary rat hepatocytes in culture also showed apoptosis when cultured in the presence of rIL-4. IL-4-dependent hepatitis was associated with increases in the intrahepatic levels of IFN-gamma, TNF-alpha, and Fas ligand. Administration of AdmIL-4 to IFN-gamma, TNF-alpha receptor type I, or TNF-alpha receptor type II knockout mice also resulted in lethal hepatitis, whereas a moderate protection was observed in Fas-deficient lpr mice. IL-4-dependent hepatocyte apoptosis could be abolished by treatment with caspase inhibitory peptides. Our results thus demonstrate that IL-4 causes hepatocyte apoptosis, which is only partially dependent on the activation of Apo-1-Fas signaling and is largely independent of any immune cells in the liver.

Acute Disease↗