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At least 649 records · Page 36Linked to original sources
PubMed2005

A DNA delivery system targeting dendritic cells for use in immunization against malaria: a rodent model.

DNA-based vaccination has emerged as a promising method of immunisation since the first demonstration of this technology. Improving the antibody responses is desirable for the protective efficacy and hence broad application of these vaccines. We examined the immunogenicity of a Plasmodium-based DNA vaccine that was targeted to antigen presenting cells by fusion to CTLA4. Fusion proteins comprising the extra-cellular domain of CTLA4, the hinge, CH2 and CH3 domains of human IgG1 and MSP-1 gene fragments were expressed in COS-7 cells. Three of the secreted proteins containing the mouse homologue of CTLA4 were shown to bind differently to the human B7-1 molecule expressed on THP-1 cells. Competition binding assays for two fusion proteins showed that binding was specific. When C57BL/6 mice were immunized with plasmids encoding the fusion proteins, antibodies against two denatured and one non-denatured MSP-1 gene fragments were successfully induced. The usefulness of this strategy in future studies of immunisaton against human malaria is discussed.

Animals↗
PubMed1999

Development of adenovirus vectors encoding rat complement regulators for use in therapy in rodent models of inflammatory diseases.

C activation has been implicated in the pathogenesis of numerous inflammatory human diseases and disease models. A therapy based on C inhibition might therefore be of benefit to reduce inflammation and ameliorate disease. C inhibition in vivo can be accomplished by the delivery of soluble recombinant C regulators either systemically or directly to a target site, but effects are transitory. We have developed a strategy for the efficient delivery of the membrane-bound rat C inhibitors, CD59, Crry, and decay-accelerating factor (DAF), using replication-deficient adenovirus vectors with the intention of treating rat models of disease in which C is implicated. The adenovirus recombinants(RAd), RAdCD59, RAdCrry, and RAdDAF, respectively, have been tested for expression and function of the transgene in vitro. Infection of human fetal foreskin fibroblasts resulted in high levels of expression of each of the rat inhibitors. The constructs were also tested for inhibition of rat C-mediated cell lysis and C3b deposition. In a cell lysis assay, each inhibited to varying degrees of efficiency in the order RAdCD59 = RAdDAF > RAdCrry. In a C3b deposition assay, RAdDAF caused a greater reduction in C3b deposition than RAdCrry and RAdCD59 was ineffective. These agents, individually or in combination, provide the tools for testing the effects of prolonged inhibition of C at a target site on the progress of experimental models of disease.

Adenoviridae↗
PubMed2000

Review of colorectal cancer and its metastases in rodent models: comparative aspects with those in humans.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) remains one of the most common cancer forms developing in industrialized countries, and its incidence appears to be rising. Studies of human population groups provide insufficient information about carcinogenesis, pathogenesis, and treatment of CRC. To study these phenomena in detail, a number of animal models of human CRC have been developed. The hypothetical ideal animal model should mimic the human disease in terms of morphology, biochemical alterations, and biological behavior. No existing model replicates the disease as an entity, but available models approximate many of the characteristics of human colonic carcinogenesis and metastasis. So far few comparative evaluations of the various animal models of CRC have been made. CONCLUSION: Animal studies cannot replace human clinical trials, but they can be used as a pre-screening tool, so that human trials become more directed, with greater chances of success. The orthotopic transplantation of colon cancer cells into the cecum of syngeneic animals or intraportal inoculation appears to resemble the human metastatic disease most closely, providing a model for study of the treatment of metastases. Which model(s) to choose depends on the goal(s) of the experiment(s). The review published here can provide help in selecting the most optimal CRC model(s) for a certain purpose and in preventing unnecessary duplication of animal experimentation.

Adenocarcinoma↗
PubMed2000

Deficit of striatal parvalbumin-reactive GABAergic interneurons and decreased basal ganglia output in a genetic rodent model of idiopathic paroxysmal dystonia.

The underlying mechanisms of various types of hereditary dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model of a type of paroxysmal dystonia, the dt(sz) mutant hamster, pointed to striatal dysfunctions. In the present study, immunhistochemical experiments demonstrated a marked decrease in the number and density of parvalbumin-immunoreactive GABAergic interneurons in all striatal subregions of mutant hamsters. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABA(A) receptor agonist muscimol on severity of dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome after striatal injections to a similar extent as after systemic treatment, supporting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striatal GABAergic projection neurons, as suggested by recent extracellular single-unit recordings in dt(sz) hamsters, should lead to an abnormal neuronal activity in the basal ganglia output nuclei. Indeed, a significantly decreased basal discharge rate of entopeduncular neurons was found in dt(sz) hamsters. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activity in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiology of hyperkinesias. The results indicate that striatal interneurons deserve attention in basic and clinical research of those movement disorders.

Action Potentials↗
PubMedDate not supplied

Rapid alterations in diffusion-weighted images with anatomic correlates in a rodent model of status epilepticus.

BACKGROUND AND PURPOSE: Diffusion-weighted MR imaging has emerged as a noninvasive tool for the detection of regional neuronal damage. We hypothesize that changes in diffusion-weighted images will correlate with pathophysiologic alterations caused by pilocarpine-induced status epilepticus. METHODS: MR images of brain tissues were examined in vivo by use of T2- and diffusion-weighted imaging at 3, 6, 12, and 24 hours after pilocarpine-induced seizures. Histologic verification of neuronal damage was also performed after imaging to assess the extent and the time course of neuronal cell death. RESULTS: The piriform cortex, amygdala, and retrosplenial (and somatosensory) cortex displayed significant apparent diffusion coefficient (ADC) decreases 12 hours after seizure initiation. In contrast, an ADC rise of 19% was observed in the hippocampus 24 hours after seizure induction. Histologic data from the piriform cortex and amygdala confirmed severe neuronal loss, whereas hippocampal damage was much less pronounced at 12 hours. Interestingly, very little histologic damage was seen in the retrosplenial cortex. CONCLUSION: This study capitalized on diffusion-weighted imaging as a sensitive technique for the early identification of seizure-induced neuronal damage and differentiation of regional severity of these alterations. Hippocampal neuropathology is slower and longer in duration (approximately 7 days), while the piriform cortex and amygdala exhibit very rapid neurodegenerative alterations (approximately 24 hours) after pilocarpine-induced status epilepticus. These histologic changes are reflected in opposing ADC values within these regions.

Analysis of Variance↗
PubMed2001

Selective dopamine receptor stimulation differentially affects [3H]arachidonic acid incorporation, a surrogate marker for phospholipase A2-mediated neurotransmitter signal transduction, in a rodent model of Parkinson's disease.

Our laboratory has developed a technique whereby radiolabeled long-chain fatty acids are injected intravenously in awake rats to pulse-label brain lipids, mainly phospholipids, to measure regional brain lipid metabolism by autoradiography. The brain incorporation of [(3)H]arachidonic acid ([(3)H]AA), a polyunsaturated fatty acid, may reflect regional changes in neurotransmitter signal transduction using phospholipase A(2). Using this radiotracer, we examined the brain dopamine system in rats with a chronic unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta, a model of Parkinson's disease. Four weeks after lesioning, rats received either vehicle; SKF38393 or quinpirole (LY-171,555) (D(1)- and D(2)-dopamine-like agonists, respectively); or (+)-butaclamol (D(1)/D(2) antagonist) followed by either vehicle, SKF38393, or quinpirole. They then were infused with [(3)H]AA and their brains processed for autoradiography. SKF38393 increased [(3)H]AA incorporation into the lesioned side compared with the intact side in the caudate putamen, somatosensory and motor cortices and subthalamic nucleus, but decreased incorporation in the ipsilateral ventrolateral thalamus. Quinpirole increased ipsilateral [(3)H]AA incorporation in the caudate putamen and somatosensory and motor cortices, and decreased it in the ventrolateral thalamus. (+)-Butaclamol blocked this effect. The data suggest up-regulation in basal ganglia and cortical dopamine circuits mediated by phospholipase A(2) ipsilateral to the substantia nigra lesion.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Propofol in subanesthetic doses terminates status epilepticus in a rodent model.

Status epilepticus is commonly refractory to first-line therapy, and thus better treatments are needed. We have investigated an experimental model of drug-resistant self-sustaining status epilepticus (SSSE) induced by 2 hours of perforant path stimulation. Propofol in subanesthetic doses administered shortly after the end of stimulation and also after a further 3 hours of SSSE terminated the SSSE without recurrence. This finding calls for a trial of propofol in refractory status epilepticus and also raises the possibility of using it as first-line therapy.

Animals↗
PubMed2001

Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson's disease.

Using permanent cannulas connected to subcutaneous pumps, we infused selective glutamate antagonists into the subthalamic nucleus of rats. Pumps were implanted immediately after the intrastriatal injection of 6-hydroxydopamine and delivered micro-quantities of the Nmethyl-D-aspartate antagonist MK-801 or the alpha-amino-3-hydroxy-5-methylisoxazole antagonist NBQX for 4 weeks. Subthalamic infusion of MK-801, but not of NBQX, prevented the basal ganglia metabolic changes and motor abnormalities caused by nigrostriatal lesion. Animals treated with MK-801 also exhibited marked reduction of nigral cell loss. We conclude that pharmacological modulation of subthalamic activity may have both symptomatic and neuroprotective effects in Parkinson's disease.

Animals↗
PubMed2001

Rodent models of anxiety-like behaviors: are they predictive for compounds acting via non-benzodiazepine mechanisms?

An overview of the preclinical literature on the effects of the most studied clinically effective or putative non-benzodiazepine anxiolytics in existing animal models of anxiety-like behavior indicates that, with the exception of 5-HT1A agonists, these compounds display highly variable effects. Because these drugs have been shown (selective 5-HT reuptake inhibitors) or proposed (CCK(B) and CRF antagonists) to have a different spectrum of therapeutic activity in anxiety disorders than benzodiazepines, agents mainly used against generalized anxiety disorder, the screening of such compounds clearly requires the validation of new techniques that may model aspects of these conditions.

Animals↗
PubMed2002

A sequential intrastriatal dopaminergic graft strategy in the rodent model for Parkinson's disease: implications for graft survival and targeting.

Optimal placement of intrastriatal dopaminergic grafts is likely crucial to optimize clinical recovery in Parkinson's disease (PD). The target sites of dopaminergic grafts vary among clinical trials and may partially explain the variable results in clinical efficacy reported thus far. In this study we hypothesized that a subsequent dopaminergic graft may promote functional recovery following a suboptimal initial graft. To test this hypothesis, rats with unilateral 6-hydroxydopamine lesions of the right nigrostriatal pathway were randomly divided into three groups. The first group received 900,000 fetal nigral cells in the medial striatum only (n = 6). The second group received 900,000 cells in both the medial and lateral striatum simultaneously (1.8 million total; n = 8). The final group received a second graft of 900,000 cells in the lateral striatum 6 weeks following initial transplantation of a medial graft (n = 6). Amphetamine-induced circling behavior was significantly reduced in both simultaneous and sequential graft groups at 9 and 12 weeks following transplantation of the initial graft. However, no recovery was noted in the single medial graft group at those time points. Furthermore, increased survival of dopaminergic cells was observed in the lateral graft of sequentially grafted animals compared with the medial graft. We conclude that a well-positioned subsequent graft can restore function in animals with a suboptimal initial graft and that the initial graft may improve survival of the second graft. These results are further discussed in relation to their important clinical implication for neural transplantation in PD.

Animals↗
PubMed1994

Establishment of an appropriate inoculum dose of Leishmania donovani promastigotes required to establish a visceral infection in laboratory animal rodent models.

Syrian hamsters and BALB/c mice were inoculated intraperitoneally with various doses of stationary phase Leishmania donovani promastigotes derived from primary, secondary and tertiary cultures. Axenic derived amastigotes from a tertiary culture and mass-culture derived promastigotes from primary, secondary, and tertiary cultures were also used. Animals were sacrificed after 30 days incubation period and parasite-loads quantified from Giemsa stained spleen smears. A primary inoculum dose of 1 x10(8) was found to be the most appropriate in effecting a visceral infection. This parasite dose resulted in a spleen parasite-load of 10-20 amastigotes per field of microscope view at x1,000 magnification. Those involved in candidate vaccine molecules or experimental drugs against kala-azar will find these results useful.

Journal Article↗
PubMed2003

Radiochemical investigations of gastrin-releasing peptide receptor-specific [(99m)Tc(X)(CO)3-Dpr-Ser-Ser-Ser-Gln-Trp-Ala-Val-Gly-His-Leu-Met-(NH2)] in PC-3, tumor-bearing, rodent models: syntheses, radiolabeling, and in vitro/in vivo studies where Dpr = 2,3-diaminopropionic acid and X = H2O or P(CH2OH)3.

Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin-releasing peptide (GRP) that binds to GRP receptors (GRPrs) with high affinity and specificity. The GRPr is overexpressed on a variety of human cancer cells, including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to develop (99m)Tc(I)-radiolabled BBN analogues that maintain high specificity for the GRPr in vivo. A preselected synthetic sequence via solid phase peptide synthesis was designed to produce 2,3-diaminopropionic acid (Dpr)-BBN conjugates with the following general structure: Dpr-Ser-Ser-Ser-Gln-Trp-Ala-Val-Gly-His-Leu-Met-(NH(2)). The new BBN constructs were purified by reversed phase high-performance liquid chromatography. Electrospray mass spectrometry was used to characterize the nonmetallated BBN conjugates. Re(I)-BBN conjugates were prepared by the reaction of [Re(Br)(3)(CO)(3)](2-) and Dpr-Ser-Ser-Ser-Gln-Trp-Ala-Val-Gly-His-Leu-Met-(NH(2)) with gentle heating. Electrospray mass spectrometry was used to determine the molecular constitution of the new Re(I) conjugates. The (99m)Tc conjugates were prepared at the tracer level by preconjugation, postlabeling approach from the reaction of [(99m)Tc(H(2)O)(3)(CO)(3)](+) and corresponding ligand. The (99m)Tc and Re(I) conjugates behaved similarly under identical reversed phase high-performance liquid chromatography conditions. Results from in vitro and in vivo models demonstrated the ability of these derivatives to specifically target GRPrs on human, prostate, cancerous PC-3 cells.

Amino Acid Sequence↗
PubMed1992

Muramyl peptide adjuvants for Plasmodium falciparum and Plasmodium vivax circumsporozoite vaccines in rodent model systems.

Circumsporozoite proteins from the malaria parasites Plasmodium falciparum and Plasmodium vivax were expressed at high levels in the yeast Saccharomyces cerevisiae. Recombinant proteins varied both in length and in number of the natural amino acid repeat motifs. The proteins were purified and used to immunize mice, guinea pigs, and rabbits. Novel muramyl peptide adjuvants were used that increased the immune response as measured by ELISA assays, indirect immunofluorescence of fixed sporozoites, and the invasion of cultured liver cells by live sporozoites. These results suggest that an improved humoral response to recombinant circumsporozoite vaccines might be achieved by varying the design of the recombinant protein and by the use of novel adjuvant systems.

Adjuvants, Immunologic↗
PubMed2002

Hypergravity-induced immunomodulation in a rodent model: lymphocytes and lymphoid organs.

The major goal of this study was to quantify changes in lymphoid organs and cells over time due to centrifugation-induced hypergravity. C57BL/6 mice were exposed to 1, 2 and 3 G and the following assays were performed on days 1, 4, 7, 10, and 21: spleen, thymus, lung, and liver masses; total leukocyte, lymphocyte, monocyte/macrophage, and granulocyte counts; level of splenocyte apoptosis; enumeration of CD3+ T, CD3+/CD4+ T helper, CD3+/CD8+ T cytotoxic, B220+ B, and NK1.1+ natural killer cells; and quantification of cells expressing CD25, CD69, and CD71 activation markers. The data show that increased gravity resulted in decreased body, spleen, thymus, and liver, but not lung, mass. Significant reductions were noted in all three major leukocyte populations (lymphocytes, granulocytes, monocyte/macrophages) [correction of macrphages] with increased gravity; persistent depletion was noted in blood but not spleen. Among the various lymphocyte populations, the CD3+/CD8+ T cells and B220+ B cells were the most affected and NK1.1+ NK cells the least affected. Overall, the changes were most evident during the first week, with a greater influence noted for cells in the spleen. A linear relationship was found between some of the measurements and the level of gravity, especially on day 4. These findings indicate that hypergravity profoundly alters leukocyte number and distribution in a mammalian model and that some aberrations persisted throughout the three weeks of the study. In certain cases, the detected changes were similar to those observed after whole-body irradiation. In future investigations we hope to combine hypergravity with low-dose rate irradiation and immune challenge.

Animals↗