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PubMed1996

Agmatine treatment is neuroprotective in rodent brain injury models.

Agmatine is a naturally occurring guanidino compound, found in bacteria and plants, with several proposed nervous system-related functions suggestive of beneficial effects in central nervous system injury. Here evidence is presented that agmatine can exert potent neuroprotection in both in vitro and in vivo rodent models of neurotoxic and ischemic brain injuries. The cumulative evidence lead us to suggest that agmatine, a relatively nontoxic compound, be tried for potential therapeutic use after neurotrauma and in neurodegenerative disorders.

Agmatine↗

PubMed2005

Establishment of graded spinal cord injury model in a nonhuman primate: the common marmoset.

Most previous studies on spinal cord injury (SCI) have used rodent models. Direct extrapolation of the results obtained in rodents to clinical cases is difficult, however, because of neurofunctional and anatomic differences between rodents and primates. In the present study, the development of histopathologic changes and functional deficits were assessed quantitatively after mild, moderate, and severe spinal cord contusive injuries in common marmosets. Contusive SCI was induced by dropping one of three different weights (15, 17, or 20 g) at the C5 level from a height of 50 mm. Serial magnetic resonance images showed significant differences in the intramedullary T1 low signal and T2 high signal areas among the three groups. Quantitative histologic analyses revealed that the number of motor neurons, the myelinated areas, and the amounts of corticospinal tract fibers decreased significantly as the injury increased in severity. Motor functions were evaluated using the following tests: original behavioral scoring scale, measurements of spontaneous motor activity, bar grip test, and cage-climbing test. Significant differences in all test results were observed among the three groups. Spontaneous motor activities at 10 weeks after injury were closely correlated with the residual myelinated area at the lesion epicenter. The establishment of a reliable nonhuman primate model for SCI with objective functional evaluation methods should become an essential tool for future SCI treatment studies. Quantitative behavioral and histopathologic analyses enabled three distinct grades of injury severity (15-g, 17-g, and 20-g groups) to be characterized with heavier weights producing more serious injuries, and relatively constant behavioral and histopathologic outcomes.

Animals↗

PubMed1991

Experimental intravesical therapy for superficial transitional cell carcinoma in a rat bladder tumor model.

A rodent bladder cancer model that is induced by intravesical instillation of N-methyl-N-nitrosourea (MNU) was characterized. Cohorts of four to five week old female Fisher 344 rats received four biweekly 1.5 mg. doses of intravesical MNU and were sacrificed at various intervals. By week 13 all animals had flat atypia and/or papillary transitional cell tumors, and 67% of the lesions were moderately (grade II) or poorly differentiated (grade III). By week 20, 83% had gross muscle invasive tumors that eventually killed the host. A cohort of 40 MNU treated animals was subsequently treated commencing at week 17 after initiation of MNU with one of three intravesical six week regimens: 1) saline; 2) BCG (Tice strain); or 3) recombinant human tumor necrosis factor (RTNF) plus adriamycin. There was no difference in animal survival or tumor growth in any group of animals commencing therapy at week 17. A second cohort of 107 animals commenced therapy at 13 weeks after initiation of MNU with one of five intravesical six week regimens: 1) intravesical BCG (Tice strain); 2) adriamycin; 3) recombinant human tumor necrosis factor (RTNF); 4) RTNF plus adriamycin; or 5) BCG plus adriamycin. BCG, RTNF or adriamycin alone had no effect on tumor growth; however, BCG plus adriamycin and RTNF plus adriamycin commencing at week 13 significantly inhibited tumor growth and progression. In conclusion, this autochthonous intravesical rodent transitional cell carcinoma model appears useful for the following reasons: 1) it closely resembles human transitional cell carcinoma histologically and biologically in that all animals develop neoplastic changes in-situ that progress to muscle invasion and kill the host; 2) as with human bladder cancer these tumors do not respond to intravesical therapy if treated when tumor burden is large; however, tumor growth is inhibited when treated early; and 3) this model appears appropriate for screening and developing new intravesical treatments for superficial bladder cancer.

Administration, Intravesical↗

PubMed2001

Neuropathology of paediatric chronic intestinal pseudo-obstruction and related animal models.

Chronic intestinal pseudo-obstruction (CIP) in paediatric patients is due to heterogeneous aetiologies that include primary disorders of the enteric nervous system. These conditions are poorly delineated by contemporary diagnostic approaches, in part because the complex nature of the enteric nervous system may shelter significant physiological defects behind subtle or quantitative anatomical changes. Until recently, relatively few experimental animal models existed for paediatric CIP. However, the availability of rodent models, particularly novel mutants created in the last few years by genetic manipulations, has brought unprecedented opportunities to investigate molecular, cellular, physiological, and histological details of enteric neuropathology. Information gleaned from studies of these animals is likely to change diagnostic and therapeutic approaches to paediatric CIP and related conditions.

Animals↗

PubMed2006

Restrictive and diversifying elements of the anti-myelin/oligodendrocyte glycoprotein antibody response in primate experimental allergic encephalomyelitis.

Autoantibody responses against conformational epitopes of myelin/oligodendrocyte glycoprotein (MOG) possess myelin destructive potential, as demonstrated in the marmoset model of human multiple sclerosis (MS) and in some rodent models of experimental allergic encephalomyelitis. We have previously characterized monoclonal Fab fragments specific for conformational epitopes of MOG that were derived from a combinatorial antibody library generated from a MOG-immune marmoset. In this paper, we address the molecular heterogeneity of humoral responses against MOG in this outbred model of MS by studying additional antibody clones derived from a genetically unrelated animal. We find that all MOG-specific IgGkappa Fab fragments, unrelated to genetic make-up, utilize a restricted set of variable region genes, IGHV1 and IGHV3 for the H chain and IGKV1, IGKV3, and IGKV5 for the L chain. Despite these restricting factors, diversity within these antibody repertoires can be observed, predominantly within the H-chain CDR3 regions. Our findings suggest that only a limited set of Ig genes is necessary to launch a diverse, destructive humoral immune response against a single CNS antigen in primates. These results are the first to contribute to a better understanding of how myelin-directed and potentially destructive autoantibody responses may develop in human MS.

Animals↗

PubMed1984

Evaluation of a proposed hamster separation model of depression.

Phodopus sungorus, the Siberian dwarf hamster, exhibits a number of reproducible and quantifiable behavioral changes when the members of a male-female pair bond are separated. Preliminary evaluation of the syndrome revealed a significant increase in body weight, decrease in social interaction, and decrease in exploratory behaviors, which occurred predominantly in separated males. Some, but not all, of the behavioral effects of separation are reversed by the tricyclic antidepressant, imipramine. Separation of pair-bonded Siberian dwarf hamsters may provide a new animal model for depression, incorporating the practical advantages of a rodent model with the conceptual advantages of a naturalistic life event precipitant.

Animals↗

PubMed1981

Neuron numbers in locus coeruleus do not change with age in Fisher 344 rat.

Counts of neurons in locus coeruleus of Fisher 344 rats of ages from 12 to 32 months showed no loss with advancing age. Species comparisons of age changes in locus coeruleus neuron counts and measures of catecholamine systems suggested that the human and nonhuman primate locus coeruleus shows age changes and seen in rodent locus coeruleus. It is suggested that although rodent models of human aging have value under some circumstances, rodent and primate brain should not be considered equivalent with regard to phenomena related to noradrenergic mechanisms.

Aging↗

PubMed2006

The use of cyclodialysis to limit exposure to elevated intraocular pressure in rat glaucoma models.

Elevated intraocular pressure (IOP) is the most common risk factor for glaucoma and pressure control is the goal of current clinical glaucoma therapy. Yet, recent clinical studies have documented that, even after therapeutic lowering of IOP, glaucomatous visual field loss can progress in many patients. Experimental elevation of IOP in the rat is commonly used to model human glaucomatous injury. However, there currently is no rodent model for the clinical situation of glaucomatous progression in eyes with apparently controlled IOP. The purpose of this study was to evaluate the ability of surgical cyclodialysis to produce both prolonged, non-injurious reduction of IOP in rat eyes and to stably normalize IOP in eyes with experimental pressure elevation. To perform cyclodialysis, a blunted spatula was fashioned from a hypodermic needle and used to separate a portion of the ciliary body from the sclera, opening a channel into the suprachoroidal space to allow aqueous outflow. Experimental IOP elevation was produced in rats by unilateral injection of hypertonic saline. Cyclodialysis in normal eyes resulted in an average 40 +/- 4% reduction in IOP, without marked hypotony. IOP lowering could be sustained for at least 6 months. The risk of retinal or optic nerve injury following a single cyclodialysis procedure was minimal as evidenced by unaltered levels of four injury-responsive retinal mRNAs and by normal optic nerve morphology. Cyclodialysis in eyes with experimental IOP elevation resulted in IOP normalization that was sustained for durations of 7 and 21 days in 88% and 53% of eyes, respectively. In addition, in eyes with the same cumulative dose of elevated IOP prior to the procedure, successful IOP normalization by cyclodialysis resulted in significantly less optic nerve injury than that seen in eyes in which IOP control was ineffective (p = 0.03). These studies show that cyclodialysis provides a simple, non-injurious method to reduce experimentally elevated IOP in rats that can be used to model the clinical situation of eyes previously damaged by pressure. This tool offers new opportunities for identifying and studying the molecular processes associated with glaucomatous progression and for testing potential neuroprotective therapies in a clinically relevant situation.

Animals↗

PubMedDate not supplied

Chlorpyrifos exposure of developing zebrafish: effects on survival and long-term effects on response latency and spatial discrimination.

Chlorpyrifos (CPF) is a widely used insecticide, which has been shown to interfere with neurobehavioral development. Rat models have been key in demonstrating that prenatal CPF exposure causes choice accuracy deficits and motor alterations, which persist into adulthood. Complementary nonmammalian models can be useful in determining the molecular mechanisms underlying the persisting behavioral effects of developmental CPF exposure. Zebrafish with their clear chorion and extensive developmental information base provide an excellent model for assessment of molecular processes of toxicant impacted neurodevelopment. To facilitate the use of the zebrafish model and to compare it to the more typical rodent models, the behavioral phenotype of CPF toxicity in zebrafish must be well characterized. Our laboratory has developed methods for assessing spatial discrimination learning in zebrafish, which can differentiate response latency from choice accuracy in a three chambered fish tank. Low and high doses of CPF (10 and 100 ng/ml on days 1-5 postfertilization) both had significant persisting effects on both spatial discrimination and response latency over 18 weeks of testing. The high, but not the low dose, significantly accelerated mortality rates of the fish during the study from 20-38 weeks of age. Developmental exposure to either 10 or 100 ng/ml of CPF caused significant spatial discrimination impairments in zebrafish when they were adults. The impairment caused by 10 ng/ml was seen during early but not later testing, while the impairment caused by 100 ng/ml became more pronounced with continued testing. The higher dose caused a more pervasive impairment. The 10 and 100 ng/ml doses had opposite effects on response latency. The low 10 ng/ml dose significantly slowed response latency, while the high 100 ng/ml dose significant increased response latency. Both of these effects diminished with continued testing. CPF exposure during early development caused clear behavioral impairments, which lasted throughout adulthood in zebrafish. The molecular mechanisms by which early developmental CPF exposure produces these behavioral impairments expressed in adulthood can now be studied in the zebrafish model.

Animals↗

PubMed1995

Cyclosporine A induced arteriolopathy in a rat model of chronic cyclosporine nephropathy.

Chronic cyclosporine (CsA) nephrotoxicity is a major complication of heart, bone marrow, and renal transplantation, and is characterized in humans by striped interstitial fibrosis, tubular dilatation and atrophy, and hyalinization of hilar arterioles. This last feature is highly specific for cyclosporine injury and has been difficult to reproduce in normotensive animal models. Salt-depletion has been shown to sensitize rodents to the effects of CsA and accelerate the disease process. We conducted sequential studies in chronically salt depleted, pair fed rats treated with CsA (15 mg/kg, s.c.) or an equivalent dose of olive oil vehicle, and found a histologic lesion associated with CsA that consisted of striped cortical interstitial fibrosis, tubular dilatation and atrophy, and hyalinization of many afferent arterioles. The arteriolopathy was first detected at day 10 with progressive hyalinization of arterioles continuing until termination of the study at day 35. The arteriolopathy consisted initially of eosinophilic granular transformation of smooth muscle cells comprising afferent hilar glomerular arterioles, and progressed to foci of smooth muscle cell vacuolization and accumulation of discrete hyaline deposits in vessel walls. Electron microscopy demonstrated marked accumulation of typical renin granules throughout the smooth muscle cell cytoplasm, corresponding to the eosinophilic granular transformation revealed histologically. Immunocytochemistry confirmed the up-regulated production of renin in these vessels. This study documents a rodent model for CsA arteriolopathy and CsA-associated interstitial fibrosis that strikingly reproduces the most characteristic nephropathic effects of cyclosporine found in human patients treated with this agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

Production of knockout rats using ENU mutagenesis and a yeast-based screening assay.

The rat is a widely used model in biomedical research and is often the preferred rodent model in many areas of physiological and pathobiological research. Although many genetic tools are available for the rat, methods to produce gene-disrupted knockout rats are greatly needed. In this study, we developed protocols for creating N-ethyl-N-nitrosourea (ENU)-induced germline mutations in several rat strains. F1 preweanling pups from mutagenized Sprague Dawley (SD) male rats were then screened for functional mutations in Brca1 and Brca2 using a yeast gap-repair, ADE2-reporter truncation assay. We produced knockout rats for each of these two breast cancer suppressor genes.

Animals↗

PubMed1994

Lazaroids improve the survival of grafted rat embryonic dopamine neurons.

In rodent models of Parkinson disease in which transplants of dissociated rodent and human embryonic mesencephalic tissue, rich in dopamine neurons, have been studied, only 5-20% of the dopamine neurons survive the implantation procedure. We have investigated the effects of inhibiting free radical generation with two lazaroids, U-74389G and U-83836E, on the survival of embryonic rat dopamine neurons. U-74389G is a 21-aminosteroid, and U-83836E combines the piperazinyl pyrimidine portion of 21-aminosteroids with the antioxidant ring of alpha-tocopherol. In an initial study, we found that the lazaroids markedly prolonged the period after tissue dissociation that an embryonic mesencephalic cell suspension exhibits high cell viability in vitro, as assessed by using a dye exclusion method. In a second series of experiments, addition of lazaroids to dissociated mesencephalic graft tissue increased the yield of surviving rat dopamine neurons 2.6-fold after implantation in the dopamine-denervated rat striatum. The improved survival correlated with an earlier onset of graft-induced functional effects in the amphetamine-induced rotation test. Thus, inhibition of free radical generation can significantly increase the yield of grafted embryonic dopamine neurons. Addition of lazaroids to the graft preparation is a relatively simple modification of the transplantation protocol and could readily be applied in a clinical setting. Moreover, since iron-dependent lipid peroxidation has been suggested to play a role in the death of nigral dopamine neurons in Parkinson disease and lazaroids are particularly potent inhibitors of such processes, the findings may have implications for the pathogenesis of this disease.

Animals↗

PubMed2006

Neonatal animal models of opiate withdrawal.

The symptoms of opiate withdrawal in infants are defined as neonatal abstinence syndrome (NAS). NAS is a significant cause of morbidity in term and preterm infants. Factors, such as polysubstance abuse, inadequate prenatal care, nutritional deprivation, and the biology of the developing central nervous system contribute to the challenge of evaluating and treating opiate-induced alterations in the newborn. Although research on the effects of opiates in neonatal animal models is limited, the data from adult animal models have greatly contributed to understanding and treating opiate tolerance, addiction, and withdrawal in adult humans. Yet the limited neonatal data that are available indicate that the mechanisms involved in these processes in the newborn differ from those in adult animals, and that neonatal models of opiate withdrawal are needed to understand and develop effective treatment regimens for NAS. In this review, the behavioral and neurochemical evidence from the literature is presented and suggests that mechanisms responsible for opiate tolerance, dependence, and withdrawal differ between adult and neonatal models. Also reviewed are studies that have used neonatal rodent models, the authors' preliminary data based on the use of neonatal rat and mouse models of opiate withdrawal, and other neonatal models that have been proposed for the study of neonatal opiate withdrawal.

Age Factors↗

PubMed2003

gamma-Aminobutyric acid-A receptors contribute to isoflurane neuroprotection in organotypic hippocampal cultures.

UNLABELLED: The mechanisms by which anesthetics such as isoflurane reduce cell death in rodent models of cerebral ischemia remain incompletely defined. Reduction in glutamate excitotoxicity explains some but not all of isoflurane's neuroprotection. Because isoflurane potentiates gamma-aminobutyric acid (GABA) receptor-mediated ion fluxes and GABA(A) receptor agonists have neuroprotective effects, we hypothesized that GABA(A) receptors contribute to isoflurane neuroprotection. As a model of cerebral ischemia and recovery, we used rat hippocampal slice cultures. Survival of CA1, CA3, and dentate neurons was examined 2 and 3 days after 1-h combined oxygen-glucose deprivation (OGD) at 37 degrees C. To define the role of GABA(A) receptors in mediating protection, the effect of 1% isoflurane on cell survival was examined in the presence of the GABA(A) antagonist bicuculline during OGD. Cell death was measured with propidium iodide fluorescence. Isoflurane and the selective GABA(A) agonist muscimol (25 micro M) reduced cell death after OGD to values similar to slices not exposed to OGD, with the exception that muscimol did not reduce cell death in CA3 neurons 2 days after OGD. The GABA(A) antagonist bicuculline reduced the neuroprotective effects of isoflurane on hippocampal neurons 2 and 3 days after OGD. We conclude that GABA(A) receptors contribute to neuroprotection against OGD produced by isoflurane in the hippocampal slice model. Based on this and other studies, it is likely that neuroprotection produced by isoflurane is multifactorial and includes actions at both GABA(A) and glutamate receptors and possibly other mechanisms. IMPLICATIONS: Isoflurane is neuroprotective in rodent brain ischemia models, but the mechanisms for this effect remain incompletely defined. In organotypic cultures of rat hippocampus, we show that protection of CA1, CA3, and dentate neurons by 1% isoflurane from death caused by oxygen and glucose deprivation involves GABA(A) receptors.

Anesthetics, Inhalation↗

PubMed1996

Fish models for environmental carcinogenesis: the rainbow trout.

Progress over the past 30 years has revealed many strengths of the rainbow trout as an alternative model for environmental carcinogenesis research. These include low rearing costs, an early life-stage ultrasensitive bioassay, sensitivity to many classes of carcinogen, a well-described tumor pathology, responsiveness to tumor promoters and inhibitors, and a mechanistically informative nonmammalian comparative status. Low-cost husbandry, for example, has permitted statistically challenging tumor study designs with up to 10,000 trout to investigate the quantitative interrelationships among carcinogen dose, anticarcinogen dose, DNA adduct formation, and final tumor outcome. The basic elements of the trout carcinogen bioassay include multiple exposure routes, carcinogen response, husbandry requirements, and pathology. The principal known neoplasms occur in liver (mixed hepatocellular/cholangiocellular adenoma and carcinoma, hepatocellular carcinoma), kidney (nephroblastoma), swim bladder (adenopapilloma), and stomach (adenopapilloma). Trout possess a complex but incompletely characterized array of cytochromes P450, transferases, and other enzymic systems for phase I and phase II procarcinogen metabolism. In general, trout exhibit only limited capacity for DNA repair, especially for removal of bulky DNA adducts. This factor, together with a high capacity for P450 bioactivation and negligible glutathione transferase-mediated detoxication of the epoxide, accounts for the exceptional sensitivity of trout to aflatoxin B1 carcinogenesis. At the gene level, all trout tumors except nephroblastoma exhibit variable and often high incidences of oncogenic Ki-ras gene mutations. Mutations in the trout p53 tumor suppressor gene have yet to be described. There are many aspects of the trout model, especially the lack of complete organ homology, that limit its application as a surrogate for human cancer research. Within these limitations, however, it is apparent that trout and other fish models can serve as highly useful adjuncts to conventional rodent models in the study of environmental carcinogenesis and its modulation. For some problems, fish models can provide wholly unique approaches.

Animals↗

PubMed2001

Of mice and men: virtual Hebb-Williams mazes permit comparison of spatial learning across species.

We developed a computer-generated virtual environment to test humans, for the first time, on the Hebb-Williams mazes. The goal was to provide a standardized test that could be used to directly compare human performance with that of C57BL/6J mice performing in real versions of the mazes. Such a comparison seems crucial if conclusions regarding genetic manipulations of rodents are to be mapped onto human cognitive disorders. The learning curves across species were strikingly similar, lending support to the rodent model of human spatial memory. Humans learned faster than rodents in both the acquisition and the test portions of the protocol, and females of both species were less efficient in solving these problems than males. These results represent the first modern comparison of human and rodent learning that uses the same test of spatial problem solving.

Adult↗

PubMed2002

A comparison of rat tracheal transplant models: implantation verses anastomotic techniques for the study of airway rejection.

BACKGROUND: In rodent models, investigators have transplanted donor tracheas into a recipient rat's abdomen or s.c. tissue to study airway rejection. We describe a modification of this model, which provides improved histology to study the airway injury related to obliterative bronchiolitis. METHODS: The standard technique of implanting the donor trachea was compared to a model in which a tracheal Y graft was created by anastomosis of the donor trachea to the recipient airway. Syngeneic and allogeneic tracheal grafts (Lewis and Brown Norway rats) were harvested at 2 and 4 weeks using each model (eight groups). RESULTS: Gross patency at the tracheal anastomosis grafts was 100%. All donor tracheas, which were implanted without an anastomosis, were occluded with mucus (syngeneic) or granulation tissue (allogeneic). Syngeneic implant grafts demonstrated significantly less lumenal granulation tissue 35.3%+/-32 than the allograft implant group (95.3%+/-9.2, P=0.0005 at 4 weeks). The anastomotic allograft group demonstrated significantly less lumenal granulation tissue 48.3%+/-23.7 when compared with the implanted allograft group (P=0.003). The implanted allograft demonstrated a severe loss of epithelial integrity by 2 weeks (16.7%+/-38), which progressed to complete loss by 4 weeks (P=0.0001 and P=0.0001 vs. native). This loss was significantly more than that of the anastomotic group at 2 weeks (89.5%+/-13, P=0.004) and 4 weeks (88.3+/-29, P=0.005). CONCLUSIONS: The rat tracheal allograft anastomosed to the recipient airway demonstrated less lumenal granulation tissue obstruction and better preservation of epithelial integrity than an implant allograft, suggesting that an open airway improves assessment of transplant-related changes associated with rejection.

Anastomosis, Surgical↗

PubMed2006

Molecular approaches to study control of glucose homeostasis.

Type 2 diabetes is a polygenic disease that can lead to severe complications in multiple tissues. Rodent models have been used widely for investigating the pathophysiology underlying type 2 diabetes and for examining the potential link with obesity, largely due to the limitations of invasive testing and of studying detailed molecular mechanisms in human tissues. Among rodents, the mouse model is especially popular because mice are easy to manipulate genetically, have a short generation time, and are relatively inexpensive. The most commonly used inbred mouse strains are reviewed in addition to several genetically engineered mouse models that have been generated to study type 2 diabetes in the context of obesity, with a focus on insulin, leptin, and peroxisome proliferator-activated receptor (PPAR) signaling pathways.

Animals↗