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PubMed2004

Cannabinoids and neuroinflammation.

Growing evidence suggests that a major physiological function of the cannabinoid signaling system is to modulate neuroinflammation. This review discusses the anti-inflammatory properties of cannabinoid compounds at molecular, cellular and whole animal levels, first by examining the evidence for anti-inflammatory effects of cannabinoids obtained using in vivo animal models of clinical neuroinflammatory conditions, specifically rodent models of multiple sclerosis, and second by describing the endogenous cannabinoid (endocannabinoid) system components in immune cells. Our aim is to identify immune functions modulated by cannabinoids that could account for their anti-inflammatory effects in these animal models.

Animals↗
PubMed2003

A squirrel monkey model of poststroke motor recovery.

Nonhuman primate models of poststroke recovery have become increasingly rare primarily due to high purchase and maintenance costs and limited availability of nonhuman primate species. Despite this obstacle, nonhuman primate models may offer important advantages over rodent models for understanding many of the brain's mechanisms for self-repair due to greater similarity in cortical organization to humans. Since the mid-1990s, surgical, neurophysiological, and neuroanatomical methods have been developed to understand structural and functional remodeling of the cerebral cortex after an ischemic event, such as occurs in stroke. These methods require long surgical procedures and entail constant physiological monitoring. With careful attention to intraoperative and postsurgical monitoring, these procedures can be repeated multiple times in individual monkeys without untoward events. This model provides a statistically powerful approach for tracking brain plasticity in the ensuing weeks and months after a stroke-like injury, reducing the number of animals required for individual experiments. This methodology is described in detail, and many of the resulting findings that are relevant for understanding stroke recovery and the effects of rehabilitative and pharmacotherapeutic interventions are summarized.

Animals↗
PubMed1999

Alloimmune injury preceding airway obliteration in porcine heterotopic lung implants: a histologic and immunohistologic study.

BACKGROUND: Obliterative bronchiolitis (OB), the major long-term complication of lung transplantation, has thus far lacked a good large-animal model. Our goal was to develop such a model on the basis of previous rodent models with tracheal implants. METHODS: Fragments of pulmonary tissue with structures of terminal bronchi were subcutaneously transplanted to four random-bred domestic piglets. Each animal received 10 autograft and 10 allograft implants. The histologic findings were graded from 0 to 3 for implants harvested repeatedly over 2 months. RESULTS: In autografts, partial destruction of the respiratory epithelium and gradual luminal obliteration as well as mild damage to the cartilage and the bronchial wall underwent rapid reversal after initial ischemic injury. In the allografts, epithelial destruction and gradual obliteration were total within 14 days, the difference being statistically significant (P<0.05) in both. The histologic features of the obliterative plug were similar to those of human OB. In the allografts, cartilaginous destruction and pericartilaginous inflammation increased gradually to severe levels, significantly worse than in the autografts (P<0.05). Necrosis and inflammation of the bronchial wall were also more severe in the allografts (P<0.05). CONCLUSIONS: At the end of follow-up, all autografts were vital, whereas the allografts were almost totally rejected and were without native structures. All bronchi in the allografts exhibited accelerated obliteration with histologic features characteristic of human OB, thus providing a model for research into OB and its prevention.

Animals↗
PubMed2003

Sp1 and Sp3 are oxidative stress-inducible, antideath transcription factors in cortical neurons.

Neuronal cell death in response to oxidative stress may reflect the failure of endogenous adaptive mechanisms. However, the transcriptional activators induced by oxidative stress in neurons that trigger adaptive genetic responses have yet to be fully elucidated. We report that basal DNA binding of the zinc finger transcription factors Sp1 and Sp3 is unexpectedly low in cortical neurons in vitro and is significantly induced by glutathione depletion-induced or hydrogen peroxide-induced oxidative stress in these cells. The increases in Sp1/Sp3 DNA binding reflect, in part, increased levels of Sp1 and Sp3 protein in the nuclei of cortical neurons. Similar induction of Sp1 and Sp3 protein is also observed in neurons in vivo in a chemical or a genetic model of Huntington's disease, two rodent models in which neuronal loss has been attributed to oxidative stress. Sustained high-level expression of full-length Sp1 or full-length Sp3, but not the Sp1 zinc finger DNA-binding domain alone, prevents death in response to oxidative stress, DNA damage, or both. Taken together, these results establish Sp1 and Sp3 as oxidative stress-induced transcription factors in cortical neurons that positively regulate neuronal survival.

Animals↗
PubMed2006

Analysis of optic nerve stroke by retinal Bex expression.

PURPOSE: Few proteins are known to be selectively expressed in retinal ganglion cells (RGCs), the neurons directly affected by optic nerve stroke and glaucoma. In addition, subsets of RGCs are reported to project to various CNS areas via the retinohypothalamic pathway in rodents and primates. Many of these areas exhibit immunoreactivity for the brain-expressed X-linked (Bex) proteins Bex1 and Bex2. This prompted us to evaluate expression of these proteins in retina. METHODS: We utilized rats and transgenic mice, coupled with a new rodent model of isolated optic nerve stroke (rodent anterior ischemic optic neuropathy, rAION). An anti-Bex1 antibody was reacted to retinal tissue extracts. To evaluate short term effects of rAION on RGC Bex expression, a double transgenic mouse strain was employed expressing cyan fluorescent protein (CFP) under control of the Thy-1 protein promotor, and beta-galactosidase (lacZ) under control of the immediate early stress c-fos gene promotor. Positive identification of rat RGCs was performed by retrograde fluorogold labeling via stereotactic CNS injection. Retinas were analyzed using both diaminobenzidine (DAB)-linked immunochemistry and confocal microscopy. RESULTS: Bex immunoreactivity is present at high levels in the retina. Bex1 and Bex2 are selectively expressed in RGCs and differentially expressed in a subset of large RGC neurons. Bex signal levels are lower in small RGC neurons, which preferentially express high levels of the transcription factor Brn3b. Post-stroke, Bex accumulates in the RGC cytoplasm, consistent with the optic nerve edema produced by clinical AION. CONCLUSIONS: Bex immunoreactivity can be used to evaluate, ex vivo, the distribution of RGC cell bodies and their axons in the retina and rAION effects on RGC axonal loss. Thus, Bex can be utilized to evaluate both long- and short-term effects of optic nerve stroke and may play a significant role in regulating RGC functions in both the axonal and cell body components of RGC neurons.

Animals↗
PubMed1996

Wistar rat-Plasmodium berghei model does not approximate human congenital malaria.

Until recently, congenital malaria was thought to be rare. Now, several reports suggest that more than 10% of newborns in some settings are parasitemic. The pathophysiology of transplacental transmission of Plasmodium is not well understood, and no animal model of congenital malaria exists. A rodent model of malaria in pregnant females, however, has been developed. In an effort to test the usefulness of this model in the study of congenital malaria, Wistar rats were injected intraperitoneally with approximately 10(6) NYU-2 strain Plasmodium berghei-infected erythrocytes at various times relative to conception. Perinatal maternal and neonatal blood was tested for the presence of parasites. Two rats infected preconceptually, 1 at 29 and the other at 11 days prior to mating, delivered aparasitemic pups. Fourteen rats were inoculated during gestation. Five of 5 rats infected on the fifth gestational day succumbed prior to delivery; 1 fetus was parasitemic. Offspring of females infected on the 9th, 10th, 12th, and 14th days of gestation were aparasitemic at birth. Four rats conceived after an initial Plasmodium infection had waned and were reinfected during pregnancy; none of their pups showed evidence of parasitemia. Thus, though rare, transplacental passage of malaria parasites can occur in rats. The Wistar rat-P. berghei model of gestational malaria, however, does not seem to be useful for the study of congenital malaria.

Animals↗
PubMed1996

Preclinical models of prostate cancer.

Prostate cancer is the most common non-skin malignancy, yet the biological and molecular characteristics of the disease remain only poorly understood. One of the many reasons for this is that there are so few animal or human laboratory models of prostate cancer. Prostate cancer rarely arises spontaneously in animals, and the human cancer is unusually hard to grow in culture or as xenografts even short-term. The prostate cancer models that do exist are basically rodent models, human cell lines, human xenografts, and gene transfer and transgenic models. Many laboratories have put great effort into developing prostate cancer models, without much success. These efforts recently have been forced to be curtailed, primarily due to a lack of funding. There is good reason to believe, however, that propagation of metastatic tissue will be much more successful. At the University of Washington, the Prostate Cancer Donor Program, organized in a manner similar to existing methods for cadaver organ harvest, has been instituted to help recruit patients for these approaches. Prospects for success of model development also have been improved because of advances in techniques for the maintenance of severe combined immunodeficiency disease mice or nude mice.

Animals↗
PubMed1987

Development and significance of cysteamine and propionitrile models of duodenal ulcer.

Cysteamine is widely used in rodents to induce duodenal ulcer. Herein, the pathogenesis of duodenal ulceration in its earliest stages was reviewed using findings from cysteamine- and propionitrile-induced duodenal ulcer in rodent models, especially taking into account changes in the secretion of gastric acid, duodenal and pancreatic bicarbonate as well as gastroduodenal motility. The effect of cysteamine-HCl in inducing ulcers in rats is circadian rhythm-dependent. The effect is greatest from just before the end of diurnal rest to just after the start of nocturnal activity. The chronobiologic effect may be in part due to the circadian rhythm-dependent increased gastric acid production from cysteamine. Titratable acidity was found to be twice as great in the gastric juice of rodents when cysteamine was given by injection at 2000 (just after the start of nocturnal activity) in comparison to when given at 0800 or 1200 (at the beginning or middle span of daily rest). Further studies have shown that adrenalectomy of rats 7 days before cysteamine administration obliterated the observed circadian susceptibility to ulcer formation. Duodenal ulceration, at least in the cysteamine model, appears to be under chronobiologic neuroendocrine control or influence, seemingly mediated by the adrenal glands.

Animals↗
PubMed1998

In vivo transgenic bioassays and assessment of the carcinogenic potential of pharmaceuticals.

There is general agreement in the scientific community on the need to improve carcinogenicity testing and the assessment of human carcinogenic risk and to incorporate more information on mechanisms and modes of action into the risk assessment process. Advances in molecular biology have identified a growing number of genes such as protooncogenes and tumor-suppressor genes that are highly conserved across species and are associated with a wide variety of human and animal cancers. In vivo transgenic rodent models incorporating such mechanisms are used to identify mechanisms involved in tumor formation and as selective tests for carcinogens. Transgenic methods can be considered an extension of genetic manipulation by selective breeding, which long has been employed in science and agriculture. The use of two rodent species in carcinogenicity testing is especially important for identifying transspecies carcinogens. The capacity of a substance to induce neoplasia across species suggests that the mechanism(s) involved in the induction of the neoplasia are conserved and therefore may have significance for humans. Based on available information there is sufficient experience with some in vivo transgenic rodent carcinogenicity models to support their application as complementary second species studies in conjunction with a single 2-year rodent carcinogenicity study. The optional substitution of a second 2-year rodent carcinogenicity study with an alternative study such as an in vivo transgenic carcinogenicity study is part of the International Conference on Harmonization guidance S1B: Testing for Carcinogenicity of Pharmaceuticals. This guidance is intended to be flexible enough to accommodate a wide range of possible carcinogenicity assessment models currently under consideration or models that may be developed in the future. The use of an in vivo transgenic mouse model in place of a second 2-year mouse study will improve the assessment of carcinogenic risk by contributing insights into the mechanisms of tumorigenesis and potential human relevance not available from a standard 2-year bioassay. It is envisioned that this will stimulate the further development of more efficient and relevant methods for identifying and assessing potential human carcinogenic risk, which will benefit public health.

Animals↗
PubMed2006

Multimammate rat (Mastomys natalensis), Tristram's jird (Meriones tristrami) and Wagner's gerbil (Gerbillus dasyurus) as laboratory models of acute neosporosis.

To test the different sensitivity of rodents of the subfamily Murinae and Gerbillinae, Wagner's gerbils (Gerbillus dasyurus), Tristram's jirds (Meriones tristrami) and multimammate rats (Mastomys natalensis) were inoculated with Neospora caninum tachyzoites. Clinical signs of neosporosis appeared in all inoculated animals. Histopathological examination confirmed the presence of tachyzoites in brains, lungs, skeletal muscle, myocardium, liver, in serosa of stomach and intestines, and in vesicular accessory genital glands. An examination of brains by PCR revealed presence of N. caninum DNA in all experimentally N. caninum infected rodents. The susceptibility of Wagner's gerbils and Tristram's jirds further proved the high sensitivity of gerbiline rodents to the N. caninum infection. The finding of N. caninum tachyzoites in the vesicular accessory genital glands of the infected gerbils suggests the usefulness of the rodent model for demonstration of N. caninum in the male reproductive system. Moreover, the multimammate rat was a susceptible experimental host to be the first immunocompetent rodent of the subfamily Murinae.

Acute Disease↗
PubMed2004

Heterotopic limb allotransplantation model to study skin rejection in the rat.

Current rodent models for investigation of limb allotransplantation typically utilize orthotopic whole-limb transplantation, a morbid and time-consuming procedure. Our objective was to design a less morbid rat model to explore the immunological obstacles of limb transplantation, and particularly skin. Twenty lower hindlimbs from 10 donors were transplanted into a heterotopic subcutaneous position into 20 animals (10 isogeneic and 10 allogeneic). Each group was further subdivided to include animals with (n = 5) and without (n = 5) a skin paddle for observation of cutaneous signs of rejection. All grafts in the isogeneic group survived for 100 days, i.e., the endpoint of the study. Allogeneic transplants rejected their allografts at a mean of 12.8 days (with skin) and 20.6 days (without). Our heterotopic limb transplantation model takes less time and is less stressful to the animals, while allowing for early observation of graft skin rejection, when compared to orthotopic whole-limb transplantation.

Anastomosis, Surgical↗
PubMed2003

Initial thermal heat hypoalgesia and delayed hyperalgesia in a murine model of bone cancer pain.

The recent development of rodent models of bone cancer pain has started to provide the basis for demonstrating the particular neurochemical and behavioral entity of cancer pain. Behaviourally, both spontaneous pain and hyperalgesia related to mechanical, but not thermal, noxious stimuli have been described in cancer-bearing animals. We have carried out a histological and behavioural study focused on the reactivity to noxious heat in C3H/HeJ mice receiving an intratibial injection of 10(5) NCTC 2472 cells. These cells, able to induce an osteosarcoma, break through bone into soft tissues 2 weeks after cell inoculation, producing a macroscopical increase of the limb size from the fourth week. Thermal reactivity is diminished during the first 2 weeks after cell implantation, this hypoalgesia being reversed by the administration of naloxone (10 mg/kg). In contrast, during the fourth and fifth weeks after NCTC 2472 cell implantation, an increased nociceptive heat reactivity, instead of hypoalgesia, was obtained. This thermal hyperalgesia was prevented by the systemic administration of morphine (15 mg/kg). Throughout the whole period studied, mice showed signs of spontaneous pain behaviour that reached its maximum 3 weeks after inoculation. In conclusion, we show that the presence of thermal heat hyperalgesia is preceded by an initial opioid-mediated hypoalgesic state, in this murine model of bone cancer pain.

Animals↗
PubMed1992

Development of a bleomycin hamster model of subchronic lung fibrosis.

The existing bleomycin (BLM)-rodent model of lung fibrosis requires large doses and is often associated with morbidity and high mortality. We have developed an intratracheal multiple-dose BLM-hamster model of lung fibrosis. In this model, 3 consecutive doses of BLM (2.5 U, 2.0 U and 1.5 U/5mL/kg) were instilled intratracheally, one dose per week. The hamsters were killed at 10, 20, 30, 60 and 90 days after the last IT instillation and the lungs were lavaged or perfused with saline. This regimen of BLM administration was devoid of morbidity and caused only 6% overall mortality. Lung prolyl hydroxylase activity at 10 days and hydroxyproline content at 20, 30, 60 and 90 days were significantly higher than noted for the controls. Bronchoalveolar lavage fluid-supernatant protein and the total number of recovered cells of all types were significantly higher than observed for the controls at all times, except at 90 days. Lungs showed a multifocal mixed mononuclear infiltrate at 10 and 20 days and septal fibrosis, which was most severe and organized at 30 days and less severe at 60 and 90 days. The parenchymal lesions were significantly greater than those of the controls at all times, except at 10 days. This model, which required only 6 U BLM/kg, induced a moderate level of lung fibrosis. It has been concluded, therefore, that this model, inasmuch as it is not associated with an overwhelmingly acute inflammation, would be more applicable for screening potential antifibrotic agents than existing models of lung fibrosis.

Animals↗
PubMed1998

[Development of mouse and rat model of Helicobacter pylori infection].

OBJECTIVE: To develop different rodent model of H. pylori infection as to meet different requirement for different purpose of study. METHODS: 40 two-grade Wistar rats, 40 two-grade C57BL/6 mice and 40 SPF BALB/c mice were randomly divided into two groups: experimental and control groups. Animals in the experimental group were inoculated orally Hp strain (Sydney Strain 1, SS1), 0.4 ml of inoculum per mouse, 1.5 ml per rat (10(9) organisms/ml) five times for a week. In 4, 8, 12 and 24 weeks after the last bacteria inoculum, 5 animals in the experimental and control groups were sacrificed respectively. Histology and Hp colonization were assessed by HE staining, Gimesa staining, Urease test, and Hp culture. RESULTS: In 4 weeks, in all experimental animals bacteria were clearly visible at antrum and body, but the number of Hp colonization varied according to the animal strain. Heavy colonization was seen in C57BL/6 in antrum and body, and in BALB/c and Wistar colonization was located mainly at antrum, less at body, which tended to increase over the experiment time, especially in Wistar. Hp was negative in the controls. All animals had no inflammatory changes in 4 weeks, however, in 8, 12 and 24 weeks in Balb/c. Wistar and C57BL/6 of the experimental group, mild to moderate chronic active gastritis was observed in antrum and body, which increased in severity over time, atrophy gastritis was still not seen in 24 weeks. In contrast, in the controls, no remarkable changes were detected. CONCLUSIONS: SS1 Hp can colonize in the glandular stomach mucosa of BALB/c, C57BL/6 mice and Wistar rats and leads to chronic active gastritis in long-term study. SS1 mouse and rat model is adaptable for animal experimentation of H. pylori including vaccine studies, screening for novel therapeutics and investigation of mechanisms of pathogenesis.

Animals↗
PubMed2004

Molecular and genetic regulation of testis descent and external genitalia development.

Testicular descent as a prerequisite for the production of mature spermatozoa and normal external genitalia morphogenesis, and therefore facilitating copulation and internal fertilization, are essential developmental steps in reproduction of vertebrate species. Cryptorchidism, the failure of testis descent, and feminization of external genitalia in the male, usually in the form of hypospadias, in which the opening of the urethra occurs along the ventral aspect of the penis, are the most frequent pediatric complications. Thus, elucidating the molecular mechanisms involved in the regulation of testis descent and the formation of external genitalia merits a special focus. Natural and transgenic rodent models have demonstrated both morphogenic processes to be under the control of a plethora of genetic factors with complex time-, space-, and dose-restricted expression pattern. The review elucidates the molecular mechanisms involved in the regulation of testis descent and the formation of external genitalia and, wherever possible, assesses the differences between these rodent animal models and other mammalian species, including human.

Androgens↗
PubMedDate not supplied

Oxidation, antioxidants and cataract formation: a literature review.

PURPOSE: This review aims to provide a literature survey of the association between photo-oxidation of lens proteins and lipid peroxidation with the genesis of age-related cataract in laboratory studies using rodent models, in epidemiological and interventional studies in humans. MATERIALS AND METHODS: A Medline search using initial search terms lens, oxidation, antioxidant, and diet was employed to search for research papers covering the areas noted above from 1995 to 2005. Literature cited in those papers was also reviewed to provide as comprehensive a coverage of research work as possible. RESULTS: Lens protein photo-oxidation and lipid peroxidation are widely acknowledged as important steps in age-related cataractogenesis. Dietary antioxidants are central in retarding cataractogenesis, although most evidence for this is gained from laboratory-based work on relatively unphysiologic rodent cataract models, using antioxidant regimes that could not be sustained in clinical practice. Most research in humans is retrospective epidemiology although some interventional research has been undertaken, with mixed results. CONCLUSIONS: Dietary antioxidants are likely to be important in retarding cataractogenesis in older animals and in humans. Work on companion animals could provide a valuable stepping stone between rodent-based laboratory work and human interventional studies.

Aging↗
PubMed1998

A rat model of chronic lumbar epidural catheterisation.

PURPOSE: There are no rodent models of chronic epidural catheterisation which can induce clinically relevant analgesic effects of morphine (potency ratio of intrathecal:epidural = 10 to 30:1). The purpose of this study was to investigate a new rat model of chronic epidural catheterisation by comparing the analgesic effect of epidural and intrathecal morphine. METHODS: In Sprague-Dawley rats, for epidural catheterisation, a skin incision and muscle dissection were made at T13 level in the midline. The intervertebral ligament was cut to insert an epidural catheter (polyethylene tube; outer diameter 0.14 mm) 2 cm caudally. The distal end of the catheter (0.61 mm) was passed s.c. to exit in the dorsal neck area. For intrathecal catheterisation, the atlanto-occipital membrane was incised to insert a catheter (0.61 mm) 8.5 cm caudally. The effects of morphine (1, 3, 10, 30, or 100 micrograms.10 microliters-1 intrathecally, and 30, 100, or 300 micrograms.5, 10, or 20 microliters-1 epidurally) on thermal escape latency were investigated by a hot box test. Behaviour and motor function were also tested. RESULTS: A volume of 20 microliters induced greater analgesic effect than 5 and 10 microliters epidural administration. The ED50 of epidural morphine (94.1 micrograms) was 30 times more than that of intrathecal morphine (3.1 micrograms). CONCLUSION: A new rat model of chronic epidural catheterisation is described, which provides a similar analgesic epidural: intrathecal potency ratio for morphine to that in humans when morphine is administered in a volume of 20 microliters.

Akathisia, Drug-Induced↗
PubMed2006

Ghrelin alleviates cancer chemotherapy-associated dyspepsia in rodents.

PURPOSE: Chemotherapy treatment may lead to delayed gastric emptying, early satiety, anorexia, nausea and vomiting, described collectively as the cancer-associated dyspepsia syndrome (CADS). METHOD: We examined the effects of ghrelin in rodent models of CADS induced by treatment with cisplatin. RESULTS: In rats, increased gastric contents and reduced feeding were observed 48 h after injection with cisplatin (6 mg/kg, i.p.). Ghrelin (0.5 mg/kg, i.p.) caused a 16-fold increase in food intake over 1 h in cisplatin/ghrelin-treated rats compared to cisplatin/vehicle-treated rats. A single dose of ghrelin also restored the decreased locomotor activity in rats induced by cisplatin to almost the same level of saline-treated rats. In mice, daily food intake was significantly decreased at 24 h (60%) and 48 h (74%) after cisplatin (20 mg/kg, i.p.). Ghrelin (1 mg/kg, i.p.x2) significantly increased food intake measured at the 48 h time-point in both saline/ghrelin-treated and cisplatin/ghrelin-treated mice, with this effect being most marked in the cisplatin-treated group, where a twofold increase in feeding was observed. In cisplatin-treated mice, delayed gastric emptying was indicated by a 7.7-fold increase in the wet weight of gastric contents and ghrelin improved the gastric emptying index (GEI) by 31% (P < 0.01). CONCLUSION: Together, these results suggest that it is possible to model cancer chemotherapy-induced dyspepsia in rodents and that ghrelin can greatly alleviate the behaviours associated with this syndrome. Agonists at the ghrelin receptor may, therefore, become a useful human therapeutic for this disorder.

Animals↗