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PubMed2005

Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism.

Autism is a severe behavioral disorder characterized by pervasive impairments in social interactions, deficits in verbal and nonverbal communication, and stereotyped, repetitive patterns of behaviors and interests. Recently, a new rodent model of autism was created by exposure of rat fetuses to valproic acid (VPA) on the 12.5th day of gestation (VPA rats). The model has striking anatomical, pathological, and etiological similarities to human data; however, it has not been characterized behaviorally. In order to determine if VPA rats present behavioral aberrations observed in autism, their behavior was extensively evaluated in a battery of tests. The results of the present experiments demonstrate that VPA rats exhibit: (1) lower sensitivity to pain and higher sensitivity to nonpainful stimuli, (2) diminished acoustic prepulse inhibition, (3) locomotor and repetitive/stereotypic-like hyperactivity combined with lower exploratory activity, and (4) decreased number of social behaviors and increased latency to social behaviors. In addition, VPA rats showed delayed maturation, lower body weight, delayed motor development, and attenuated integration of a coordinated series of reflexes, delayed nest-seeking response mediated by olfactory system, and normal negative geotaxis. Interestingly, all behavioral aberrations described in this paper appear before puberty, which could distinguish the VPA rat model of autism from other animal models of neurodevelopmental disorders, especially rodent models of schizophrenia. Our results bring further support to validity of the proposed VPA animal model of autism, suggesting similarities between the observed pattern of behavioral alterations in VPA rats and features of disturbed behavior in autistic patients.

Acoustic Stimulation↗
PubMed1992

Functional properties of the rat and human beta 3-adrenergic receptors: differential agonist activation of recombinant receptors in Chinese hamster ovary cells.

beta 3-Adrenergic receptors (beta 3AR) mediate lipolytic and thermogenic responses in rodent adipose tissues in vitro, and "atypical" beta AR agonists that active these receptors have potent therapeutic effects in in vivo rodent models of adult-onset diabetes and obesity. However, experiments with rodent cells that natively express the beta 3AR, as well as those with cells that express cloned rodent beta 3AR, have suggested that the pharmacological properties of the rodent and human beta 3AR differ. Given that rodent models of obesity and diabetes are used to develop human therapeutic agents, we sought to compare directly the ligand-binding and functional properties of the rat and human beta 3AR in parallel studies using Chinese hamster ovary cells expressing the recombinant receptors. The endogenous catecholamines epinephrine (EPI) and norepinephrine (NE) were found to have low affinities (micromolar) for the beta 3AR of both species. The rank orders of potency of various agonists in stimulating adenylyl cyclase were clearly different, i.e., for the human beta 3AR, CGP12177 (CGP) > isoproterenol (ISO) > or = BRL34377 (BRL) = Pindolol > NE > EPI; for the rat, CGP > or = BRL > ISO > or = NE > Pindolol > EPI. The intrinsic activities of various agonists were also different, with the following rank orders (compared with ISO): for the human beta 3AR, NE > EPI > BRL = CGP > Pindolol; for the rat beta 3AR, BRL > NE > EPI > CGP > Pindolol. Competition binding studies with 125I-cyanopindolol and these agonists gave similar rank orders of potency. Thus, although the human and rat receptors exhibited similar properties with respect to catecholamine agonists, numerous differences in the potency and efficacy of synthetic noncatecholamine agonists were noted, indicating that the action of atypical agonists at rodent beta 3AR may not be predictive of therapeutic potential in humans.

Adenylyl Cyclases↗
PubMed2002

Gabapentin and vigabatrin increase GABA in the human neocortical slice.

The effects of antiepileptic drugs, gabapentin and vigabatrin, on gamma-aminobutyric acid (GABA) concentrations were studied in human (n=14) and rat (n=6) neocortical slice preparations. In this study, neocortical slices were incubated with gabapentin, vigabatrin or no drugs for 3 h in an oxygenated environment. Proton magnetic resonance spectroscopy (MRS) of perchloric acid (PCA) extracts was used to measure GABA concentrations. Vigabatrin increased cellular GABA concentrations in both human and rat neocortical slices by 62% (P<0.001) and 88% (P<0.03), respectively. Gabapentin significantly increased GABA concentrations by 13% (P<0.02) in human neocortical slices made from tissue resected during epilepsy surgery. However, in the rat neocortical slice exposed to the same conditions as the human tissue, gabapentin did not increase GABA significantly. These results confirm our MRS studies in vivo that gabapentin increases GABA levels in epileptic patients, but has minimal or no effect in a healthy rodent model. Caution must be used in extrapolating negative results obtained in rodent models to the human condition.

Acetates↗
PubMed2005

Modeling liver fibrosis in rodents.

Animal models of hepatic fibrosis provide a means to study the cell and molecular mediators of fibrosis in a serial manner during both progression and recovery. Several approaches to induction of fibrosis have been described. Of these, CCl(4) intoxication in rats and mice is probably the most widely studied. In addition, the CCl(4) model is the best characterized with respect to histological, biochemical, cell, and molecular changes associated with the development of fibrosis. CCl(4) can be given intraperitoneally or by oral gavage; it induces zone III necrosis and hepatocyte apoptosis with associated hepatic stellate cell activation and tissue fibrosis. With repetitive dosing CCl(4) can be used to induce bridging hepatic fibrosis (4 wk of twice-weekly dosing), cirrhosis (8 wk of twice-weekly dosing) and advanced micronodular cirrhosis (12 wk of twice-weekly dosing). In addition, for each of these models spontaneous recovery from fibrosis can be studied after cessation of dosing. Mechanistic studies using gene knockout and transgenic animals can also be established using CCl(4). Together these models have provided unparalleled insights into the mechanisms underlying hepatic fibrosis.

Actins↗
PubMed2006

Immunoglobulin gene implicated in murine herpes stromal keratitis is not associated with the human disease.

PURPOSE: Susceptibility to herpes stromal keratitis (HSK) is strongly influenced by genetic factors, as shown by multiple rodent models using human herpes simplex virus. A single gene, encoding the immunoglobulin G (IgG) 2a heavy chain protein, confers susceptibility or resistance through a mechanism involving molecular mimicry in one mouse model. However, other rodent studies have produced contradictory results. This study tested the hypothesis that the GM23 gene (the human IgG2a homolog) influences susceptibility to HSK in humans. METHODS: The study population consisted of all consenting patients diagnosed with HSK (25 whites, 2 African Americans) at the Medical University of South Carolina Storm Eye Institute Clinic in Charleston, SC, between August 2000 and June 2004. Healthy controls (23 white adults with no history of HSK) were recruited from the same local population. Genomic DNA from subjects was genotyped at the GM23 locus, which has been implicated as an HSK resistance gene in animal models, by polymerase chain reaction-restriction fragment length polymorphism (RFLP) analysis. RESULTS: No difference in GM23 genotype frequency was observed between patients with HSK and controls. CONCLUSION: Susceptibility to HSK in whites is not predicted by GM23 genotype.

Adolescent↗
PubMed1998

Loss of glucose transporter-2 precedes insulin loss in the nonobese diabetic and the low-dose streptozotocin mouse models: a comparative immunohistochemical study by light and confocal microscopy.

Glucose transporter-2 (glut2) is underexpressed in beta cells of several rodent models of non-insulin-dependent diabetes mellitus (NIDDM). This may also be true for rodent models of insulin-dependent diabetes mellitus (IDDM). The present study examines two murine models of autoimmune IDDM, the nonobese diabetic (NOD) and the low-dose streptozotocin (stz) murine models for changes in the expression of glut2 by double-label light and confocal microscopy during various stages of the disease. The spatial distribution of glut2 cells was also examined in relation to insulin immunoreactive cells and the islet inflammatory cells during these stages. In both the female NOD mouse and the female Swiss mouse without stz treatment, glut2 colocalized with insulin in virtually all the beta cells. In the NOD mouse, islets with moderate to advanced insulitis showed either an absence or considerably reduce expression of glut2 in insulin-containing beta cells. Cells with reduced glut2 expression were usually located adjacent to the region of insulitis. At onset of diabetes, glut2 immunolabeling was reduced despite the preservation of weak insulin immunoreactivity. In Swiss mice treated repeatedly with stz, glut2 labeling began to decline in select Beta cells after the fourth injection in approximately 50% of the islets, despite the lack of insulitis. At this stage expression of glut2 fell in a small number of islets with evidence of early macrophage infiltration. Loss of glut2 became more pronounced in nondiabetic Swiss mice after the fifth injection. At this stage glut2 labeling in the plasma membrane appeared diffuse and variable. At onset of stz-induced diabetes, glut2 expression significantly fell, despite weak immunoreactivity for insulin. This loss was associated with an enhanced influx of both macrophages and T lymphocytes within the islets of diabetes mice. In both the NOD and the low-dose stz mouse models, loss of glut2 thus occurs from an early stage and precedes hyperglycaemia. This loss may be mediated by immune and nonimmune mechanisms.

Animals↗
PubMed2002

Obstructive nephropathy and renal fibrosis.

Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.

Animals↗
PubMedDate not supplied

Inhibition of aberrant crypt foci by chemopreventive agents.

The colon carcinogenic process is believed to begin with both genetic and morphological alterations in a few individual crypts. These select crypts, called aberrant crypt foci (ACF), are widely agreed upon as precursors of colon cancer. The ACF assay involves testing potential chemopreventive agents by counting the number of ACF in a carcinogen-treated colon. This assay has the advantage of not only being less expensive and time-consuming than tumor-producing studies, but will also allow the elucidation of the colon carcinogenic process by letting the researcher explore the changes that occur at a pre-cancerous stage. The ACF assay has been used most frequently in rodent models. In the rodent colon, ACF are easy to distinguish due to their distinct morphological, histological, and biological characteristics. In addition, the ACF assay has been used to look at specific genetic alterations in the crypts such as K-ras, p53, and APC mutations. Our laboratory has consistently used the ACF assay to test many potential chemopreventive agents using rats induced by the colon carcinogen azoxymethane (AOM). Potential chemopreventive agents have been tested in both the initiation or the post-initiation period Research supports the notion that aberrant crypt foci represent a true neoplastic lesion for colon cancer. By studying these lesions both grossly and genetically it may be possible to learn more about the causes of colon carcinogenesis. In addition, by testing new compounds through the ACF assay, it is possible not only to discover potentially new chemopreventive compounds, but also to discover the mechanisms behind them. Because of this, the ACF assay is an invaluable method that will help reveal the process of colon carcinogenesis.

Animals↗
PubMed2001

Modulation of antigen-specific cellular immune responses to DNA vaccination in rhesus macaques through the use of IL-2, IFN-gamma, or IL-4 gene adjuvants.

Extensive experiments have shown DNA vaccines' ability to elicit immune responses in vivo in a safe and well-tolerated manner in several model systems, including rodents and non-human primates. As the DNA-based vaccine and immunotherapy approaches are being explored in humans, significant efforts have also been focused on further improving the immune potency of this technology. One strategy to enhance immune responses for DNA vaccines is the use of molecular or genetic adjuvants. These molecular adjuvant constructs (which encodes for immunologically important molecules such as cytokines) can be co-administered along with DNA vaccine constructs. Once delivered, these adjuvants have shown to modulate the magnitude and direction (humoral or cellular) of the vaccine-induced immune responses in rodent models. To date, however, there has been very little data reported from studies in primates. In this study, we examined the effects of cytokine gene adjuvants to enhance the level of cell-mediated immune responses in rhesus macaques. We co-immunized rhesus macaques with expression plasmids encoding for IL-2, IFN-gamma or IL-4 cytokines along with the DNA vaccine constructs encoding for HIV env/rev (pCEnv) and SIV gag/pol (pCSGag/pol) proteins. We observed that coadministration of IL-2 and IFN-gamma cDNA resulted in enhancement of antigen-specific T cell-mediated immune responses.

AIDS Vaccines↗
PubMed1998

Cerebral ischemia and CNS transplantation: differential effects of grafted fetal rat striatal cells and human neurons derived from a clonal cell line.

Stroke mortality has declined over recent decades, prompting a demand for the development of effective rehabilitative therapies for stroke survivors. This effort has been facilitated by significant progress in replicating the behavioral and neuropathological changes of authentic human cerebral ischemia using relevant animal models. Since the rodent model of middle cerebral artery occlusion mimics several motor abnormalities seen in clinical cerebral ischemia, we have utilized this model to investigate treatment strategies for stroke. The present study explored the potential benefits of neural transplantation of fetal rat striatal cells or human neurons derived from a clonal embryonal carcinoma cell line to correct the abnormalities associated with cerebral ischemia. We report here that ischemia-induced behavioral dysfunctions were ameliorated by the neural grafts as early as 1 month post-transplantation. Of note, transplantation of human neurons induced a significantly more robust recovery than fetal rat striatal grafts. Thus, the logistical and ethical concerns about the use of fetal striatal cells for transplantation therapy can be eliminated by exploiting cell line-derived human neurons as alternative graft sources. Transplantation of human neurons has a therapeutic potential for treatment of behavioral deficits associated with cerebral ischemia.

Animals↗
PubMedDate not supplied

Animal models for male pattern (androgenetic) alopecia.

The stump-tailed macaque (Macaca arctoides) appears to be a suitable biological model for human androgenetic alopecia. The expense, danger, and low availability compromise its value but macaques currently remain the model of choice. Rodent models, both testosterone induced alopecia and various xenograft approaches, show promise for elucidating fundamental information on normal and abnormal hair growth as well as serving as models to develop new therapies to treat hair loss.

Alopecia↗
PubMed2006

Animal models of inherited neuropathies.

PURPOSE OF REVIEW: Mutations in a number of genes have been associated with inherited neuropathies (Charcot-Marie-Tooth or CMT disease). This review highlights how animal models of demyelinating CMT have improved our understanding of disease mechanisms. Transgenic CMT models also allow therapies to be developed in a preclinical setting. RECENT FINDINGS: Rodent models for the most common subtypes of human CMT disease are now available, and two mouse mutants modeling the rare CMT4B subform have lately extended this repertoire. In a peripheral myelin protein 22 kDa (Pmp22) transgenic rat model of CMT1A, administration of a progesterone receptor antagonist reduced Pmp22 overexpression, axon loss and clinical impairments. Dietary ascorbic acid prevented dysmyelination and premature death in a Pmp22 transgenic mouse line. Neurotrophin-3 promoted small fiber remyelination in CMT1A xenografts and sensory functions in CMT1A patients. Gene expression profiling in rodent models of CMT may identify further therapeutical targets. While original classifications distinguish the demyelinating and axonal forms of CMT, recent findings emphasize that axon loss is a common feature, possibly caused by Schwann cell defects rather than demyelination per se. This supports our model that myelination and long-term axonal support are distinct functions of all myelinating glial cells. SUMMARY: Animal models have opened up new perspectives on the pathomechanisms and possible treatment strategies of inherited neuropathies.

Animals↗
PubMed2006

Lymph from a primate baboon trauma hemorrhagic shock model activates human neutrophils.

We have reported that toxic factors in intestinal lymph are responsible for acute lung injury and bone marrow suppression and that they contribute to a systemic inflammatory state based on studies in rodent models of trauma-hemorrhagic shock. Rodent models may not completely reflect the responses of injured patients. Thus, it is important to confirm these findings in primates before applying them to injured human patients with trauma. Thus, we have recently established baboon trauma-hemorrhagic shock (T/HS) and trauma-sham shock (T/SS) models that showed that gut-derived factors carried in the lymph potentiates lung injury and causes human endothelial dysfunction and suppresses human bone marrow progenitor cell growth. Here, we further investigated the effects of these primate lymph samples on human neutrophils. We hypothesized that toxic factors in baboon lymph may prime and/or activate human polymorphonuclear leukocyte (PMN) leading to overproduction of superoxide, thereby contributing to the development of adult respiratory distress syndrome and multiple organ failure. To this effect, we have examined the priming effect of baboon T/HS and T/SS lymph on PMN respiratory burst and expression of adhesion molecule in human neutrophils. The results of these studies indicate that PMN treated with baboon T/HS lymph showed significantly induced respiratory burst responses compared with PMN treated with T/SS lymph or medium when phorbol myristate acetate PMA was applied after lymph pretreatment. Secondly, we found that the expression of CD11b adhesion molecule was increased by incubation with T/HS lymph. These results suggest that baboon lymph from T/HS models can increase respiratory burst and adhesion molecule expression in human PMN, thereby potentially contributing to PMN-mediated organ injury.

Animals↗
PubMed2004

Efficacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents.

Duloxetine, a selective but balanced serotonergic and noradrenergic reuptake inhibitor, was evaluated in the acute nociceptive pain models of tail flick and hot plate in mice and in the persistent and/or inflammatory pain models of acetic acid-induced writhing in mice, carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats, and capsaicin-induced mechanical allodynia in rats. In acute pain models, duloxetine had no significant effect on response latency in the mouse tail-flick test but produced modest increases in response latencies in the mouse hot plate test. Morphine produced dose-related analgesic effects in both the mouse tail-flick and hot plate tests. In models of inflammatory and/or persistent pain, duloxetine, morphine, and ibuprofen produced dose-related decreases in acetic acid-induced writhing in mice. Duloxetine, ibuprofen, and gabapentin also produced dose-dependent reversals of both thermal hyperalgesia and mechanical allodynia produced by carrageenan in rats. In addition, both duloxetine and morphine produced a significant reduction of capsaicin-induced mechanical allodynia in rats. Duloxetine and gabapentin were without substantial effect on the Rotorod test in mice, whereas morphine and ibuprofen produced a significant impairment. Our data indicate that duloxetine may be efficacious in the treatment of persistent and/or inflammatory pain states at doses that have modest or no effect on acute nociception or motor performance.

Adrenergic Uptake Inhibitors↗
PubMed2002

Bayesian methods for a three-state model for rodent carcinogenicity studies.

The objective of a chronic rodent bioassay is to assess the impact of a chemical compound on the development of tumors. However, most tumor types are not observable prior to necropsy, making direct estimation of the tumor incidence rate problematic. In such cases, estimation can proceed only if the study incorporates multiple interim sacrifices or we make use of simplified parametric or nonparametric models. In addition, it is widely accepted that other factors, such as weight, can be related to both dose level and tumor onset, confounding the association of interest. However, there is not typically enough information in the current study to assess such effects. The addition of historical data can help alleviate this problem. In this article, we propose a novel Bayesian semiparametric model for the analysis of data from rodent carcinogenicity studies. We develop informative prior distributions for covariate effects through the use of historical control data and outline a Gibbs sampling scheme. We implement the model by analyzing data from a National Toxicology Program chronic rodent bioassay.

Animals↗
PubMed1991

New small animal model for human gastric Helicobacter pylori infection: success in both nude and euthymic mice.

In order to develop an experimental rodent model, we administered 2 ml (10(8) organisms/ml) broth culture of any of four human isolated strains of Helicobacter pylori by the oral route on a one-time basis to both BALB/c nude and BALB/c euthymic mice. After 20-wk examination, we have successfully demonstrated that the gastric mucosa of nude mice was continuously, and that of euthymic mice, temporarily (for 2 wk), colonized by orally administered, freshly isolated strains obtained from humans with gastritis, gastric ulcer, and duodenal ulcer, but never by the established strain. After colonization, gastritis and duodenitis were produced, and the presence of bacteria in gastric mucus was pathologically proved in all infected animals. We have confirmed that such colonization is always established when a large dose of a freshly isolated strain of H. pylori is administered at one time. We believe that this is the first reported rodent model of H. pylori-associated gastritis.

Animals↗
PubMed2004

Animal models for studying respiratory syncytial virus infection and its long term effects on lung function.

BACKGROUND: Human respiratory syncytial virus (hRSV) infection causes a spectrum of illnesses ranging from mild infection to life-threatening bronchiolitis and respiratory failure. Human studies on the pathogenesis of RSV infection are invaluable, but animal models permit advances with the use of experimental strategies that would be inappropriate in human studies. METHODS: We review the advantages and disadvantages of various animal models for the study of hRSV infection. RESULTS: No animal model of hRSV infection replicates the complete spectrum of disease severity seen in humans. Available models differ in their ability to incorporate genetic technology and to allow the study of immunity, vaccine efficacy and treatment interventions. Although hRSV establishes disease in primates, this advantage is outweighed by the impracticalities and cost of using such models. The study of bovine RSV infection in calves is appealing because of parallels with human disease. Among rodent models, BALB/c mice have helped delineate the mechanisms underlying vaccine-enhanced RSV disease, and cotton rats have been used for preclinical testing. The single major disadvantage of studying hRSV in rodent models is the limited extent to which this host-restricted human pneumovirus replicates in mouse lung tissue. The rodent-specific Pneumovirus pathogen, pneumonia virus of mice, causes an infection that mirrors severe bronchiolitis and pneumonia in infants infected with RSV, including robust virus replication with profound inflammation. CONCLUSION: The recent development of the pneumonia virus of mice model has permitted exploration of the mechanisms of severe Pneumovirus disease in vivo with the use of sophisticated genetic tools and genetically manipulated mouse strains.

Animals↗
PubMed1998

Prevalence of microalbuminuria in children with sickle cell disease.

Renal involvement is common in homozygous sickle cell disease (HbSS), including glomerular hypertension and hypertrophy similar to that seen in rodent models of ablative nephrectomy and stage I diabetic nephropathy (DN). The proteinuria in the rodent models is attenuated by angiotensin converting enzyme inhibition (ACEI). Microalbuminuria (MA) is a sensitive marker for renal involvement in DN prior to the development of proteinuria, and is also attenuated with ACEI. Elevated urinary microalbumin/creatinine ratios (U Alb/Cr) >20 mg/g Cr are reported in 39%-43% of adults with HbSS, and studies are ongoing in this age group to assess the effect of attenuated proteinuria by ACEI on long-term renal function. The purpose of this study was to prospectively investigate the prevalence of MA in children with HbSS and determine factors which affect its expression. U Alb/Cr values were measured on spot urine samples in 102 children (aged 2-18 years, mean 9.47+/-4.62, M:F=53:49) by rate nephelometry. Children with prior known proteinuria, hypertension, or fever/pain episode in the last 15 days were excluded. MA was present in 26.5% of all children with HbSS. However, in children between the ages of 10 and 18 years, the prevalence was 46% (similar to the prevalence in adults). There was a strong correlation between patient age and prevalence of MA (P<0.0001) by both univariate and multivariate analysis. However, pain frequency, hospitalization, transfusion program, ferritin levels, and Cr clearance (C(Cr)) did not correlate with prevalence, although C(Cr) (as estimated by Schwartz formula) was elevated in all. We conclude that the prevalence of MA in the 2nd decade of life is similar to that in adults.

Adolescent↗