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PubMed1986

A review of the use of primates in studying human schistosomiasis.

Rodents, useful models for studies of human schistosomiasis not ethically possible in man, are not satisfactory in every respect. Primates, in many ways better models than rodents, though too expensive for general use, remain invaluable for testing the relevance of rodent findings to man. Higher primates such as chimpanzees are ideal models but, as endangered species, should only be used for critical studies for which lower, nonhuman primates are unsuitable.

Animal Diseases↗
PubMed2005

The roe deer as a model for studying seasonal regulation of testis function.

In mature male seasonal breeders, the circannual cycles of testicular growth and involution involve significant changes in structure and function of both the tubular and interstitial testicular compartment. Roe deer (Capreolus capreolus) are seasonal breeders with a short defined rutting season from mid-July to mid-August and represent a unique non-rodent model for studying testicular functions during the course of a complete reproductive cycle with naturally changing photoperiod. Germ cells and Sertoli cells of the seminiferous tubules and the interstitial Leydig cells all display significant morphological and physiological alterations during the seasonal changes. In contrast to the germ cell population, Sertoli and Leydig cells persist as a numerically constant cell population in the roe deer testis. This report emphasizes the intricate relationship between seasonal cellular differentiation, intratesticular growth factor networks and their impact on the functional dynamics during the seasonal changes in roe deer testis.

Animals↗
PubMed2006

Potential protection of skin by acute UVA irradiation--from cellular to animal models.

The UVA (320-380 nm) component of sunlight has oxidizing properties which may be deleterious to skin cells and tissue but can also lead to the strong up-regulation of the heme-catabolizing enzyme, heme oxygenase-1. This enzyme has well-established antioxidant actions in cells as well as anti-inflammatory properties in mammals. There is also evidence from rodent models that this enzyme is responsible for the UVA-mediated protection against UVB-induced immunosuppression that occurs in skin. The relevance of these findings to acute and chronic effects of sunlight including skin carcinogenesis is currently under investigation as are the potential implications for sunlight protection in humans.

Animals↗
PubMed2002

Antidepressant activity of standardized extract of Bacopa monniera in experimental models of depression in rats.

Bacopa monniera Wettst. (syn. Herpestis monniera L.; Scrophulariaceae) is a commonly used Ayurvedic drug for mental disorders. The standardized extract was reported earlier to have significant anti-oxidant effect, anxiolytic activity and improve memory retention in Alzheimer's disease. Presently, the standardized methanolic extract of Bacopa monniera (bacoside A - 38.0+/-0.9) was investigated for potential antidepressant activity in rodent models of depression. The effect was compared with the standard antidepressant drug imipramine (15 mg/kg, ip). The extract when given in the dose of 20 and 40 mg/kg, orally once daily for 5 days was found to have significant antidepressant activity in forced swim and learned helplessness models of depression and was comparable to that of imipramine.

Administration, Oral↗
PubMed2002

Cardiovascular alterations and autonomic imbalance in an experimental model of depression.

Depressed patients with and without a history of cardiovascular pathology display signs, such as elevated heart rate, decreased heart rate variability, and increased physiological reactivity to environmental stressors, which may indicate a predisposition to cardiovascular disease. The specific physiological mechanisms associating depression with such altered cardiovascular parameters are presently unclear. The current study investigated cardiovascular regulation in the chronic mild stress rodent model of depression and examined the specific autonomic nervous system mechanisms underlying the responses. Sprague-Dawley rats exposed to a series of mild, unpredictable stressors over 4 wk displayed anhedonia (an essential feature of human depression), along with elevated resting heart rate, decreased heart rate variability, and exaggerated pressor and heart rate responses to air jet stress. Results obtained from experiments studying autonomic blockade suggest that cardiovascular alterations in the chronic mild stress model are mediated by elevated sympathetic tone to the heart. The present findings have implications for the study of pathophysiological links between affective disorders and cardiovascular disease.

Animals↗
PubMed2003

Marker-assisted congenic screening (MACS): a database tool for the efficient production and characterization of congenic lines.

Over the past decades, genetic studies in rodent models of human multifactorial disorders have led to the detection of numerous chromosomal regions associated with disease phenotypes. Owing to the complex control of these phenotypes and the size of the disease loci, identifying the underlying genes requires further analyses in new original models, including chromosome substitution (consomic) and congenic lines, derived to evaluate the phenotypic effects of disease susceptibility loci and fine-map the disease genes. We have developed a relational database (MACS) specifically designed for the genetic marker-assisted production of large series of rodent consomic and congenic lines ("speed congenics"), the organization of their genetic and phenotypic characterizations, and the acquisition and archiving of both genetic and phenotypic data. This database, originally optimized for the production of rat congenics, can also be applied to mouse mapping projects. MACS represents an essential system for significantly improving efficiency and accuracy in investigations of multiple consomic and congenic lines simultaneously derived for different disease loci, and ultimately cloning genes underlying complex phenotypes.

Animals↗
PubMed1993

Prophylactic nutritional modification of the incidence of diabetes in autoimmune non-obese diabetic (NOD) mice.

Experiments in rodent models of insulin-dependent diabetes mellitus (IDDM) suggest that destruction of pancreatic beta cells can be both initiated and inhibited by certain environmental factors such as dietary constituents. We studied nutritional impact of certain protein sources of natural-ingredient, non-purified (NP) rodent diet on diabetes incidence and insulitis severity in the spontaneous diabetic, non-obese diabetic (NOD) mouse. Long-term ad lib. feeding of diets containing wheat flour (800 g/kg), and to a lesser extent soya-bean meal (400 g/kg), were associated with relatively high diabetes incidence (65 and 45% respectively), whereas a diet based on hydrolysed casein (HC; 200 g/kg) as the only source of protein significantly (compared with the wheat-flour diet) inhibited expression of diabetes (22%). Feeding a hypo-allergenic soya-bean-protein hydrolysate resulted in diabetes incidence and insulitis severity similar to that of the soya-bean-meal-fed group. This may indicate that protein hydrolysis per se may not be necessary for dietary modification of diabetes in the NOD mouse. The window of vulnerability to diabetogenic diets was found to be between weaning and about 70 d of age. In the diabetic mice insulitis was less frequent in the HC-fed group when compared with those fed NP (P = 0.04), soybean meal (P = 0.03), soya-bean-protein hydrolysate (P = 0.012) or wheat flour (P = 0.0002). In the non-diabetic mice the wheat-flour diet was associated with a high insulitis severity in comparison with the HC group (P = 0.004). Early avoidance of NP diet was associated with lower degree of insulitis in both diabetic (P = 0.00003) and non-diabetic mice (P = 0.001) when compared with the mice fed on the HC diet later in life. These findings are contributing to further clarification of diabetes-promoting dietary constituents, which may have some nutritional implications for IDDM-susceptible children.

Animals↗
PubMed1995

SB 201823-A antagonizes calcium currents in central neurons and reduces the effects of focal ischemia in rats and mice.

BACKGROUND AND PURPOSE: Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. We evaluated the ability of a novel neuronal calcium channel blocker, SB 201823-A, to block central neuronal calcium influx in vitro and to reduce ischemic injury in two rodent models of focal stroke. METHODS: Patch-clamp electrophysiology and intracellular Ca2+ imaging in rat hippocampal and cerebellar neurons were used to determine effects on neuronal calcium channel activity. Middle cerebral artery occlusion was performed in Fisher 344 rats and CD-1 mice to determine the effects on rodent focal ischemic injury and neurological deficits. Cardiovascular monitoring in conscious rats was conducted to determine cardiovascular liabilities of the compound. RESULTS: In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36 +/- 8% and 89 +/- 4% after 5 and 20 mumol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 mumol/L SB 201823-A totally prevented initial calcium influx and reduced later calcium influx by 50 +/- 2.5% after N-methyl-D-aspartate/glycine stimulation (P < .01). KCl depolarization-induced calcium influx also was reduced by more than 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A beginning 30 minutes after focal ischemia decreased (P < .05) hemispheric infarct by 30.4% and infarct volume by 29.3% and reduced (P < .05) forelimb deficits by 47.8% and hindlimb deficits by 36.3%. In mice, treatments with 10 mg/kg IP SB 201823-A beginning 30 minutes after focal ischemia significantly reduced infarct volume by 41.5% (P < .01). No blood pressure effects were observed with the therapeutic dose of the compound. CONCLUSIONS: These results indicate that the new neuronal calcium channel blocker SB 201823-A can block stimulated calcium influx into central neurons and can provide neuroprotection in two models of focal cerebral ischemia without affecting blood pressure. Data from several different studies now indicate that the neuronal calcium channel antagonists are a promising therapy for the postischemic treatment of stroke.

Animals↗
PubMed2006

Combination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a familial tumor syndrome characterized by the development of hamartomas in the brain, heart, kidney, and skin. Disease-causing mutations in the TSC1 or TSC2 gene result in constitutive activation of the highly conserved mTOR signal transduction pathway, which regulates cell growth, proliferation, and metabolism. The mTOR inhibitor, rapamycin (sirolimus), reduces disease severity in rodent models of TSC, and is currently in phase II clinical trials. The cytokine interferon-gamma (IFN-gamma) is another potential therapeutic agent for TSC. A high-expressing IFN-gamma allele is associated with a lower frequency of kidney tumors in TSC patients, and treatment with exogenous IFN-gamma reduces the severity of TSC-related disease in mouse models. Here, we examine the effects of treating tumor-bearing nude mice with a combination of a rapamycin analog (CCI-779) and IFN-gamma. We observed that combination therapy was more effective than single agent therapy in reducing tumor growth and improving survival in this mouse model of TSC. Immunoblot and immunohistochemical analyses showed that tumors treated with CCI-779 plus IFN-gamma had decreased cell proliferation and increased cell death in comparison with untreated tumors or tumors treated with either agent alone. We also observed that CCI-779 resistance could develop with prolonged treatment. Taken together, our results show that targeting multiple cellular pathways is an effective strategy for treating TSC-related tumors, and underscore the importance of investigating combination therapy in future clinical trials for patients with TSC.

Animals↗
PubMed2001

Up-regulation of D3 dopaminergic receptor mRNA in the core of the nucleus accumbens accompanies the development of seizures in a genetic model of absence-epilepsy in the rat.

The basal ganglia system is thought to play a key role in the control of absence-seizures and there is ample evidence that epileptic seizures modify brain dopamine function. We recently reported that local injections of dopamine D1 or D2 agonists in the core of the nucleus accumbens suppressed absence-seizures in a spontaneous, genetic rodent model of absence-epilepsy whereas injections of D1 or D2 antagonists had aggravating effects. These findings raised the possibility that the dopaminergic system may be altered in absence-epilepsy prone rats. Therefore, we studied by in situ hybridization histochemistry the expression of pre- and postsynaptic components of the dopaminergic system in this strain of rats. When compared to non-epileptic control rats, epileptic rats displayed no change in the expression of mRNAs coding for the neuronal dopaminergic markers (tyrosine hydroxylase, membraneous and vesicular dopamine transporters). In addition, there was no difference between the two strains concerning the expression of the dopamine receptor transcripts D1, D2 and D5. In adult absence-epilepsy prone rat with an overt epileptic phenotype, however, an elevated level of D3 mRNA expression was observed in neurons of the core of the nucleus accumbens (+23% increase in silver grain density compared to non-epileptic control rats). D3 transcripts were not increased in juvenile epileptic rats without seizures. These findings suggests that up-regulation of D3 receptor mRNA is part of the epileptic phenotype in absence-epilepsy prone rats. Its localization in the core of the nucleus accumbens bears close resemblance to the dopamine-sensitive antiepileptic sites in ventral striatum and further support the involvement of ventral structures of the basal ganglia system in the control of absence-seizures.

Animals↗
PubMed2006

A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination.

Recent studies have revealed widespread demyelination in the cortex of patients with chronic multiple sclerosis. In contrast to white matter lesions, cortical multiple sclerosis lesions are accompanied by only minor inflammation. Research into the pathogenesis of cortical lesion formation has been hampered by the fact that the conventional rodent model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), does not regularly affect the cortex. To overcome this limitation we developed a new rat model of cortical multiple sclerosis. Lesions were stereotactically targeted to the cerebral cortex by injection of pro-inflammatory mediators in animals that were immunized subclinically with myelin oligodendrocyte glycoprotein (MOG). We thus generated highly reproducible demyelinated lesions in the neocortex with remarkable histological similarities to cortical multiple sclerosis lesions. The focal cortical EAE model led to the typical pattern of intracortical and subpial demyelination, infiltration with inflammatory cells, complement deposition, acute axonal damage and neuronal cell death. Surprisingly, extensive cortical inflammation largely resolved within 2 weeks. Furthermore, cortical demyelination was readily compensated by rapid remyelination. Our data thus suggest that cortical inflammation is a transient phenomenon, and that remyelination of cortical inflammatory-demyelinating lesions may occur rapidly.

Animals↗
PubMed2005

Comparison of the pharmacokinetics of oxycodone and noroxycodone in male dark agouti and Sprague--Dawley rats: influence of streptozotocin-induced diabetes.

PURPOSE: The aims of this study are to evaluate whether cytochrome P450 (CYP)2D1/2D2-deficient dark agouti (DA) rats and/or CYP2D1/2D2-replete Sprague-Dawley (SD) rats are suitable preclinical models of the human, with respect to mirroring the very low plasma concentrations of metabolically derived oxymorphone seen in humans following oxycodone administration, and to examine the effects of streptozotocin-induced diabetes on the pharmacokinetics of oxycodone and its metabolites, noroxycodone and oxymorphone, in both rodent strains. METHODS: High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to quantify the serum concentrations of oxycodone, noroxycodone, and oxymorphone following subcutaneous administration of bolus doses of oxycodone (2 mg/kg) to groups of nondiabetic and diabetic rats. RESULTS: The mean (+/-SEM) areas under the serum concentration vs. time curves for oxycodone and noroxycodone were significantly higher in DA relative to SD rats (diabetic, p<0.05; nondiabetic, p<0.005). Serum concentrations of oxymorphone were very low (<6.9 nM). CONCLUSIONS: Both DA and SD rats are suitable rodent models to study oxycodone's pharmacology, as their systemic exposure to metabolically derived oxymorphone (potent micro-opioid agonist) is very low, mirroring that seen in humans following oxycodone administration. Systemic exposure to oxycodone and noroxycodone was consistently higher for DA than for SD rats showing that strain differences predominated over diabetes status.

Alcohol Oxidoreductases↗
PubMed1990

Excitotoxic injury of the neostriatum: a model for Huntington's disease.

Intrastriatal lesions with excitatory amino acids mimic some of the neurochemical and neuropathological characteristics of Huntington's disease (HD); this has led to the hypothesis that an endogenous excitotoxin may be involved in the disease. Recent advances in understanding the metabolic pathways of endogenous excitotoxins and the distribution and function of excitatory amino acid receptors have helped to refine the excitotoxin hypothesis, which is still inadequate to explain some aspects of the disease. However, as an experimental model for producing neuronal depletion in the neostriatum, excitotoxic injury has allowed the study of other neuronal characteristics of HD such as progressive atrophy and regeneration; it has also permitted extensive exploration of the anatomical and functional recovery induced by intrastriatal grafts. Moreover, adaptation of the rodent model to the non-human primate has enabled investigators to examine lesion-induced motor dysfunctions that are more comparable to those in HD. Thus, beyond its potential importance in the pathogenesis of HD, excitotoxic injury as an experimental tool promises to help further elucidate the pathological and functional alterations characteristic of the disease.

Amino Acids↗
PubMed1997

Disparate effects of antidiabetic drugs on arterial contraction.

Type II diabetic patients and others with insulin resistance are at risk for development of hypertension characterized by elevated peripheral vascular resistance and loss of insulin's normal vasodilating activity. Oral antidiabetic drugs have recently been recognized to have disparate effects on arterial pressure in such patients and in related rodent models. Sulfonylureas (e.g., glyburide), which stimulate insulin secretion, have been reported either to increase or not to affect arterial pressure, whereas nonsulfonylurea agents with insulin-sensitizing properties, the biguanide metformin and various thiazolidinediones (eg, pioglitazone), have been reported to decrease arterial pressure in humans and rodents. To help elucidate these disparate effects, we investigated these agents for direct actions on arterial vascular contractility and its sensitivity to insulin. Preincubation of intact rat tail arterial tissue rings for 2 hours with known therapeutically effective antidiabetic concentrations of metformin and pioglitazone significantly attenuated the force of contractions produced by either potassium (membrane depolarization) or norepinephrine ([NE] adrenergic receptor activation). Glyburide did not influence these contractions. Preincubation with metformin also induced an attenuating (vasodilating-like) action of insulin on arterial tissue rings contracted by potassium. Conversely, glyburide induced an accentuating action of insulin on potassium-mediated contractions. These results are consistent with measures of vascular function obtained in the past after oral administration of the drugs, which suggested but did not prove that they may exert direct effects on arterial vascular contractility. Thus, metformin and thiazolidinediones may decrease arterial pressure partly by direct vasorelaxant mechanisms, with metformin having an additional effect of inducing vasorelaxation by insulin. In contrast, sulfonylureas may directly induce a paradoxical vasoconstrictor response to insulin.

Animals↗
PubMed1997

Exercise training down-regulates ob gene expression in the genetically obese SHHF/Mcc-fa(cp) rat.

The recently cloned obesity gene (ob) encodes a protein, leptin, which is secreted from adipose tissue and interacts with hypothalamic receptors to decrease appetite, increase energy expenditure, and reduce body lipid stores. The levels of ob mRNA are increased in several models of obesity, consistent with the hypothesis that obese animals may be resistant to the actions of leptin. The present study examined the impact of increased energy expenditure through exercise training on ob mRNA gene expression and body composition in the SHHF/Mc-fa(cp) male rat, a rodent model of obesity, insulin resistance, and type II diabetes. Six week old lean and obese animals were trained 8-12 weeks by treadmill running at 70% peak oxygen uptake, 5 days/wk, for 1.5 hr/day. After endurance training, exercised rats had significantly lower total body fat compared to sedentary rats of the same age, despite maintaining the same body weight. In the obese SHHF/Mcc-fa(cp) rat, the level of ob mRNA expression was markedly increased by four fold in subcutaneous adipose tissue compared to lean controls (p<0.05). In response to exercise training, there was a significant 85 % decrease in ob mRNA in exercised-training lean rats (p < 0.05) compared with non-exercised controls, while in obese-exercised rats, ob gene expression was significantly reduced only by 50% relative to non-exercised obese rats (p < 0.05). These results demonstrate that exercise training reduces fat mass and ob mRNA in lean and obese rats, and supports the hypothesis of a feedback loop between the adipocyte and hypothalamus that attempts to maintain body weight at a constant level by reducing ob gene expression in response to increased energy expenditure.

Adipose Tissue↗
PubMed1999

Isolation and antihyperglycemic activity of bakuchiol from Otholobium pubescens (Fabaceae), a Peruvian medicinal plant used for the treatment of diabetes.

The known compound bakuchiol (1) was isolated from an extract of Otholobium pubescens (Fabaceae) by bioassay-guided fractionation using the db/db mouse model for type 2 diabetes. Oral administration of 1 reduced blood glucose levels in a dose-dependent fashion in db/db mice and did not display a hypoglycemic effect when tested in lean mice at 250 mg/kg q.d. Compound 1 was further evaluated in a new rodent model for type 2 diabetes, the fat-fed, streptozotocin (STZ)-treated rat. In this model, an oral dose of 1 at 150 mg/kg q.d. significantly lowered plasma glucose and triglyceride levels.

Analysis of Variance↗
PubMed2001

Beta 3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans.

In the early 1980s, an "atypical" beta-adrenergic receptor was discovered and subsequently called the beta (3)-adrenoceptor (beta(3)-AR). Agonists of the beta(3)-AR were observed to simultaneously increase lipolysis, fat oxidation, energy expenditure and insulin action leading to the belief that this receptor might serve as an attractive target for the treatment of diabetes and obesity. In vivo studies lent credence to this postulate with the finding that stimulation of this receptor by selective agonists lead to glycemic improvements and weight loss in rodent models of diabetes and obesity. This lead to intensive research efforts directed at developing beta(3)-AR selective agonists for the treatment of type 2 diabetes and obesity in humans. Unfortunately, endeavour been largely unsuccessful to date. Major obstacles have included the pharmacological differences between the rodent and human beta(3)-AR, the lack of selectivity of previous compounds for the beta(3)-AR over beta(1)-/beta(2)-ARs, and unsatisfactory oral bioavailability and pharmacokinetic properties. Cloning of the human beta(3)-AR has allowed for the development of novel compounds targeted specifically at the human receptor. Encouraging data has emerged from clinical studies wherein CL-316,243, a highly selective, albeit rodent specific beta(3)-AR agonist was observed to increase lipolysis, fat oxidation and insulin action in humans. More recently, beta(3)-AR agonists directed at the human receptor are showing promising results in their ability to increase energy expenditure in humans following a single dose. However, they do nor appear to be able to sustain their effects when administered chronically. Further clinical testing will be necessary, using compounds with improved oral bioavailability and potency, to help assess the physiology of the beta(3)-AR in humans and its attractiveness as a potential therapeutic for the treatment of type 2 diabetes and obesity.

Adrenergic beta-3 Receptor Agonists↗
PubMed2006

ER stress and UPR in familial amyotrophic lateral sclerosis.

The primary mechanism by which mutations in Cu, Zn-superoxide dismutase (SOD1) contribute to progressive motor neuron loss in familial amyotrophic lateral sclerosis (FALS) remains unknown. Misfolded protein aggregates, ubiquitin-proteasome system impairment and neuronal apoptosis mediated by death receptor or mitochondrial-dependent pathways are implicated in mutant SOD1-induced toxicity. Recent evidence from cellular and transgenic rodent models of FALS proposes activation of a third apoptotic pathway linked to sustained endoplasmic reticulum (ER) stress. Here, we review the emerging role of ER stress and the unfolded protein response (UPR) in the pathogenesis of mutant SOD1-linked FALS. The UPR observed in FALS rodents is described which encompasses induction of key ER-resident chaperones during presymptomatic disease, leading to activation of stress transducers and pro-apoptotic molecules by late stage disease. Importantly, mutant SOD1 co-aggregates with UPR components and recruits to the ER, suggesting a direct adverse effect on ER function. By contrast, the opposing neuroprotective effects of wild-type SOD1 overexpression on UPR signalling are also highlighted. In addition, the potential impact of neuronal Golgi apparatus (GA) fragmentation and subsequent disturbances in intracellular protein trafficking on motor neuron survival in FALS is also discussed. We propose that ER stress and UPR may be coupled to GA dysfunction in mutant SOD1-mediated toxicity, promoting ER-initiated cell death signalling in FALS.

Amyotrophic Lateral Sclerosis↗