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Effect of exercise on cardiac muscle performance in aged rats.

Most investigations of a direct impact of chronic physical conditioning on cardiac muscle physiology and biochemistry have utilized relatively young animal models. Some, but not all, of these studies have demonstrated beneficial effect of relatively modest magnitude. With advancing age, i.e., with the onset of senescence, characteristic changes in many aspects of cardiac physiology and biochemistry in rodent models have been noted to occur. In general, these consist of a reduction in the kinetics of events that determine myocardial excitation-contraction relaxation and energetics. Recently it has been shown that several of these apparent age-related functional declines can be reversed by chronic physical conditioning, which in some instances have no effect on cardiac muscle of younger animals. This suggests that the relative efficacy of chronic exercise to modulate myocardial performance may, in part, be determined by the level of function present before the intervention, as is the case for other modulators of cardiac muscle function. In addition, that apparent age-related deficits in myocardial function can be reversed by conditioning suggests an interaction between life-style and aging.

Action Potentials↗

Additive effects of a bradykinin antagonist, NPC 17761, and a leumedin, NPC 15669, on survival in animal models of sepsis.

The effects of coadministration of NPC 17761 (D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Hype (transthiophenyl)-Oic-Arg), a potent bradykinin antagonist, and NPC 15669 (N-[9H-(2,7-dimethylfluoren-9-yl-methoxy)carbonyl]-L-leucine), a leukocyte recruitment inhibitor, were examined in rodent models of experimental shock. In mice, ED50 doses of NPC 17761 (0.12 mg/kg) and NPC 15669 (4 mg/kg), administered together, increased survival (83%) and inhibited leukopenia (60% at 4 h) in response to a lethal dose of endotoxin. In rats, independent administration of NPC 15669 (10 mg/kg, i.v. bolus) or NPC 17761 (0.1 mg/kg/h, 4 h) did not significantly increase survival (36 +/- 4 and 46 +/- 9 h, respectively) versus controls (27 +/- 1 h). However, co-treatment essentially "cured" (survival > 1 week) all septic animals, suggesting synergistic effects of the two agents.

Amino Acid Sequence↗

Changes in antioxidant defense enzymes after d-amphetamine exposure: implications as an animal model of mania.

Studies have demonstrated that oxidative stress is associated with amphetamine-induced neurotoxicity, but little is known about the adaptations of antioxidant enzymes in the brain after amphetamine exposure. We studied the effects of acute and chronic amphetamine administration on superoxide dismutase (SOD) and catalase (CAT) activity, in a rodent model of mania. Male Wistar rats received either a single IP injection of D-: amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle (acute treatment). In the chronic treatment rats received a daily IP injection of either D-: amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle for 7 days. Locomotor behavior was assessed using the open field test. SOD and CAT activities were measured in the prefrontal cortex, hippocampus, and striatum. Acute and to a greater extent chronic amphetamine treatment increased locomotor behavior and affected SOD and CAT activities in the prefrontal cortex, hippocampus and striatum. Our findings suggest that amphetamine exposure is associated with an imbalance between SOD and CAT activity in the prefrontal cortex, hippocampus and striatum.

Amphetamine↗

Hyperpolarized NMR study of the impact of alzheimer's disease on diabetes using a novel rat model.

Most researchers have long focused on linkage between type 2 diabetes (T2D) and the increased risk of Alzheimer's disease (AD) but have often overlooked whether AD modulates T2D. Investigating the reciprocal interaction between two complex diseases provides perspectives on the mechanistic linkage. The endeavor, however, confronts challenges without a robust rodent model that develops T2D and AD as the animal ages. Cross breeding a T2D rat with a hemizygous TgF344AD +/- rat that contains the mutant human amyloid precursor protein (APPsw) and the presenilin 1 (PS1ΔE9) genes has produced a new T2D-AD +/- rat model. The T2D-AD +/- rat expresses both the T2D and AD phenotypes as the animal ages. As AD progresses, the time to T2D onset decreases, and the diabetes severity increases. Hyperpolarized NMR experiments using dynamic nuclear polarization (DNP) show that T2D and T2D-AD rats share a common metabolic impairment in the brain pyruvate dehydrogenase (PDH) activity as reflected in the NMR determined decline in the bicarbonate/lactate (bic/lac) ratio. The bic/lac ratio decreases in both T2D and T2D-AD brain. AD exacerbates the decline of the bic/lac ratio.

Animals↗

Validation of a near-infrared probe for detection of thin intracranial white matter structures.

OBJECT: The authors have developed an intracranial near-infrared (NIR) probe that analyzes the scattering of light emitted from its tip to measure the optical properties of cerebral tissue. Despite its success in distinguishing graymatter from white matter in humans during stereotactic surgery, the limits of this instrument's resolution remain unclear. In this study, the authors determined the spatial resolution of this new probe by using a rodent model supplemented with phantom measurements and computer simulation. METHODS: A phantom consisting of Intralipid and gelatin was constructed to resemble a layer of white matter overlying a layer of gray matter. Near-infrared measurements were obtained as the probe was inserted through the gray-white matter transition. A computer simulation of NIR measurements through a gray-white matter transition was also performed using Monte Carlo techniques. The NIR probe was then used to study 19 tracks from the cortical surface through the corpus callosum in an in vivo rodent preparation. The animals were killed and histological sections through the tracks were obtained. Data from the phantom models and computer simulations showed that the NIR probe samples a volume of tissue extending 1 to 1.5 mm in front of the probe tip (this distance is termed the "lookthrough" distance). Measurements obtained from an NIR probe passing through a thin layer of white matter consisted of an initial segment of increasing values, a maximum (peak) value, and a trailing segment of decreasing values. The length of the initial segment is the lookthrough distance, the position of the peak indicates the location of the superficial white matter boundary, and the length of the trailing segment is the thickness of the layer. These considerations were confirmed in experiments with rodents. All tracks passed through the corpus callosum, which was demonstrated as a broad peak on each NIR graph. The position of the dorsal boundary of the corpus callosum and its width (based on histological measurements) correlated well with the peak of the NIR curve and its trailing segment, respectively. The initial segments correlated well with estimates of the lookthrough distance. Five of the tracks transected the smaller anterior commissure (diameter 0.2 mm), producing a narrow NIR peak at the correct depth. CONCLUSIONS: Data in this study confirm that the NIR probe can reliably detect and measure the thickness of layers of white matter as thin as 0.2 mm. Such resolution should be adequate to detect larger structures of interest encountered during stereotactic surgery in humans.

Animals↗

Local application of rhTGF-beta2 enhances peri-implant bone volume and bone-implant contact in a rat model.

Orthopedic and dental implant fixation depends upon bone regeneration. Growth factors such as transforming growth factor-beta (TGF-beta) have been shown to enhance bone repair and strengthen the mechanical connection between implant and host skeleton in canine models. To provide a platform for studying molecular mechanisms of growth factor stimulated bone regeneration and implant fixation, the present study examined peri-implant bone volume as a response to TGF-beta treatment in a rodent model. The rat femoral ablation model in which an implant is placed in the medullary cavity of the femur was used to examine the dose response to TGF-beta2 applied to the implant (0, 0.1, 1.0, or 10 microg). The study included a total of 40 rats (10 per dose) examined at 28 days. Peri-implant bone volume and bone-implant contact were assessed through microcomputed tomography and implant fixation strength was determined by a mechanical pullout test. Treatment of the implant with 10 microg TGF-beta2 led to a 2-fold increase in bone volume (P<0.001) and a 1.5-fold increase in bone-implant contact (P<0.01) with a trend of increasing fixation strength (non-significant increase of 1.4-fold). TGF-beta2 treatment with 10 microg led to uniform peri-implant bone volume and bone-implant contact along the length of the implant, whereas the other groups had less bone at the mid-point compared to the proximal and distal aspects of the implant. About 50% of the variance in implant fixation strength was explained by a regression model involving both bone-implant contact and peri-implant bone volume.

Animals↗

Stress and pathogenesis of infectious disease.

Despite inherent difficulties in defining and measuring stress, a scientific framework has been provided in recent years for understanding how disruptive life experiences might be translated into altered susceptibility to infectious diseases. Studies of the effects of stress on pathogenesis of infectious disease are highly relevant to assessment of the biological importance of the immune impairments that have been associated with stress. With a few notable exceptions, investigations of viral infections in humans and in animal models support the hypothesis that stress promotes the pathogenesis of such infections. Similar conclusions can be drawn from studies of bacterial infections in humans and animals and from a small number of studies of parasitic infections in rodent models. While many of these studies have substantial limitations, the data nonetheless suggest that stress is a potential cofactor in the pathogenesis of infectious disease. Given recent unprecedented advances in the neurosciences, in immunology, and in the field of microbial pathogenesis, the relationship between stress and infection should be a fruitful topic for interdisciplinary research.

Animals↗

Glucagon-like peptide 2.

Glucagon-like peptide 2 (GLP-2) is a 33 amino acid peptide-encoded carboxyterminal to the sequence of GLP-1 in the proglucagon gene. Both GLP-1 and GLP-2 are secreted from gut endocrine cells and promote nutrient absorption through distinct mechanisms of action. GLP-2 regulates gastric motility, gastric acid secretion, intestinal hexose transport, and increases the barrier function of the gut epithelium. GLP-2 significantly enhances the surface area of the mucosal epithelium via stimulation of crypt cell proliferation and inhibition of apoptosis in the enterocyte and crypt compartments. The cytoprotective and reparative effects of GLP-2 are evident in rodent models of experimental intestinal injury. GLP-2 reduces mortality and decreases mucosal injury, cytokine expression, and bacterial septicemia in the setting of small and large bowel inflammation. GLP-2 also enhances nutrient absorption and gut adaptation in rodents or humans with short bowel syndrome. The actions of GLP-2 are transduced by the GLP-2 receptor, a G protein-coupled receptor expressed in gut endocrine cells of the stomach, small bowel, and colon. Activation of GLP-2 receptor signaling in heterologous cells promotes resistance to apoptotic injury in vitro. The cytoprotective, reparative, and energy-retentive properties of GLP-2 suggests that GLP-2 may potentially be useful for the treatment of human disorders characterized by injury and/or dysfunction of the intestinal mucosal epithelium.

Amino Acid Sequence↗

Are animal models of diabetes relevant to the study of the genetics of non-insulin-dependent diabetes in humans?

Although it is well-recognized that non-insulin-dependent diabetes-mellitus (NIDDM) shown a strong genetic component the search for candidate genes has been very difficult since NIDDM is a complex, heterogeneous, multifactorial syndrome resulting from both genetic susceptibility and environmental risk factors. Therefore, the use of inbred animal models is an essential component of genetic investigations in this field. As these lines are genetically homogeneous, it is possible to direct mating for optimal genetic crosses and control environmental factors. Strains with spontaneous NIDDM may be constituted from animals with one or several genetic mutation(s) transmitted generation to generation or selected from non-diabetic outbred animals by repeated breeding. The ob/ob and db/db mice, which are rodent models of NIDDM and obesity, belong to the first category. Recent studies using the positional cloning approach allowed the mapping of ob gene and identification of its product, leptin, which is a protein secreted by white adipose tissue and involved in the control of food intake. The db gene encodes the leptin receptor. The search for genetic linkage was undertaken in polygenic models, especially the Goto-Kakisaki (GK) rat which was obtained by selective breeding of individuals with glucose intolerance from a non-diabetic Wistar rat colony. Though precise definition of sub-phenotypes of glucose tolerance and insulin secretion, the mapping of microsatellite markers and QTL analysis, it has proved possible to identify many independent loci containing genes regulating glucose homeostasis and insulin secretion. In another polygenic model, the OLETF rat, a locus present on chromosome X was identified. Many complementary approaches in different strains may lead to the identification of candidate genes for NIDDM and help direct the search for candidate genes in humans who show synteny relationships with rodents.

Animals↗

Genes, models and Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that is claiming an increasing number of victims as the world population ages. The identification of gene mutations and polymorphisms that either cause AD or significantly increase the risk for developing it enabled the creation of a whole generation of realistic rodent models of the disease. Animals expressing mutated human amyloid precursor protein and presenilin 1 show dramatic parallels to AD, although none of the models appear to capture the full range of pathologies that characterize the human disease. Increased refinement of these models will enhance the already tantalizing possibility of treatment.

Alzheimer Disease↗

Cortical malformations and epilepsy: new insights from animal models.

In the last decade, the recognition of the high frequency of cortical malformations among patients with epilepsy especially children, has led to a renewed interest in the study of the pathophysiology of cortical development. This field has also been spurred by the recent development of several experimental genetic and non-genetic, primarily rodent, models of cortical malformations. Epileptiform activity in these animals can appear as spontaneous seizure activity in vivo, in vitro hyperexcitability, or reduced seizure susceptibility in vitro and in vivo. In the neonatal freeze lesion model, that mimics human microgyria, hyperexcitability is caused by a reorganization of the network in the borders of the malformation. In the prenatal methylazoxymethanol model, that causes a diffuse cortical malformation, hyperexcitability is associated with alteration of firing properties of discrete neuronal subpopulations together with the formation of bridges between normally unconnected structures. In agreement with clinical evidence, these experimental data suggest that cortical malformations can both form epileptogenic foci and alter brain development in a manner that causes a diffuse hyperexcitability of the cortical network.

Abnormalities, Drug-Induced↗

New model of renal warm ischaemia-reperfusion injury for comparative functional, morphological and pathophysiological studies.

BACKGROUND: Renal warm ischaemia-reperfusion injury is pertinent to vascular and transplant surgery. While established models provide functional and morphological data the authors wanted to be able to correlate this with the underlying pathophysiology at any chosen time point, thus allowing future interventional effects on reperfusion injury to be evaluated. METHODS: In a rodent model bilateral renal warm ischaemia (15-60 min) and then reperfusion (20 or 80 min) before nephrectomy allowed for analysis of early reperfusion pathophysiology. The remaining kidney provided functional data (glomerular filtration rate (GFR)) at days 2 and 7 before nephrectomy for late analysis and morphology using a new grading system. RESULTS: Acceptable survival rate (ten of 12 animals) was seen with up to 45 min of warm ischaemia. Renal function was impaired at day 2 following 30-60 min of warm ischaemia (P< 0.01) and day 7 in the 45- and 60-min groups (P < 0.05 and P < 0.01 respectively). Strong correlation existed between duration of ischaemia and GFR at day 2 (r2=0.88) and day 7 (r2=0.95). Histological damage in the cortical tubules was evident in the 45- and 60-min groups (P< 0.01). CONCLUSION: This new model allowed comparative functional, morphological and pathophysiological studies while minimizing the number of animals required. Overall 45 min of warm ischaemia gave significant, recoverable injury and is recommended for investigating renal reperfusion injury.

Animals↗

In vitro modeling of human dorsal root ganglion neurons for GCaMP6-based calcium imaging of sensory responses to HSV-1 infection.

Dorsal root ganglion (DRG) neurons play a pivotal role in transmitting sensory information from the periphery to the central nervous system, mediating diverse stimuli such as pain, touch, and temperature. Despite advances, translating findings from rodent models to human applications remains challenging due to species-specific differences, necessitating reliable human DRG neuron models. The immortalized human DRG neuronal cell line HD10.6, derived from embryonic DRG cells and capable of differentiating into functional nociceptive-like neurons, offers a promising in vitro system for studying sensory neuron biology and drug screening. This study explores the utility of GCaMP6s, a genetically encoded calcium indicator, as a molecular tool for imaging sensory activation in HD10.6 cells. To establish HD10.6 as a robust human DRG model, we constructed and characterized adeno-associated virus (AAV9) vectors for efficient GCaMP6s delivery. Differentiated HD10.6 cells were efficiently transduced, and calcium dynamics were validated to assess functional responses to sensory stimuli. The results showed that AAV9 serotype was sufficient to infect HD10.6 and the GCaMP6s was successfully introduced into the cells. The HD10.6-GCaMP6s responded to capsaicin well under the appropriate condition. A series of viral infection studies indicated that herpesvirus HSV-1 triggered robust calcium influx within 5&#x202f;min after the exposure to the virus. Our findings highlight the potential of GCaMP6s-expressing HD10.6 cells as a high-throughput platform for studying nociception, neuronal signaling, host cell responses to viruses, and therapeutic interventions, bridging the gap between preclinical research and clinical applications.

Humans↗

Understanding autoimmune diabetes: insights from mouse models.

Type 1 or insulin-dependent diabetes is an autoimmune disease that causes the selective destruction of insulin-secreting beta cells in the pancreatic islets. Although this is a polygenic disease, with at least 20 genes implicated, the dominant susceptibility locus maps to the major histocompatibility complex (MHC), both in humans and in rodent models. However, in spite of progress on several fronts, the molecular pathology of autoimmune diabetes remains incompletely defined. Major areas of research include environmental trigger factors, the identification and role of beta-cell antigens in inducing and maintaining the autoimmune response, and the nature of the pathogenic and protective lymphocytes involved. In this review, we will focus on these areas to highlight recent advances in understanding the pathogenesis of autoimmune diabetes, drawing extensively on insights gained by studying the non-obese diabetic (NOD) mouse.

Alleles↗

Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury.

Hypoxic-ischemic brain injury in the perinatal period is a major cause of morbidity and mortality. Presently, there are no proven effective therapies with which to safeguard the human neonatal brain against this type of injury. Minocycline, a semisynthetic tetracycline, has been shown to be neuroprotective in certain adult ischemic injury/stroke and neurodegenerative disease models. However, minocycline's neuroprotective effects have not been assessed after insults to the neonatal brain. We now report that minocycline administered either immediately before or immediately after a hypoxic-ischemic insult substantially blocks tissue damage in a rodent model of neonatal hypoxic-ischemic brain injury. Minocycline treatment prevents the formation of activated caspase-3, a known effector of apoptosis, as well as the appearance of a calpain cleaved substrate, a marker of excitotoxic/necrotic cell death. To our knowledge, this is the first report of a systemic treatment that can be administered after a hypoxic-ischemic insult, which provides robust, nearly complete neuroprotection to the developing brain. Our data suggest that minocycline or a related neuroprotective tetracycline may be a candidate to consider in human clinical trials to protect the developing brain against hypoxic-ischemic-induced damage.

Animals↗

The use of FK506 and RS61443 for reversal of small-bowel rejection.

Successful clinical small-bowel transplantation is still difficult to achieve. Two features render the small intestine unique among vascularised solid organ grafts. First, the bowel contains a large amount of lymphoid tissue within the Peyer's patches, mesenteric lymph nodes, and intraepithelial lymphocytes, which are thought to mediate graft-versus-host disease and provide a major stimulus for the recipient's immune system. Unfortunately, mere surgical reduction of these tissues, by using segmental allografts, does not furnish any immunological advantage. Second, the small bowel lacks specific serum markers such as blood urea nitrogen (BUN) in the kidney or bilirubin in liver transplantation. Clinical signs such as fever, pain, or tenderness of the abdomen may indicate an already advanced destruction of the graft. Therefore, very potent immunosuppressive regimens are necessary to avoid small-bowel allograft rejection or even to reverse an ongoing rejection process. Cyclosporin was shown in small and large animal models to control rejection reactions sufficiently. However, there are two even more promising immunosuppressive agents currently under investigation. FK506, a macrolide lactone isolated from Streptomyces tsukubaensis, leads to long-term survival of small-bowel allografts in a rodent model and has already been used in a few clinical small-bowel transplantations. RS61443, a mycophenolic acid morpholinoethylester, selectively inhibits T- and B-cell proliferation. We have investigated the use of FK506 and RS61443 for the reversal of small-bowel allograft rejection in a small animal model.

Animals↗

Transcription factor abnormalities as a cause of beta cell dysfunction in diabetes: a hypothesis.

Well-characterized defects in insulin secretion, most notably a loss of glucose-induced insulin secretion, are found in virtually all forms of NIDDM, as well as in early IDDM. Similar abnormalities have been found in all animal models of diabetes in which they have been studied. A novel hypothesis is being proposed to explain the mechanisms responsible for these alterations. Many abnormalities in the various steps of glucose-induced insulin secretion have been identified in rodent models of diabetes, but none by itself seems sufficient to explain the defects. These include a loss of GLUT2, glycogen accumulation, glucose recycling, abnormal glucokinase or hexokinase, altered mitochondrial glycerol phosphate dehydrogenase (mGPDH) activity, abnormal ion channel function and beta cell degranulation. We propose that optimal secretory function is dependent upon the unique differentiation of beta cells that is maintained by a set of transcription factors and that this control is disrupted by the diabetic state. Therefore, we propose that key transcription factors are affected even when beta cells are stressed by insulin resistance in very earliest stages of diabetes and that the abnormality becomes more severe as full-blown diabetes develops, which leads to loss of beta cell differentiation and a resultant derangement of insulin secretion.

Animals↗

Mutant and genetically modified mice as models for studying the relationship between aging and carcinogenesis.

Increased interest is emerging in using mouse models to assess the genetics of aging and age-related diseases, including cancer. However, only limited information is available regarding the relationship between aging and spontaneous tumor development in genetically modified mice. Analysis of various transgenic and knockout rodent models with either a shortened or an extended life span, provides a unique opportunity to evaluate interactions of genes involved in the aging process and carcinogenesis. There are only a few models which show life span extension. Ames dwarf mutant mice, p66(-/-) knockout mice, alpha MUPA and MGMT transgenic mice live longer than wild-type strains. The incidence of spontaneous tumors in these mutant mice was usually similar to those in controls, whereas the latent period of tumor development was increased. Practically all models of accelerated aging showed increased incidence and shorter latency of tumors. This phenomenon has been observed in animals which display a phenotype that more closely resembles natural aging, and in animals which manifest only some features of the normal aging process. These observations are in agreement with an earlier established positive correlation between tumor incidence and the rate of tumor incidence increase associated with aging and the aging rate in a population. Thus, genetically modified animals are a valuable tool in unravelling mechanisms underlying aging and cancer. Systemic evaluation of newly generated models should include onco-gerontological studies.

Aging↗