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PubMed2002

Pharmaceutical use of mouse models humanized for the xenobiotic receptor.

The regulation of hepatic cytochrome P450 (CYP) enzymes is implicated in both drug metabolism and drug-drug interactions. The CYP genes are induced by numerous xenobiotics, yet the inducibility shows clear species specificity. Recently, the rodent nuclear receptor PXR and its human homolog, SXR or hPXR, have been established as species-specific xeno-sensors that regulate CYP3A enzymes. By knocking-out the rodent gene and replacing it with the human receptor, a 'humanized' mouse model has been established. Displaying a human drug-response profile, this mouse represents a unique tool to dissect the drug-induced xenobiotic response and should aid the development of safer drugs.

Animals↗
PubMed2000

Inhibitory effect of Byakko-ka-ninjin-to on itch in a mouse model of atopic dermatitis.

Byakko-ka-ninjin-to (BN) is composed of gypsum, the root of anemarrhena, ginseng, licorice and rice. The effect of BN on the inhibition of itch was studied using an NC mouse model of atopic dermatitis. BN (200 mg/kg, p.o.) significantly inhibited the scratching frequency in NC mice, and decreased the skin temperature by 1.97 degrees C. The cooling action on the skin by BN may be involved in the inhibitory mechanism of itch, at least in part, since cooling the skin is known to inhibit the itch sensation in humans. Although the myocyte-specific enhancer binding factor 2C (MEF2C) mRNA is known to be increased in the cerebral cortex correlated with the itch sensation and skin lesions in NC mice, BN did not affect the expression level of the MEF2C mRNA. This result suggests that the inhibitory effect of BN on itch does not relate to inhibition of MEF2C expression in the cerebral cortex. The present study indicates that BN has an inhibitory effect on itch, and may be a useful antipruritic drug for atopic dermatitis.

Animals↗
PubMed2004

A fluorescent orthotopic mouse model for reliable measurement and genetic modulation of human neuroblastoma metastasis.

Neuroblastoma is the most common extra-cranial solid tumor of infancy and childhood, and majority of patients die from the metastatic disease. Orthotopic xenograft mouse models are valuable tools for improving our understanding and control of neuroblastoma metastasis, because they readily represent genetic diversity and allow spontaneous metastasis. Intra-adrenal injection is commonly used for establishing the orthotopic animal models since human neuroblastoma frequently originates in the adrenal gland. However, it is unclear whether the metastatic potential of neuroblastoma can be reliably determined in adrenally-injected mice because their gland size is so small. In this study, we developed and characterized a fluorescent orthotopic xenograft animal model of NB69-derived human neuroblastoma. By comparing animals receiving adrenal injection and adrenal overlay, with the latter mimicking injection spillover, we found that the metastatic potential of neuroblastoma can be reliably determined in animal lungs. Furthermore, the lung metastasis can be genetically modulated in these animals. The results also show that the expression of Renilla green fluorescent protein (GFP) was exceptionally stable in NB69 cells, allowing rapid and sensitive detection of lung metastases at the macroscopic level. Additional features of our model include 100% tumor take, a 1-week tumor latency, resemblance to tumor behaviors in neuroblastoma patients, and the ability to monitor the expression of a gene of interest with GFP. This animal model of human neuroblastoma will be useful for studying genes involved in the metastatic process and for evaluating anti-metastasis agents in pre-clinical trials.

Adrenal Gland Neoplasms↗
PubMed2005

Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease.

Multiple lines of evidence demonstrated that increased brain oxidative stress is a key feature of Alzheimer's disease (AD). Melatonin is a potent endogenous antioxidant and free radical scavenger. A transgenic mouse model for AD mimics the accumulation of senile plaques, neuronal loss, and memory impairment. Four-month-old transgenic mice were administrated melatonin at 10 mg/kg for 4 months. We investigated the long-term influence of melatonin on these mice before amyloid plaques were deposited. We found an increase in the levels of brain thiobarbituric acid-reactive substances (TBARS) and a decrease in glutathione (GSH) content, as well as accelerated upregulation of the apoptotic-related factors, such as Bax, caspase-3, and prostate apoptosis response-4 (Par-4) in transgenic mice, but not in wild-type (WT) littermates. Significantly, the increase in TBARS levels, reduction in superoxide dismutase activity, and GSH content were reinstated by melatonin. In addition, transgenic mice administered melatonin (10 mg/kg) showed a significant reduction in upregulated expression of Bax, caspase-3 and Par-4, indicating inhibited triggering of neuronal apoptosis. These results supported the hypothesis that oxidative stress was an early event in AD pathogenesis and that antioxidant therapy may be beneficial only if given at this stage of the disease process. In sharp contrast to conventional antioxidants, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential therapeutic candidate in AD treatment.

Alzheimer Disease↗
PubMed2004

Sleep-wake architecture in mouse models for Down syndrome.

Sleep-wake homeostasis is crucial for behavioral performances and memory both in the general population and in patients with learning disability, among whom were Down syndrome (DS) patients. We investigated, in mouse models of DS, cortical EEG and sleep-wake architecture under baseline conditions and after a 4-h sleep deprivation (SD). Young hemizygous mice (hSODwt/+) transgenic for the human CuZn superoxide dismutase (hSOD1) or for the human amyloid precursor protein (HuAPP(695); hAPPwt/+) were obtained on the same FVB/N inbred background. Baseline records for slow wave sleep (SWS) and wake (W) parameters were unchanged, whereas paradoxical sleep (PS) episode numbers were decreased and PS latency increased after lights off in hSODwt/+ mice versus controls. hSODwt/+ mice did not experience SWS or PS rebounds after SD but EEG activity in the delta-SWS activity (SWA) was enhanced. hAPPwt/+ mice exhibited no change in PS but an increase in W and a decrease in SWS before light transition as well as an increase in theta-power in PS and W. After SD, hAPPwt/+ mice exhibited SWS and PS rebounds as well as enhancement of SWA. We investigated also the nitrite/nitrate levels in all mice and found an increase in the brainstem of hSODwt/+ mice only versus control ones. These preliminary data provide useful results to investigate other genetically manipulated mice and to better understand the biochemical basis of sleep disorders in DS patients.

Animals↗
PubMed2002

Loss of Stat5a delays mammary cancer progression in a mouse model.

A genetic study was conducted to determine if activated Stat5a contributes to mammary carcinogenesis and to evaluate the mechanism. Similar to human breast cancers, a proportion of mammary adenocarcinomas in the WAP-TAg transgenic mouse model demonstrate constitutive Stat5a/b and Stat3 activation. Stat5a activation is linked to mammary epithelial cell survival and differentiation, and proliferation in hematopoetic cell lineages. Breeding WAP-TAg mice to mice carrying germ-line deletions of the Stat5a gene generated mice with reduced levels of Stat5a. Hemizygous loss of the Stat5a allele significantly reduced levels of Stat5a expression without altering mammary gland development or transgene expression levels. In comparison to mice carrying two wild-type Stat5a alleles, hemizygous loss of the Stat5a allele reduced the number of mice with palpable tumors at 7 months of age (67% from 100%, P<0.05), resulted in smaller tumors at 7 months of age (3.8 cm3 from 7.6 cm3, P=0.003), delayed first tumor appearance (208 days from 188 days, P=0.01), and increased the apoptotic index in the adenocarcinomas (4.3+/-0.3 from 1.2+/-0.2, P=0.016). Neither cell proliferation nor differentiation in the cancers was altered. Decreasing Stat5a activation levels could be a therapeutic approach for reducing survival of breast cancer cells.

Adenocarcinoma↗
PubMed1997

Protective effect of granulocyte colony-stimulating factor (G-CSF) in a granulocytopenic mouse model of Pseudomonas aeruginosa lung infection through enhanced phagocytosis and killing by alveolar macrophages through priming tumour necrosis factor-alpha (TNF-alpha) production.

We investigated the effects of G-CSF in a granulocytopenic mouse model of Pseudomonas aeruginosa lung infection. The model was prepared by intratracheal instillation of the bacteria, while granulocytopenia was induced by intraperitoneal injection of 4.0 mg of cyclophosphamide (CPA). There was no difference in the survival rate between G-CSF-treated animals and the normal group, and the number of neutrophils in the blood and lung recovered to normal in the former group. However, the phagocytic and killing activities of neutrophils were lower in G-CSF-treated mice than in controls. Interestingly, the mortality rate increased significantly when anti-TNF-alpha antibody was combined with G-CSF, although it was intermediate between CPA alone and CPA-G-CSF-treated mice. However, the improved mortality was not associated with a change in the number of neutrophils in the circulation and lung. Administration of anti-TNF-alpha antibody resulted in a significant suppression of TNF-alpha in bronchoalveolar lavage fluid and of enhanced alveolar macrophage function (phagocytic and bactericidal activity) against P. aeruginosa in G-CSF-treated granulocytopenic mice. We showed also increased TNF-alpha mRNA expression and TNF-alpha production in vitro using G-CSF-pretreated alveolar macrophages compared with control untreated macrophages. Our results are the first evidence to suggest that G-CSF provides a synergistic protective effect against lethal P. aeruginosa lung infection in the granulocytopenic host. This effect is probably due to enhancement of alveolar macrophage function through endogenous TNF-alpha production, in addition to increasing the number of circulating neutrophils.

Animals↗
PubMed2006

Severe feto-placental abnormalities precede the onset of hypertension and proteinuria in a mouse model of preeclampsia.

Preeclampsia is a prevalent and potentially devastating disorder of pregnancy. Characterized by a sudden spike in blood pressure and urinary protein levels, it is associated with significant obstetric complications. BPH/5 is an inbred mouse model of preeclampsia with borderline hypertension before pregnancy. BPH/5 mice develop hypertension, proteinuria, and endothelial dysfunction during late gestation (after E14.5). We hypothesized that BPH/5 mice might exhibit early feto-placental abnormalities before the onset of maternal disease. All placental cell lineages were present in BPH/5 mice. However, the fetal and placental weights were reduced, with abnormalities in all the placental zones observed starting early in gestation (E9.5-E12.5). The fractional area occupied by the junctional zone was significantly reduced at all gestational timepoints. Markedly fewer CDKN1C-stained trophoblasts were seen invading the proximal decidual zone, and this was accompanied by reductions in Cdkn1c gene expression. Trophoblast giant cell morphology and cytokeratin staining were not altered, although the mRNA levels of several giant cell-specific markers were significantly downregulated. The labyrinth layer displayed decreased branching morphogenesis of endothelial cells, with electron microscopy evidence of attenuated trophoblast layers. The maternal decidual arteries showed increased wall-to-lumen ratios with persistence of actin-positive smooth muscle cells. These changes translated into dramatically increased vascular resistance in the uterine arteries, as measured by pulse-wave Doppler. Collectively, these results support the hypothesis that defects at the maternal-fetal interface are primary causal events in preeclampsia, and further suggest the BPH/5 model is important for investigations of the underlying pathogenic mechanisms in preeclampsia.

Animals↗
PubMed2000

Polymorphonuclear neutrophils are necessary for the recruitment of CD8(+) T cells in the liver in a pregnant mouse model of Chlamydophila abortus (Chlamydia psittaci serotype 1) infection.

The role of polymorphonuclear neutrophils (PMNs) in the development of the specific immune response against Chlamydophila abortus (Chlamydia psittaci serotype 1) infection was studied in a pregnant mouse model involving treatment with RB6-8C5 monoclonal antibody. PMN depletion significantly affected the immune response in the liver, in which the T-lymphocyte and F4/80(+) cell populations decreased, particularly the CD8(+) T-cell population. A Th1-like response, characterized by high levels of gamma interferon without detectable levels of interleukin 4 (IL-4) in serum, was observed in both depleted and nondepleted mice, although an increased production of IL-10 was detected in the depleted group. Our results suggest that PMNs play a very important role in the recruitment of other leukocyte populations to the inflammatory foci but have little influence in the polarization of the immune specific response toward a Th1-like response.

Animals↗
PubMed2006

Voltage-dependent sodium channels in spinal cord motor neurons display rapid recovery from fast inactivation in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a substantial loss of motor neurons in the spinal cord, brain stem, and motor cortex. Previous evidence showed that in a mouse model of a familial form of ALS expressing high levels of the human mutated protein Cu,Zn superoxide dismutase (Gly(93)-->Ala, G93A), the firing properties of single motor neurons are altered to induce neuronal hyperexcitability. To determine whether the functionality of the macroscopic voltage-dependent Na(+) currents is modified in G93A motor neurons, in the present work their physiological properties were examined. The voltage-dependent sodium channels were studied in dissociated motor neurons in culture from nontransgenic mice (Control), from transgenic mice expressing high levels of the human wild-type protein [superoxide dismutase 1 (SOD1)], and from G93A mice, using the whole cell configuration of the patch-clamp recording technique. The voltage dependency of activation and of steady-state inactivation, the kinetics of fast inactivation and slow inactivation of the voltage-dependent Na(+) channels were not modified in the mutated mice. Conversely, the recovery from fast inactivation was significantly faster in G93A motor neurons than that in Control and SOD1. The recovery from fast inactivation was still significantly faster in G93A motor neurons exposed for different times (3-48 h) and concentrations (5-500 microM) to edaravone, a free-radical scavenger. Clarification of the importance of these changes in membrane ion channel functionality may have diagnostic and therapeutic implications in the pathogenesis of ALS.

Algorithms↗
PubMed2001

Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex.

Cardiomyopathy is a multifactorial disease, and the dystrophin-glycoprotein complex has been implicated in the pathogenesis of both hereditary and acquired forms of the disease. Using mouse models of cardiomyopathy made by ablating genes for components of the sarcoglycan complex, we show that long-term treatment with verapamil, a calcium channel blocker with vasodilator properties, can alleviate the severe cardiomyopathic phenotype, restoring normal serum levels for cardiac troponin I and normal cardiac muscle morphology. Interruption of verapamil treatment leads again to vascular dysfunction and acute myocardial necrosis, indicating that predilection for cardiomyopathy is a continuing process. In contrast, verapamil did not prevent cardiac muscle pathology in dystrophin-deficient mdx mice, which neither show a disruption of the sarcoglycan complex in vascular smooth muscle nor vascular dysfunction. Hence, our data strongly suggest that pharmacological intervention with verapamil merits investigation as a potential therapeutic option not only for patients with sarcoglycan mutations, but also for patients with idiopathic cardiomyopathy associated with myocardial ischemia not related to atherosclerotic coronary artery disease.

Age Factors↗
PubMed1992

Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene.

A group of neonates with Gaucher disease with a particularly devastating clinical course is described. The phenotype of these infants is analogous to that of a Gaucher mouse, which was created by targeted disruption of the mouse glucocerebroside gene. Similar to the homozygous mutant mice with glucocerebrosidase deficiency, these infants present at or shortly after birth, have rapidly progressing fulminant disease, and many have associated ichthyotic skin and/or hydrops fetalis. This transgenetic mouse model of Gaucher disease has helped us to appreciate a distinct Gaucher phenotype. Potentially, as this technology is applied to create other animal models of metabolic diseases, it may enable the recognition of other, as yet unappreciated presentations of inherited disorders.

Animals↗
PubMed2005

Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease.

Huntington's disease (HD) is an adult-onset neurodegenerative disorder involving motor dysfunction, cognitive deficits, and psychiatric disturbances that result from underlying striatal and cortical dysfunction and neuropathology. The YAC128 mouse model of HD reproduces both the motor deficits and selective degeneration observed in the human disease. However, the presence of cognitive impairment in this model has not been determined. Here, we report mild cognitive deficits in YAC128 mice that precede motor onset and progressively worsen with age. Rotarod testing revealed a motor learning deficit at 2 months of age that progresses such that by 12 months of age, untrained YAC128 mice are unable to learn the rotarod task. Additional support for cognitive dysfunction is evident in a simple swimming test in which YAC128 mice take longer to find the platform than wild-type (WT) controls beginning at 8 months of age. YAC128 mice also have deficits in open-field habituation and in a swimming T-maze test at this age. Strikingly, in the reversal phase of the swimming T-maze test, YAC128 mice take twice as long as WT mice to locate the platform, indicating a difficulty in changing strategy. At 12 months of age, YAC128 mice show decreased prepulse inhibition and habituation to acoustic startle. The clear pattern of cognitive dysfunction in YAC128 mice is similar to the symptoms and progression of cognitive deficits in human HD and provides both the opportunity to examine the relationship between cognitive dysfunction, motor impairment, and neuropathology in HD and to assess whether potential therapies for HD can restore cognitive function.

Acoustic Stimulation↗
PubMed1992

Human xenograft-nude mouse model of adoptive immunotherapy with human melanoma-specific cytotoxic T-cells.

We investigated the efficacy of human melanoma-specific cytotoxic T-cells (CTLs) in treating experimental human melanoma metastases in a nude mouse model of adoptive immunotherapy. Hepatic metastases were generated by the intrasplenic injection of 1.5 x 10(6) human melanoma cells. Animals were then randomized to receive saline, interleukin-2 only, or CTLs and interleukin-2. CTLs were effective when administered 3 or 7 days after generation of hepatic metastases, with 96 and 88% of animals disease-free, respectively, when examined at one month. Interleukin-2 alone was not effective. In addition, CTLs were effective when as few as 2.5 x 10(6) T-cells were adoptively transferred. Only 33% of the animals were tumor-free when CTLs were administered on day 10, and CTLs were not effective when given at day 14. Human CTLs that were not cytotoxic for the tumor line used in vivo, when tested in a 51Cr assay, were also not effective in the model of immunotherapy. This suggests that the tumor-specific CTLs maintain their specificity in vivo, and eliminates a nonspecific inflammation directed against the human CTLs as a possible cause of the antitumor effect. These studies lay the foundation for clinical trials of CTLs in the adoptive immunotherapy of patients with metastatic melanoma.

Animals↗
PubMed1987

Antitumor activity of an immunotoxin in a nude mouse model of human ovarian cancer.

An immunotoxin composed of an antibody to the human transferrin receptor (454A12) and ricin A chain (RTA) was shown to inhibit the growth of NIH:OVCAR-3 tumors in a nude mouse model of human ovarian cancer. Inhibition of tumor growth by 454A12-RTA was related to the dose administered. The antitumor activity of the immunotoxin was blocked by coinjection of excess antibody with immunotoxin. An immunotoxin made using 454A12 and recombinant ricin A chain (rRTA) had an activity similar to that made with native RTA. The administration of 10 micrograms or greater of the immunotoxin 454A12-RTA/rRTA had significant antitumor activity. The injection of 30 micrograms of an irrelevant immunotoxin, MOPC21-RTA, or 30 to 500 micrograms of the 454A12 antibody had no antitumor activity.

Animals↗
PubMed2001

Prior cryopreservation of ex vivo-expanded cord blood cells is not detrimental to engraftment as measured in the NOD-SCID mouse model.

Cytokine-mediated expansion has been proposed and successfully used to facilitate engraftment post transplantation. This study examined whether cryopreservation following expansion has a detrimental effect on the ability of cells to engraft, using the NOD-SCID mouse model. Cord blood (CB) CD34(+) cells were incubated for 7 days with stem cell factor (SCF), flt-3 ligand (FL), and megakaryocyte growth and development factor (MGDF). Expanded CD34(+) cells were transplanted into NOD-SCID mice either fresh or following cryopreservation and thawing. After thawing, recovery of nucleated cells was 94%, of CD34 cells was 63%, and of day-14 progenitors was 17%. The loss of day-14 progenitor cells among the thawed expanded cells did not influence the kinetics of human engraftment in the mouse. Bone marrow (BM) of mice transplanted with thawed expanded CD34(+) cells (14 +/- 3.9%) showed significantly higher levels of human engraftment than mice transplanted with fresh expanded CD34(+) cells (1.5 +/- 0.5%, p = 0.0064). Thawed expanded CD34(+) cells had significantly higher SCID Engrafting Potential (SEP) than freshly expanded CD34(+) cells (p < 0.001). Results suggest that prior cryopreservation does not prevent expanded cells engrafting in NOD-SCID mice.

Animals↗
PubMed2005

Depletion of rabphilin 3A in a transgenic mouse model (R6/1) of Huntington's disease, a possible culprit in synaptic dysfunction.

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by progressive psychiatric, cognitive, and motor disturbances. We studied the expression of synaptic vesicle proteins in the R6/1 transgenic mouse model of HD. We observed that the levels of rabphilin 3A, a protein involved in exocytosis, is substantially decreased in synapses of most brain regions in R6/1 mice. The appearance of the reduction coincides with the onset of motor deficits and behavioral disturbances. Double immunohistochemistry did not show colocalization between rabphilin 3A and huntingtin aggregates in the HD mice. Using in situ hybridization, we demonstrated that rabphilin 3A mRNA expression was substantially reduced in the R6/1 mouse cortex compared to wild-type mice. Our results indicate that a decrease in mRNA levels underlie the depletion of protein levels of rabphilin 3A, and we suggest that this reduction may be involved in causing impaired synaptic transmission in R6/1 mice.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Non-lipooligosaccharide-mediated signalling via Toll-like receptor 4 causes fatal meningococcal sepsis in a mouse model.

Meningococcal lipooligosaccharide (LOS) is a major inflammatory mediator of fulminant meningococcal sepsis and meningitis with disease severity correlating with circulating concentrations of LOS and proinflammatory cytokines. In this study we show that the proinflammatory response to live meningococci in a mouse model of sepsis involves TLR4, but can develop independently of the expression of LOS. This is supported by data showing that in vivo an isogenic LOS-deficient strain, lpxA, induced equivalent disease severity and similar proinflammatory responses as the serogroup C wild-type parent strain FAM20. This response was abolished in TLR4-/- mice, and neither the wild-type strain of meningococci nor the LOS-deficient mutant was able to cause fatal sepsis in these mice. Mouse survival correlated with low levels of cytokines and chemokines, the chemotactic complement factor C5a and neutrophil levels in blood at 24 h post infection. These data suggest that during meningococcal sepsis the recognition of one or more unidentified non-LOS component(s) by TLR4 is important in stimulating proinflammatory responses, and that fatality associated with meningococcal sepsis in mice is induced by the proinflammatory host response.

Animals↗