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PubMed2006

Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease.

Batten disease, a lysosomal storage disorder, is caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3-/-) mouse model of the disease exhibits many characteristic pathological features of the human disorder. Here, we show that Cln3-/- mice, similarly to Batten disease patients, have a deficit in cerebellar motor coordination. To explore the possible cellular cause of this functional impairment, we compared the vulnerability of wild type (WT) and Cln3-/- cerebellar granule cell cultures to different toxic insults. We have found that cultured Cln3-/- cerebellar granule cells are selectively more vulnerable to AMPA-type glutamate receptor-mediated toxicity than their WT counterparts. This selective sensitivity was also observed in organotypic cerebellar slice cultures. Our results suggest that lack of the CLN3 protein has a significant influence on the function of AMPA receptors in cerebellar granule neurons, and that AMPA receptor dysregulation may be a major contributor to the cerebellar dysfunction in Batten disease.

Animals↗

PubMed2002

Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer's disease.

Vaccinations against amyloid beta protein (A beta P) reduce amyloid deposition and reverse learning and memory deficits in mouse models of Alzheimer's disease. This has raised the question of whether circulating antibodies, normally restricted by the blood-brain barrier (BBB), can enter the brain [Nat. Med. 7 (2001) 369-372]. Here, we show that antibody directed against A beta P does cross the BBB at a very low rate. Entry is by way of the extracellular pathways with about 0.11% of an intravenous (i.v.) dose entering the brain by 1h. Clearance of antibody from brain increasingly dominates over time, but antibody is still detectable in brain 72 h after i.v. injection. Uptake and clearance is not altered in mice overexpressing A beta P. This ability to enter and exit the brain even in the presence of increased brain ligand supports the use of antibody in the treatment of Alzheimer's and other diseases of the brain.

Aging↗

PubMed2006

Metabolic characterization of the R6/2 transgenic mouse model of Huntington's disease by high-resolution MAS 1H NMR spectroscopy.

The metabolic consequences of Huntington's disease in the R6/2 mouse model were investigated using NMR spectroscopy and pattern recognition to characterize selected brain regions, muscle, blood, and urine. Global increases in relative brain concentrations of osmolytes, creatine, glutamine, and lactate, and decreases in acetate and N-acetylaspartate were found together with striatal-specific lower concentrations of GABA and choline. Clear differentiation of R6/2 and wild-type mice was also obtained for urine and blood metabolite profiles that may have applicability for monitoring HD in human populations.

Animals↗

PubMed1999

A nude mouse model of human osteosarcoma lung metastases for evaluating new therapeutic strategies.

The purpose of these studies was to develop a metastatic osteosarcoma nude mouse model to evaluate the in vivo efficacy of new therapeutic compounds. Human SAOS-2 osteosarcoma cells (10(6) cells) were injected i.v. into nude mice. Cells isolated from a rare pulmonary metastases 6 months later were established (SAOS-LM1) in culture and re-injected. This procedure was repeated 5 additional times to produce the SAOS-LM6 cell line. Visible pulmonary nodules were present 8 weeks following i.v. injection of 10(6) SAOS-LM6 cells as compared to 17 weeks using SAOS-LM2 cells. Microscopic SAOS-LM6 pulmonary metastases were demonstrated at 6 weeks. Administration of adriamycin on week 9 resulted in regression of macroscopic SAOS-LM6 lung tumors. The ability of the model to be used to evaluate the effectiveness of a biologic agent against microscopic disease was also verified. It was concluded that this model can assess therapeutic efficacy and therefore, may have a role in investigating the potential of novel approaches aimed at eliminating pulmonary metastatic osteosarcoma.

Animals↗

PubMed2000

In vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia.

We evaluated the in vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia using a susceptible strain and one with low-level resistance (MIC/MBC of levofloxacin: 0.06/0.06 and 4/4 mg/L, respectively). As demonstrated previously with other pathogens, the AUC/MIC ratio predicted the efficacy of fluoroquinolones against A. baumannii. This parameter correlated with bactericidal effect and survival. Combination therapy did not enhance the efficacy of levofloxacin.

Acinetobacter Infections↗

PubMed1994

Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model.

The effect of the number of cystic fibrosis (CF) alleles on cholera toxin (CT)-induced intestinal secretion was examined in the CF mouse model. CF mice that expressed no CF transmembrane conductance regulator (CFTR) protein did not secrete fluid in response to CT. Heterozygotes expressed 50 percent of the normal amount of CFTR protein in the intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion in intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion and fluid secretion suggests that CF heterozygotes might possess a selective advantage of resistance to cholera.

Alleles↗

PubMed2000

Anticonvulsant effect of nimodipine alone and in combination with diazepam and phenytoin in a mouse model of status epilepticus.

The effect of nimodipine alone and in combination with diazepam or phenytoin was tested in the electroshock-induced mouse model of status epilepticus. Status epilepticus was induced by transauricular electrical stimulation with a stimulus of 15 mA at 0.5, 3, 10, 20 and 30 min, starting half an hour after intraperitoneal administration of vehicle/drug. The median effective doses of diazepam and phenytoin alone and in combination with a fixed dose of nimodipine (24 mg/kg) was calculated. The ED50s of diazepam and phenytoin were found to be 10.5 and 9 mg/kg, respectively. When nimodipine was combined with diazepam or phenytoin, the ED50 values decreased to 3.77 mg/kg and 7.15 mg/kg, respectively. The severity of seizures was also decreased by combination with nimodipine as compared to diazepam and phenytoin given alone. To study the effect of nimodipine on psychomotor impairments produced by diazepam and phenytoin three tests were performed: rotarod, behavioral despair and hole board. Nimodipine did not show protective effects on its own but potentiated the anticonvulsant effects of diazepam and phenytoin. Furthermore, the combination of nimodipine with diazepam and phenytoin produced lesser impairment of psychomotor functions.

Animals↗

PubMed2001

Alteration in goblet cell numbers and mucin gene expression in a mouse model of allergic conjunctivitis.

PURPOSE: To determine whether the number of filled conjunctival goblet cells and mucin gene expression are altered in a mouse model of allergic conjunctivitis. METHODS: A/J mice were sensitized intraperitoneally with cat dander or the peptide P3-1 from the protein Fel d1. Two weeks later, the mice were challenged for 7 consecutive days with eye drops containing the allergens. Conjunctival tissue was harvested at 0, 6, 24, or 48 hours after final antigen challenge. Control samples were naïve animals and mice sensitized with cat dander and challenged with OVA-peptide or PBS. The mean number of filled goblet cells per square millimeter in three forniceal fields for each group was determined in wholemounts of conjunctiva prepared using rhodamine-phalloidin labeling followed by confocal microscopy. RNA was isolated from conjunctiva of the contralateral eye and taken for relative quantitation of mRNA of the goblet cell mucin Muc5AC and the epithelial membrane-spanning mucin Muc4, by real-time RT-PCR. RESULTS: The number of filled goblet cells was significantly decreased with both cat dander and P3-1, after final ocular challenge (P < 0.001). The most significant decrease over naïve mice was seen at 6 hours after final challenge with both allergens. The number of filled goblet cells was still decreased but was returning toward naïve levels at 24 hours (P < 0.05), and at 48 hours no significant difference was seen compared with naïve, PBS-treated, and OVA-peptide-treated control samples. For both cat dander and P3-1, Muc5AC and Muc4 mRNA was found to be decreased at the time of final ocular challenge. The level of Muc5AC mRNA from goblet cells rebounded from the decrease to show an increase over control by 24 hours after final challenge, and by 48 hours, the mRNA level had returned to naïve control range. In contrast, significant increases in Muc5AC mRNA were evident after final control challenge with PBS or OVA-peptide, indicating a potential irritant effect of drop application. The Muc4 mRNA level was significantly reduced at all time points except 24 hours after the last challenge. By comparison with allergen-challenged eyes, no change in Muc4 message levels was noted at any time point in OVA-peptide- or PBS-treated control eyes. CONCLUSIONS: These findings demonstrate that, in the conjunctiva of mice, repetitive application of allergens induces a reduction in the number of filled goblet cells and a decrease in Muc5AC and Muc4 mRNAs. After a period of 24 to 48 hours, the goblet cell number return to naïve levels, and goblet cell mucin mRNA levels return to above or within normal range, indicating a rapid recovery in the mucus secretion system.

Allergens↗

PubMed2001

[Effect of intratracheally administered IL-12 recombinant adenovirus on ovalbumin induced bronchial hyresponsiveness in mouse model].

OBJECTIVE: To assess the effect of intratracheally administered IL-12 recombinant adenovirus (Adm IL-12) on ovalbumin (OVA) induced bronchial hyperresponsiveness in mouse model. METHODS: C57BL/6 mice were sensitized by ovalbumin. Adm IL-12 with the dose of 10(8)pfu/mouse was administered intratracheally before OVA challenge. IL-4, IL-5 and IFN-gamma in BALF, bronchial responsiveness, eosinophil count in peripheral blood and BALF, serum total IgE and specific IgE were measured. RESULTS: There was IL-12 gene expression in the lung tissue after Adm IL-12 administration, concentration of IL-12 in sera and BALF were (540 +/- 60) U/ml and (4 700 +/- 800) U/ml respectively, but were unable to be detected in control group (P < 0.01). Compared with the control group, there were significantly lower levels of IL-4 [(3.5 +/- 2.0) ng/ml vs (85.0 +/- 25.0) ng/ml] (t = 27.97, P < 0.01) and IL-5 [(6.5 +/- 4.5) ng/ml vs (54.0 +/- 14.0) ng/ml], (t = 7.92, P < 0.01) in BALF, accompanying with a higher level of IFN-gamma [(690.0 +/- 32.0) ng/ml vs (12.5 +/- 3.2) ng/ml] (t = 51.6, P < 0.01), lower airway resistance [(360 +/- 30) cm H(2)O vs (810 +/- 50) cm H(2)O] (t = 18.9, P < 0.01) and lower eosinophil counts in both peripheral blood [(0.7 +/- 0.1)% vs (9.2 +/- 0.5)%] (t = 47.1, P < 0.01) and in BALF [(3.5 +/- 0.7) x 10(4)/ml vs (21.6 +/- 4.7) x 10(4)/ml)] (t = 9.33, P < 0.01). However, neither serum total IgE [(65 +/- 9) microgram/ml vs (67 +/- 10) microgram/ml], nor specific IgE [(32 +/- 8) microgram/ml vs (33 +/- 8) microgram/ml] showed significant difference (all P > 0.05). CONCLUSIONS: Intratracheally administered Adm IL-12 inhibits ovalbumin induced airway hyperresponsiveness, which may be an effective approach in the management of antigen induced bronchial asthma.

Adenoviridae↗

PubMed1996

[Effects of recombinant human tumor necrosis factor on the development of ascitic tumor and expression of c-erbB2 in the nude mouse models of ovarian cancer].

OBJECTIVE: To investigate the effects of recombinant human tumor necrosis factor (rhTNF) on the growth of ascitic tumor and expression of c-erbB2 in the nude mouse models of ovarian cancer. METHODS: By intraabdominal injection, rhTNF was delivered to the peritoneal cavity of nude mouse with ovarian cancer as well as control group, after 6 days treatment, tumor cell counting and expression of c-erbB2 were detected by indirect fluorescence flow cytometry. RESULTS: There is a significant difference in tumor cell counting between the study group and control group (P < 0.01). Expression of c-erbB2 in study group was lower than that in control group. CONCLUSION: rhTNF was demonstrated to have effects on both inhibition of ascitis tumor development and down regulation of c-erbB2 expression in nude mouse with ovarian cancer.

Animals↗

PubMed2002

Lens defects and age-related fiber cell degeneration in a mouse model of increased AbetaPP gene dosage in Down syndrome.

Early-onset cataract and Alzheimer's disease occur with high frequency in Down syndrome (trisomy 21), the most common chromosome duplication in human live births. Previously, we used in vivo and lens organ culture models to demonstrate Alzheimer pathophysiology in oxidative stress-related lens degeneration. Currently, well-characterized Alzheimer transgenic mouse models are used to extend these findings. Here, we report on mice carrying a complete copy of a wild-type human AbetaPP (hAbetaPP) gene from the Down syndrome critical region on chromosome 21. hAbetaPP mice produce fiber cell membrane defects similar to those described in human cataracts and increased age-related lens degeneration. hAbetaPP expression and mRNA alternative splicing in human and mouse lens and cornea favor longer, potentially more amyloidogenic forms. Endogenous mouse AbetaPP expression is increased in transgenic lenses, consistent with the cycle of oxidative stress proposed in the mechanism of Alzheimer pathophysiology. Alternative splicing previously designated as neuron-specific occurs in human lens and cornea, and is maintained by hAbetaPP expressed in mouse tissues. These present data implicate AbetaPP in fiber cell formation and in early-onset cataracts in Down syndrome. Finally, our findings provide further support for our hypothesis that Alzheimer pathophysiology contributes to the cataract formation that is increasing in the aging population.

Alternative Splicing↗

PubMed2005

Disodium Ascorbyl Phytostanyl Phosphates (FM-VP4) reduces plasma cholesterol concentration, body weight and abdominal fat gain within a dietary-induced obese mouse model.

PURPOSE: The purpose of this study was to determine if Disodium Ascorbyl Phytostanol Phosphates (FM-VP4) alters animal body weight and plasma lipid levels in a dietary-induced obese mouse model. METHODS: Twenty-four C57BL6 mice (28 days old) were housed individually and fed a standard mouse diet for 2 weeks upon arrival. After 2 weeks the animals were weighed and divided in 4 groups of similar average weight, and the groups received a low fat (10% kcal from fat) and high fat (45% kcal from fat) diet with or without FM-VP4 (2% w/w) for 12 continuous weeks. Food, water and caloric intake and body weight were recorded on a daily basis throughout the duration of the study. Following the 12th week of the study all animals were humanely sacrificed and blood and abdominal fat pads were harvested for further analysis. Plasma cholesterol, triglyceride, AST/ALT and creatinine levels were measured using enzymatic kits. RESULTS: There is a significant difference in weight gain between the low-fat diet and the low-fat diet + 2% w/w FM-VP4 treatment groups (P<0.05), as well as between the high-fat diet and the high-fat diet + 2% w/w FM-VP4 treatment groups (P<0.05). However, the reduction of weight gain of the high-fat diet + 2% FM-VP4 treatment group compared to the high-fat group was 51%, while the reduction in weight gain between the low-fat diet + 2% w/w FM-VP4 treatment group and the low-fat diet group was 17% over the duration of the study. No significant differences in food and water intakes, serum creatinine and AST/ALT levels were observed between the four groups. No significant differences in caloric intake between the low-fat diet and the low-fat diet + 2% w/w FM-VP4. However, a significant difference in caloric intake between high-fat diet and the high-fat diet + 2% w/w FM-VP4 treatment groups was observed. In addition, significant reductions in plasma cholesterol levels and abdominal fat pad weight between diet alone and diet + FM-VP4 treatment groups were observed. CONCLUSIONS: These findings suggest that FM-VP4 may have potential weight-loss and cholesterol lowering activity in both High Fat and Low Fat Diets treated groups.

Abdominal Fat↗

PubMed2006

In vivo measurement of plaque burden in a mouse model of Alzheimer's disease.

PURPOSE: To demonstrate an MRI method for directly visualizing amyloid-beta (Abeta) plaques in the APP/PS1 transgenic (tg) mouse brain in vivo, and show that T1rho relaxation rate increases progressively with Alzheimer's disease (AD)-related pathology in the tg mouse brain. MATERIALS AND METHODS: We obtained in vivo MR images of a mouse model of AD (APP/PS1) that overexpresses human amyloid precursor protein, and measured T1rho via quantitative relaxometric maps. RESULTS: A significant decrease in T1rho was observed in the cortex and hippocampus of 12- and 18-month-old animals compared to their age-matched controls. There was also a correlation between changes in T1rho and the age of the animals. CONCLUSION: T1rho relaxometry may be a sensitive method for noninvasively determining AD-related pathology in APP/PS1 mice.

Alzheimer Disease↗

PubMed1989

The beige mouse model for Mycobacterium avium complex (MAC) disease: optimal conditions for the host and parasite.

We extended our earlier studies to establish the beige (C57B1/6/bgJ/bgJ) mouse model for experimental acute infections with Mycobacterium avium complex (MAC). Optimal conditions of the host and the parasites have been determined. Mice bred at our center showed similar responses to those obtained from Jackson Laboratories, the original supplier. Both male and female mice showed similar responses, but older mice in both sexes showed less susceptibility than younger mice. Strain 101 of MAC showed remarkable consistency in its pathogenicity to beige mice, as evidenced by the distribution of colony forming unit (CFU) counts at various time points after intravenous challenge, in several experiments. CFU counts showed an association with the dose of challenge, and histopathological observations.

Animals↗

PubMed2006

Early abnormalities in transgenic mouse models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative and fatal human disorder characterized by progressive loss of motor neurons. Transgenic mouse models of ALS are very useful to study the initial mechanisms underlying this neurodegenerative disease. We will focus here on the earlier abnormalities observed in superoxide dismutase 1 (SOD1) mutant mice. Several hypotheses have been advanced to explain the selective loss of motor neurons such as apoptosis, neurofilament disorganisation, oxidative stress, mitochondrial dysfunction, astrogliosis and excitotoxicity. Although disease onset appears at adulthood, recent studies have detected abnormalities during embryonic and postnatal maturation in animal models of ALS. We reported that SOD1(G85R) mutant mice exhibit specific delays in acquiring sensory-motor skills during the first week after birth. In addition, physiological measurements on in vitro spinal cord preparations reveal defects in evoking rhythmic activity with N-methyl-DL-aspartate and serotonin at lumbar, but not sacral roots. This is potentially significant, as functions involving sacral roots are spared at late stages of the disease. Moreover, electrical properties of SOD1 lumbar motoneurons are altered as early as the second postnatal week when mice begin to walk. Alterations concern the input resistance and the gain of SOD1 motoneurons which are lower than in control motoneurons. Whether or not the early changes in discharge firing are responsible for the uncoupling between motor axon terminals and muscles is still an open question. A link between these early electrical abnormalities and the late degeneration of motoneurons is proposed in this short review. Our data suggest that ALS, as other neurodegenerative diseases, could be a consequence of an abnormal development of neurons and network properties. We hypothesize that the SOD1 mutation could induce early changes during the period of maturation of motor systems and that compensatory mechanisms-linked to developmental spinal plasticity-might explain the late onset of the disease.

Amyotrophic Lateral Sclerosis↗

PubMed2000

Hepatocyte cytokeratins are hyperphosphorylated at multiple sites in human alcoholic hepatitis and in a mallory body mouse model.

Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). Studies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation. However, no data exist on phosphorylation of CK8/18 in human AH. In this study, antibodies that selectively recognize phosphorylated epitopes of CK8 or CK18 were used to analyze CK8/18 phosphorylation states in normal human and murine livers, human AH biopsies, and livers of 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC)-intoxicated mice, the last serving as model for MB induction. Hepatocyte cytokeratins become hyperphosphorylated at multiple sites in AH and in DDC-intoxicated mice. Hyperphosphorylation of CK8/18 occurred rapidly, after 1 day of DDC intoxication and preceded architectural changes of the cytoskeleton. In long-term DDC-intoxicated mice as well as in human AH, MBs preferentially contain hyperphosphorylated CK8/18 as compared with the cytoplasmic cytokeratin intermediate filament network suggesting that CK8/18 hyperphosphorylation may play a contributing role in MB pathogenesis. Furthermore, the site-specific phosphorylation of cytokeratin in different stages of MB induction provides indirect evidence for the involvement of a variety of protein kinases known to be activated in stress responses, mitosis, and apoptosis.

Animals↗

PubMed2002

Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models.

Cancer directly affects at least one-third of the human population, but the inherited genetic determinants of cancer risk remain largely unknown. Mouse models of human cancer are helping us to understand this disease as a complex genetic trait and thus to identify the multiple genetic variant alleles involved in pathways that affect individual cancer susceptibility.

Alleles↗

PubMed2000

Comparative therapeutic efficacy of clinafloxacin in a pneumococcal meningitis mouse model.

The therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, was compared with that of ciprofloxacin and ceftriaxone in a novel pneumococcal meningitis mouse model. Mice were challenged by the intracerebral ventricular route with 50 IL of a lethal bacterial suspension and treated subcutaneously 2 h later. Both penicillin-susceptible and multidrug-resistant pneumococcal strains were used for evaluation. Survival percentages were calculated as the median curative dose (CD50) using log-probit statistical methods. Ceftriaxone was the most active agent against the penicillin-susceptible strain (CD50 = 2 mg/kg), but showed a 30-fold decrease in potency against the resistant strain. Clinafloxacin was equally effective against both strains, and proved to be the most active agent against the penicillin-resistant pneumococcus.

Animals↗