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PubMed2006

Is estradiol mandatory for an adequate follicular and embryo development? A mouse model using aromatase inhibitor (anastrozole).

BACKGROUND: Although high levels of estradiol are found in the follicular fluid, little is known about its necessity for adequate follicular growth, oocyte maturation and embryo development. Arimidex (anastrozole) is a potent aromatase inhibitor capable to induce an in-vivo milieu deprived of estradiol. This study uses a mouse model applying Arimidex to create an in-vivo system lacking of estradiol, in order to explore whether this gonadal steroid hormone is mandatory for folliculogenesis followed by normal fertilization and embryo development. METHODS: Experiment 1: Immature C57 Black female mice, aged 3-4 weeks were superovulated by 5 IU PMSG given intraperitoneally. A study group (9 mice) was concomitantly injected with 0.1 mg of Arimidex intraperitoneally given the morning day before PMSG, the morning day of PMSG injection and the following two days. The control group (8 mice) was similarly injected with normal saline. Estradiol (E2) and progesterone (P) serum levels were tested 48 hours after PMSG and the ovaries of each mouse blindly examined by a pathologist to evaluate follicular development. Experiment 2: 48 h after PMSG superovulation, hCG (7.5 IU) was injected intraperitoneally, followed by mating. The study group was treated with Arimidex 0.1 mg intraperitoneally daily from a day prior to PMSG injection to the day of sacrifice. The control group was treated similarly by normal saline. Forty-two hours after mating blood was withdrawn for E2 and P levels followed by tubal dissection. Embryos of 2-4 cells were cultured in-vitro and the development to the morula, blastocyst and hatching blastocyst stages were examined 24, 42, and 48 h later. RESULTS: Experiment 1: A significant reduction of E2 levels was achieved in the Arimidex group in comparison to control group (126.3+/-104.8 and 1910+/-960 pmol/L, respectively; p < 0.0001). Nevertheless, the two groups did not differ by the mean number of follicles (27+/-9.5 and 30.4+/-13.0) or the distribution for antral (65% and 68.4%) and pre-antral (35% and 31.6%) follicles, respectively. Experiment 2: The reduction of estradiol during follicular phase did not hamper follicular development, in-vivo fertilization and in-vitro embryo development. Similar rates of embryo development to the morula stage (90.6% and 86%), blastocyst stage (86% and 89%) and hatching blastocyst (81% and 78%) were achieved in the Arimidex group and the control group, respectively. CONCLUSIONS: Adequate folliculogenesis is independent of estrogen but is conditioned on gonadotropin stimulation. Moreover, depletion of estradiol in the vicinity of the oocyte did not impair its developmental potential, including its fertilization and development into morulae, blastocysts and hatching blastocysts.

Anastrozole↗
PubMed2007

Breaches of the pial basement membrane and disappearance of the glia limitans during development underlie the cortical lamination defect in the mouse model of muscle-eye-brain disease.

Neuronal overmigration is the underlying cellular mechanism of cerebral cortical malformations in syndromes of congenital muscular dystrophies caused by defects in O-mannosyl glycosylation. Overmigration involves multiple developmental abnormalities in the brain surface basement membrane, Cajal-Retzius cells, and radial glia. We tested the hypothesis that breaches in basement membrane and the underlying glia limitans are the key initial events of the cellular pathomechanisms by carrying out a detailed developmental study with a mouse model of muscle-eye-brain disease, mice deficient in O-mannose beta31,2-N-acetylglucosaminyltransferase 1 (POMGnT1). The pial basement membrane was normal in the knockout mouse at E11.5. It was breached during rapid cerebral cortical expansion at E13.5. Radial glial endfeet, which comprise glia limitans, grew out of the neural boundary. Neurons moved out of the neural boundary through these breaches. The overgrown radial glia and emigrated neurons disrupted the overlying pia mater. The overmigrated neurons did not participate in cortical plate (CP) development; rather they formed a diffuse cell zone (DCZ) outside the original cortical boundary. Together, the DCZ and the CP formed the knockout cerebral cortex, with disappearance of the basement membrane and the glia limitans. These results suggest that disappearance of the basement membrane and the glia limitans at the cerebral cortical surface during development underlies cortical lamination defects in congenital muscular dystrophies and a cellular mechanism of cortical malformation distinct from that of the reeler mouse, double cortex syndrome, and periventricular heterotopia.

Animals↗
PubMed2006

Sjögren's syndrome in the NOD mouse model is an interleukin-4 time-dependent, antibody isotype-specific autoimmune disease.

NOD.B10-H2b and NOD/LtJ mice manifest many features of primary and secondary Sjögren's syndrome (SjS), respectively, an autoimmune disease affecting primarily the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes). A previous study suggested that the T(H2) cytokine, interleukin (IL)-4, plays an integral role in the development and onset of SjS-like disease in the NOD mouse model. To define further the role of IL-4 in onset of murine SjS-like disease, we have examined two IL4 gene knockout (KO) mouse strains, NOD.IL4-/- and NOD.B10-H2b.IL4-/-. Unlike NOD.IL4-/- mice, NOD.B10-H2b.IL4-/- mice are resistant to development of diabetes. The presence of a dysfunctional IL4 gene did not impede leukocyte infiltration of the salivary glands, yet prevented development of secretory dysfunction. Whereas NOD.B10-H2b.IL4-/- mice exhibited many pathophysiological manifestations of SjS-like disease common to the parental strains, these mice failed to produce anti-muscarinic acetylcholine type-3 receptor (M3R) autoantibodies of the IgG1 isotype. Cytokine mRNA expression profiles and adoptive transfers of T lymphocytes from NOD.B10-H2b.Gfp mice into NOD.B10-H2b.IL4-/- mice at different ages suggest IL-4 is required during the pre-clinical disease stage (around 12 weeks of age) to initiate clinical xerostomia. The results of this study indicate that the failure of NOD.IL4-/- and NOD.B10-H2b.IL4-/- mice to synthesize anti-M3R autoantibodies of the IgG1 isotype apparently explains why these mice fail to develop exocrine gland dysfunction, despite exhibiting pre-clinical manifestations of SjS-like disease.

Amylases↗
PubMed1980

Suppression and acceleration of experimental amyloidosis in mouse model.

Leupeptins, protease inhibitors, suppress the appearance of experimental amyloidosis in CBA mice induced by the injections with complete Freund's adjuvant. This substance, however, should be administered continuously from 1 week prior to amyloid induction to the end of the experiment. On the other hand, Trypan blue, inhibitors of lysosomal enzymes, accelerates experimental amyloidosis in the mouse model above-mentioned. Trypan blue is effective when given either prior to or at the same time of the initiation of amyloid induction. Organic Germanium has not been confirmed to be a potent suppressor of experimental murine amyloidosis but the experimental group administered this substance continuously from 1 week prior to the induction shows a rather low incidence of amyloidosis, and the average number of amyloidotic organs per affected mouse is about half of that of the control group. The suppression and acceleration of experimental murine amyloidosis presented here are a useful tool for investigating the pathogenesis of amyloidosis.

Amyloidosis↗
PubMed2005

Neural stem cell grafts reduce the extent of neuronal damage in a mouse model of global ischaemia.

The therapeutic potential of neural stem cell transplantation has been well demonstrated in many models of focal brain damage. However, few studies have sought to determine whether neural stem cells are therapeutic in models of diffuse brain injury, such as observed in Alzheimer's disease and global ischaemia. The present study investigated the effects of transplanted MHP36 neural stem cells on the extent of ischaemic damage in a mouse model of global ischaemia and the effects of the immunosuppressive agent cyclosporin A (CsA). C57Bl/6J mice received an intrastriatal graft of MHP36 neural stem cells 3 days after selective neuronal damage had been induced by global ischaemia. The experimental group was subdivided into CsA or saline controls. We discovered that grafts of MHP36 neural stem cells were able to differentiate into neurons and reduce the extent of ischaemic neuronal damage. This reduction was particularly apparent at 4 week post-transplantation and is independent of CsA immunosuppression. MHP36 cells survived robustly in host ischaemic brain and migrated away from the injection tract towards the caudate nucleus and corpus callosum. Although MHP36 grafts were associated with an acute inflammatory response from reactive astrocytes and microglia at 1 week post-transplantation, this decreased markedly by 4 weeks post-transplantation even in the absence of CsA immunosuppression. This is the first study showing a therapeutic benefit of neural stem cells in a highly diffuse brain injury, further highlighting the possibilities of stem cell transplantation for all types of neurodegenerative disease.

Animals↗
PubMed2006

Induction of antioxidant gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species.

Ischemia and reperfusion (I/R) are characterized by oxidative stress as well as changes in the antioxidant enzymes of the heart. However, little is known about the transcriptional regulation of myocardial antioxidant enzymes in repetitive I/R and hibernating myocardium. In a mouse model of ischemic cardiomyopathy induced by repetitive I/R, we postulated that induction of antioxidant gene expression was dependent on reactive oxygen species (ROS). Repetitive closed-chest I/R (15 min) was performed daily in C57/BL6 mice and in mice overexpressing extracellular superoxide dismutase (EC-SOD). Antioxidant enzyme expression was measured at 3, 5, 7, and 28 days of repetitive I/R as well as 15 and 30 days after discontinuation of I/R. In order to determine whether ROS directly modulates antioxidant gene expression, transcript levels were measured in cardiomyocytes exposed to hydrogen peroxide. Repetitive I/R caused an early and sustained increase in glutathione peroxidase (GPX) transcript levels, while heme oxygenase-1 (HO-1) expression increased only after 7 days of repetitive I/R. Overexpression of EC-SOD prevented the upregulation of GPX and HO-1 transcript levels by repetitive I/R, suggesting that both genes are regulated by ROS. However, while HO-1 transcript levels increased in cardiomyocytes exposed to hydrogen peroxide, oxidative stress failed to induce the expression of GPX implying that ROS regulates GPX transcript levels only indirectly in repetitive I/R. In conclusion, repetitive I/R was associated with an early upregulation of GPX expression as well as a delayed increase of HO-1 transcript levels in the heart. The induction of both antioxidant genes was dependent on ROS, suggesting that alterations in redox balance mediate not only tissue injury but also components of "programmed cell survival" in hibernating myocardium.

Animals↗
PubMed2005

Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis.

ALS is a devastating neurodegenerative disorder for which no effective treatment exists. Multiple molecular mechanisms are involved in the pathogenesis. We tested the catalytic antioxidant AEOL 10150, the histone deacetylase inhibitor phenylbutyrate (PBA), and the combination of PBA and AEOL 10150 in the G93A transgenic mouse model, administered from disease onset. AEOL 10150 alone improved motor function and extended survival by 11%, PBA alone significantly improved motor function and extended survival by 13%. PBA and AEOL 10150 together increased survival by 19%. Increased histone acetylation was confirmed by Western blot. Quantitative real-time RT-PCR analysis revealed upregulation of compounds capable of protecting cells against oxidative stress and apoptosis. Markers of oxidative damage were reduced in the lumbar spinal cord as compared to vehicle administration. These results suggest that agents inhibiting apoptosis and blocking oxidative stress show efficacy in treating mutant-SOD1-associated ALS and that a combination of agents targeting different disease mechanisms may exert additive therapeutic effects.

Acetylation↗
PubMed2006

Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease.

Transgenic mice carrying disease-linked forms of genes associated with Alzheimer disease often demonstrate deposition of the beta-amyloid as senile plaques and cerebral amyloid angiopathy. We have characterized the natural history of beta-amyloid deposition in APPswe/PS1dE9 mice, a particularly aggressive transgenic mouse model generated with mutant transgenes for APP (APPswe: KM594/5NL) and PS1 (dE9: deletion of exon 9). Ex vivo histochemistry showed Abeta deposition by 4 months with a progressive increase in plaque number up to 12 months and a similar increase of Abeta levels. In vivo multiphoton microscopy at weekly intervals showed increasing beta-amyloid deposition as CAA and plaques. Although first appearing at an early age, CAA progressed at a significantly slower rate than in the Tg2576 mice. The consistent and early onset of beta-amyloid accumulation in the APPswe/PS1dE9 model confirms its utility for studies of biochemical and pathological mechanisms underlying beta-amyloid deposition, as well as exploring new therapeutic treatments.

Age Factors↗
PubMed2006

Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.

Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.

Animals↗
PubMed1998

Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors.

Little is known about stepwise deregulation of specific genes leading to lymphoid malignancy. Aberrant myc gene expression in transgenic mice is correlated with B cell lymphomagenesis. We generated a unique transgenic mouse model in which deregulated murine E mu-N-myc transgene expression leads to development of indolent B cell lymphoma. Tumor cells were monoclonal, morphologically mature and surface immunoglobulin expressing B cells. Tumors arose in a disease course and exhibited a cytoarchitectural appearance reminiscent of human follicular lymphoma. Yet tumor cells were staged as preB since they failed to rearrange the immunoglobulin light chain genes. Retroviral insertion mutagenesis analyses of adult transgenic mice infected as newborns with murine leukemia virus revealed decreased disease latency, increased lymphoma incidence and a histologically more mature tumor type. Proviral insertion sites were not equivalent when accelerated E mu-N-myc indolent lymphomas were compared to accelerated c-myc preB cell lymphomas. The bcl-2 gene was not disrupted in either spontaneous or provirally accelerated E mu-N-myc lymphomas. These findings suggest that tumor progression in N-myc-associated indolent B cell lymphoma can proceed along diverse pathways involving distinctly different combinations of deregulated and/or intact genes than those pathways described in highly aggressive forms of myc-related murine preB cell disease.

Animals↗
PubMed2002

Altered flurothyl seizure induction latency, phenotype, and subsequent mortality in a mouse model of juvenile neuronal ceroid lipofuscinosis/batten disease.

PURPOSE: Juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is a pediatric neurodegenerative disease characterized by vision loss, seizure activity, cognitive decline, and premature death. Discovery of the Batten disease-related gene, CLN3, led to creation of a Cln3 protein-deficient mouse model (Cln3-/-), which recapitulates some of the histopathologic characteristics of the human condition. We hypothesized that lack of Cln3 would alter seizure-related behavioral parameters. METHODS: Using flurothyl gas inhalation, we examined seizure-induction latencies in Cln3-/- mice and wildtype (wt) controls at time points that represent late neonatal, immature, mature, and aged time points. We examined latency to first myoclonic jerk (LMJ), latency to loss of posture (LOP), and subsequent mortality. RESULTS: Our results demonstrate an age-dependent alteration of seizure-induction latencies in Cln3-/-. Immature Cln-/- mice aged 35-42 days had an increased latency to both LMJ and LOP compared with age-matched wt controls. There were no significant latency differences between Cln3-/- and wt at other time points examined. Mortality after generalized seizure was high in both Cln3-/- and wt animals at late neonatal and immature developmental stages. No mortality was seen in wt mice past maturity at 6 weeks. Mature and aged Cln3-/- animals retained a vulnerability to death after seizure activity. CONCLUSIONS: These results suggest that a deficiency of Cln3 protein in the Batten model mice may result in age-dependent alteration of the neuroanatomic and biochemical substrates involved in seizure propagation and recovery. This may be important in understanding seizures, neurodegeneration, and premature death in human Batten disease.

Administration, Inhalation↗
PubMed2002

Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease.

Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-beta (Abeta) in vitro. To determine whether endogenous clusterin plays a role in influencing Abeta deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin(-/-) mice. By 12 months of age, PDAPP, clusterin(-/-) mice had similar levels of brain Abeta deposition as did PDAPP, clusterin(+/+) mice. Although Abeta deposition was similar, PDAPP, clusterin(-/-) mice had significantly fewer fibrillar Abeta (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Abeta structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.

Alzheimer Disease↗
PubMed2006

Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy.

In polyglutamine diseases such as X-linked spinobulbar muscular atrophy (SBMA), it is unknown whether the toxic form of the protein is an insoluble or soluble aggregate or a monomer. We have addressed this question by studying a full-length androgen receptor (AR) mouse model of SBMA. We used biochemistry and atomic force microscopy to immunopurify oligomers soluble after ultracentrifugation that are comprised of a single approximately 50-kDa N-terminal polyglutamine-containing AR fragment. AR oligomers appeared several weeks prior to symptom onset, were distinct and temporally dissociated from intranuclear inclusions, and disappeared rapidly after castration, which halts disease. This is the first demonstration of soluble AR oligomers in vivo and suggests that they underlie neurodegeneration in SBMA.

Aging↗
PubMed2001

A new immunodeficient mouse model for human myoblast transplantation.

Design of efficient transplantation strategies for myoblast-based gene therapies in humans requires animal models in which xenografts are tolerated for long periods of time. In addition, such recipients should be able to withstand pretransplantation manipulations for enhancement of graft growth. Here we report that a newly developed immunodeficient mouse carrying two known mutations (the recombinase activating gene 2, RAG2, and the common cytokine receptor gamma, gammac) is a candidate fulfilling these requirements. Skeletal muscles from RAG2(-/-)/gammac(-/-) double mutant mice recover normally after myotoxin application or cryolesion, procedures commonly used to induce regeneration and improve transplantation efficiency. Well-differentiated donor-derived muscle tissue could be detected up to 9 weeks after transplantation of human myoblasts into RAG2(-/-)/gammac(-/-) muscles. These results suggest that the RAG2(-/-)/gammac(-/-) mouse model will provide new opportunities for human muscle research.

Animals↗
PubMed2025

Pentatricopeptide repeat protein targeting CUG repeat RNA ameliorates RNA toxicity in a myotonic dystrophy type 1 mouse model.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by the expansion of a CTG-triplet repeat in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. It results in the transcription of toxic RNAs that contain expanded CUG repeats (CUGexp). Splicing factors, such as muscleblind-like 1 (MBNL1), are sequestered by CUGexp, thereby disrupting the normal splicing program that is essential for various cellular functions. Pentatricopeptide repeat (PPR) proteins, originally found in plants, regulate RNA in organelles by binding in a sequence-specific manner. Here, we designed PPR proteins that specifically bind to the hexamer of CUG repeat RNAs (CUG-PPRs) and showed that CUG-PPR1 could ameliorate RNA toxicity induced by CUGexp in cell models of DM1. A single systemic recombinant adeno-associated virus (AAV9) vector-mediated gene delivery of CUG-PPR1 demonstrated long-term therapeutic effects on myotonia and restored splicing activity in a mouse model of DM1. These results highlight the potential of PPR molecules to target pathogenic RNA sequences in DM1 and potentially other RNA-mediated disorders.

Animals↗
PubMed2003

Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models.

Tubulointerstitial fibrosis is a hallmark feature of chronic renal injury. Specific therapies to control the progression of renal fibrosis toward end-stage renal failure are limited. Previous studies have demonstrated that expression of endogenous bone morphogenic protein-7 (BMP-7) is reduced in the kidneys of several inducible mouse models of acute and chronic renal disease and that administration of exogenous recombinant human BMP-7 (rhBMP-7) has a beneficial effect on kidney function. Here we report that treatment with rhBMP-7 leads to improved renal function, histology, and survival in mice deficient in the alpha3-chain of type IV collagen and MRL/MpJlpr/lpr lupus mice, two genetic models for chronic renal injury and fibrosis. Such therapeutic benefit is also associated with a significant decrease in the expression of profibrotic molecules, such as type I collagen and fibronectin, in renal fibroblasts. Additionally, rhBMP-7 induces expression of active matrix metalloproteinase-2, which is potentially important for removal of fibrotic matrix. Collectively, these studies provide further evidence for rhBMP-7 as an important bone-associated protein with protective function against renal pathology.

Animals↗
PubMed2004

Combined effect of liposomal and conventional amphotericin B in a mouse model of systemic infection with Candida albicans.

Amphotericin B may be employed as a potentially toxic deoxycholate complex or incorporated in liposomes and other particles which have an altered tissue distribution. A combination of both preparations could help to overcome the drawbacks of the individual preparations. We have employed a mouse model of systemic infection with Candida albicans to investigate whether this assumption was essentially true. We found that the combination of low dosages of both preparations (0.5 mg/kg of body weight/day of conventional and 0.5 mg kg of body weight/day liposomal amphotericin B) was more efficient than a similar dosage of conventional amphotericin B (1 mg/kg of body weight/day) in the liver and similar or higher dosages of liposomal amphotericin B (1 or 5 mg/kg of body weight/day) in the kidneys.

Amphotericin B↗
PubMed2004

A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma.

Mucus hypersecretion is a crucial feature of pulmonary diseases such as asthma, chronic bronchitis and cystic fibrosis. Despite much research, there is still no effective therapy for this condition. Recently, we showed that the myristoylated, alanine-rich C-kinase substrate (MARCKS) protein is required for mucus secretion by human bronchial epithelial cells in culture. Having synthesized a peptide corresponding to the N-terminal domain of MARCKS, we now show that the intratracheal instillation of this peptide blocks mucus hypersecretion in a mouse model of asthma. A missense peptide with the same amino acid composition has no effect. Based on quantitative histochemical analysis of the mouse airways, the peptide seems to act by blocking mucus release from goblet cells, possibly by inhibiting the attachment of MARCKS to membranes of intracellular mucin granules. These results support a pivotal role for MARCKS protein, specifically its N-terminal region, in modulating this secretory process in mammalian airways. Intratracheal administration of this MARCKS-related peptide could therapeutically reduce mucus secretion in the airways of human patients with asthma, chronic bronchitis and cystic fibrosis.

Animals↗