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PubMedDate not supplied

Rodent models of the human isoniazid-acetylator polymorphism.

Inbred strains and subpopulations of rats, laboratory mice, and deer mice were examined for individual variation in the ability to metabolize several arylamines (p-aminobenzoic acid, sulfamethazine, aniline, alpha-naphthylamine, and aminofluorene) by N-acetylation. Individual differences within species were found to be dependent upon the tissue source of N-acetyltransferase activity and the acetyl acceptor employed. Long-Evans rats possessed about 2-fold more p-aminobenzoic acid N-acetyltransferase activity in blood and liver than Sprague-Dawley rats; no strain differences could be found with sulfamethazine. Nine strains of laboratory mice (Mus musculus) were found to have considerable liver p-aminobenzoic acid N-acetyltransferase activity but only slight activity towards sulfamethazine. No strain differences were apparent in regard to liver N-acetyltransferase activity. Blood p-aminobenzoic acid N-acetyltransferase activity was distinctly polymorphic in laboratory mice; of the nine strains tested, only A/J mice did not have this activity. Partially inbred deer mice (Peromyscus maniculatus) showed a narrower phenotypic range than random-bred stock from which they were obtained, which suggests the existence of distinct subpopulations with respect to N-acetylation capacity. Presumptive evidence for multiple forms of N-acetyltransferase in liver and blood was obtained through a study of substrate specificity.

Acetylation↗
PubMed1993

A unique rodent model for both the cardiotoxic and hepatotoxic effects of prolonged iron overload.

BACKGROUND: Hemochromatosis is a disease of excessive iron storage leading to tissue damage and fibrosis. Both genetic hemochromatosis, which can affect 1 in 500 of some populations, and the form of this disease which occurs as a secondary consequence of the hemoglobinopathy, homozygous beta-thalassemia, with 40 million carriers worldwide, have a common pathology. The cardiotoxicity and hepatotoxicity, which occurs with this disease, have never been produced experimentally in other species. EXPERIMENTAL DESIGN: Using a regimen of iron dextran administered subcutaneously to gerbils on a weekly basis for 7 weeks, we have produced severe hemosiderosis, especially of the liver and heart. By examining gerbils at 1, 2 and 3 months after the final iron injections we followed the subsequent development of hemochromatosis in the hearts and livers of iron overloaded animals. RESULTS: Hemochromatosis of the liver was evident as a scarring fibrosis in all cases between 1 and 3 months after iron dextran administration to gerbils. The iron burden in the cardiac myocytes of gerbils gradually increased between 1 and 3 months, resulting in hemochromatosis of the heart 2 and 3 months after the final iron dextran injections. CONCLUSIONS: Repeated parenteral injections of iron dextran to gerbils resulted in hemochromatosis affecting the liver and heart with a pathology which is the same as occurs in the end-stage disease in man. This model will allow the detailed study of the mechanism of iron induced, free radical tissue damage, which is though to be the cause of these lesions and will also be useful in the evaluation of iron chelating therapies to determine whether the hepatic and cardiac pathology of iron overload can be modulated over a long period.

Animals↗
PubMed1994

Transplantation of cholinergic-rich spinal tissue from spontaneously aborted human fetuses into a rodent model of Alzheimer's disease.

The results from this study provided the first piece of evidence that intrahippocampal transplants of cholinergic-rich spinal grafts derived from a human fetus can ameliorate the performance of fornix lesioned rats in both spatial reference memory and spatial navigation tasks. Although many questions remain to be answered, these results point to the therapeutic potential of human fetus-derived cholinergic-rich grafts in treating spatial memory impairments.

Abortion, Spontaneous↗
PubMed1994

Expression of the CYP3A and CYP2C11 enzymes in a nutritionally obese rodent model: response to phenobarbital treatment.

In this study, the overfed rat was employed as a model for examining the influence of obesity on the regulation of hepatic cytochromes P450 3A and 2C11 (CYP3A and CYP2C11, respectively). These proteins represent the predominant constitutive hepatic P450 enzymes of male rats. Sprague-Dawley rats were chronically fed a standard pelleted diet or an energy-dense diet which typically results in significant increases in body weight, serum triglyceride levels and liver lipid content. Obesity did not influence baseline levels of spectral cytochrome P450 content. Similar baseline activities of CYP3A (testosterone 6 beta-hydroxylation), comparative CYP3A protein levels (Western blot) and steady-state CYP3A mRNA (slot blot), were found in rats fed either diet. Likewise, obesity did not appear to influence CYP2C11 at the enzyme activity (testosterone 2 alpha-hydroxylation) or mRNA levels. Half of the animals in each group received 20 mg phenobarbital (intraperitoneal injection) per animal every 12 hours for three consecutive days. This resulted in similar phenobarbital plasma concentrations in both groups. Phenobarbital treatment increased the concentrations of total cytochrome P450 in both lean and obese rats to the same extent. CYP3A activity, protein and mRNA levels were induced to a similar magnitude in rats fed either diet. Furthermore, obesity did not influence CYP2C11 activity or mRNA levels following administration of phenobarbital. A lack of an effect of obesity and the altered lipid environment on the regulation of CYP3A and CYP2C11 is in contrast to other enzymes studied previously. It is apparent that the consequences of obesity on hepatic cytochrome P450 may be enzyme-specific.

Animals↗
PubMed1996

Molecular indices of neuronal and glial plasticity in the hippocampal formation in a rodent model of age-induced spatial learning impairment.

Spatial learning ability was quantitated in young and aged Long-Evans rats, and molecular markers were assessed in the striatum and hippocampal formation using immunocytochemical, immunoblotting, and in situ hybridization histochemical procedures. The mRNA for beta-amyloid precursor protein (beta APP), most likely the transcript encoding the 695-amino acid form of this protein, was elevated in pyramidal and granule cells in the hippocampus of aged rats exhibiting poorer spatial learning. In immunoblots of hippocampal protein extracts, however, the level of beta APP-like immunoreactivity was depressed in the more impaired subjects. Similarly, the level in hippocampus of the mRNA for manganese-dependent superoxide dismutase (Mn-SOD), a marker of oxidative stress, was positively correlated with the degree of behavioral impairment, but immunoblotting revealed that Mn-SOD protein was depressed in the aged hippocampus compared with young. The mRNAs for the neuronal form of nitric oxide synthase and for the astrocyte marker glial fibrillary acidic protein (GFAP) were elevated in the hippocampus in correlation with the extent of learning impairment. In the striatum, the levels of mRNA and protein for several candidate genes, including GFAP, were elevated in parallel with the learning index, but these were age effects. Several hippocampal proteins were unchanged (GFAP) or depressed (beta APP and Mn-SOD) in level, despite elevations in corresponding mRNAs. In the aged cohort, hippocampal GFAP mRNA, Mn-SOD mRNA, and beta APP emerged as predictors of behavioral impairment, suggesting the involvement of these hippocampal systems in age-related cognitive impairment.

Aging↗
PubMed1996

Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington's disease.

Delivery of neurotrophic molecules to the CNS has gained considerable attention as a potential treatment strategy for neurological disorders. In the present study, a DHFR-based expression vector containing the human ciliary neurotrophic factor (hCNTF) was transfected into a baby hamster kidney fibroblast cell line (BHK). Using a polymeric device, encapsulated BHK-control cells and those secreting hCNTF (BHK-hCNTF) were transplanted unilaterally into the rat lateral ventricle. Twelve days later, the same animals received unilateral injections of quinolinic acid (QA; 225 nmol) into the ipsilateral striatum. After surgery, animals were behaviorally tested for apomorphine-induced rotation behavior and for skilled forelimb function using the staircase test. Rats receiving BHK-hCNTF cells rotated significantly less than animals receiving BHK-control cells. No behavioral effects of hCNTF were observed on the staircase test. Nissl-stained sections demonstrated that BHK-hCNTF cells significantly reduced the extent of striatal damage produced by QA. Quantitative analysis of striatal neurons further demonstrated that both choline acetyltransferase- and GAD-immunoreactive neurons were protected by BHK-hCNTF implants. In contrast, a similar loss of NADPH-diaphorase-positive cells was observed in the striatum of both implant groups. Analysis of retrieved capsules revealed numerous viable and mitotically active BHK cells that continued to secrete hCNTF. These results support the concepts that implants of polymer-encapsulated hCNTF-releasing cells can be used to protect striatal neurons from excitotoxic damage and that this strategy may ultimately prove relevant for the treatment of Huntington's disease.

Animals↗
PubMed1996

Biological disposition and imaging of a radioiodinated alkylphosphocholine in two rodent models of breast cancer.

UNLABELLED: Iodine-125-12-[m-iodophenyl]-dodecylphosphocholine (NM-324) has been shown to accumulate in a variety of animal tumor models. Moreover, preliminary pharmacokinetic studies with NM-324 are being conducted in cancer patients. The present study was undertaken to examine the potential application of NM-324 as a breast tumor-imaging agent. METHODS: Two animal models of breast cancer were utilized: namely, syngenic inbred Lewis female rats bearing the rat mammary tumor (RMT) and athymic mice with HT-39 human tumor xenografts. After i.v. administration of NM-324, the tissue distribution of radioactivity was determined at various time points. Gamma camera scintigrams were also acquired to confirm the biodistribution results. Macro- and microautoradiography were used to analyze cellular distribution of radioactivity in tumors. RESULTS: In the rat mammary tumor model, levels of radioactivity in the tumor reached a maximum at 24 hr after i.v. administration (1.65% ID/g, tumor-to-blood 6.4). These tumors could be visualized by gamma camera scintigraphy as early as 1 hour after administration. In the nude mouse model, levels of radioactivity in tumor reached a maximum at 48 hr after i.v. administration (4.96 %ID/g, tumor-to-blood 5.5). Tissues expected to interfere with the resolution of breast lesions such as fat, heart, lung and muscle displayed much lower concentrations of the radioactivity. Gamma camera scintigraphy confirmed the results observed from biodistribution experiments. Lipid extraction of the tumors and major organs in both animal models showed the sole presence of unchanged NM-324. Microautoradiographic analysis of slices of rat mammary and HT-39 tumors provided additional information regarding the intratumoral distribution of radioactivity. CONCLUSION: The ability of radioiodinated phospholipid analogs to accumulate in breast tumors reinforces the need for further investigation of this type of radiopharmaceutical as tumor imaging agents.

Animals↗
PubMed1997

A rodent model of in utero chimeric tolerance induction.

BACKGROUND: In utero tolerance induction has potential application in pediatric heart transplantation. Immunotolerance appears to be more easily induced in the fetus before full immunocompetence is established; however, the mechanisms behind this phenomenon are still undefined. METHODS: One hundred thirty Lewis (RT1l) rat fetuses from 10 litters were inoculated intraperitoneally at 18 days gestation with 1 x 10(7) ACI (RT1a) rat fetal liver cells. Fifty of the 100 viable neonates successfully brought to term were grafted with neonatal ACI skin within 24 hours of birth and heterotopic ACI hearts at 8 to 10 weeks of age (group 1A); the remaining 50 neonates only received heterotopic ACI heart grafts at 8 to 10 weeks (group 1B). Control groups consisted of 50 Lewis fetuses (five litters) inoculated in utero with phosphate-buffered saline solution (group 2) and 50 Lewis fetuses (five litters) that received no inoculum (group 3); all of these surviving progeny received both neonatal ACI skin and adult ACI cardiac allografts. Skin and cardiac grafts were monitored by daily visual inspection and palpation, respectively. Limiting dilution analysis was performed among all groups to assess precursor cytotoxic lymphocyte frequencies. Likewise, peripheral blood lymphocyte and splenocyte populations were analyzed with flow cytometry to detect allogeneic chimerism. RESULTS: Abortion rates among groups 1, 2, and 3 were 23% (30/130 abortions), 10% (5/50 abortions), and 6% (3/50 abortions), respectively. Tolerance to both ACI skin and cardiac allografts was induced in 14 of the 50 group 1A Lewis recipients (28%). Tolerance was not achieved in any of the recipients in groups 1B, 2, or 3. Limiting dilution analysis among all groups revealed a marked reduction of precursor cytotoxic T-lymphocytes in tolerant allograft recipients compared with recipients in the other groups. Flow cytometry detected significant splenocyte chimerism among tolerant rats; significant peripheral blood chimerism was not noted. CONCLUSIONS: We describe allogeneic tolerance induction in utero to both rat skin and heart tissue by use of donor-strain fetal liver cells. Compared with previous studies with adult splenocytes as the tolerogen, we achieved a higher frequency of tolerance with a markedly lower cell inoculum and lower abortion rate. Allogeneic chimerism was noted in the tolerant recipients, suggesting hematopoietic stem cell engraftment. Cytotoxic T-lymphocyte precursor frequencies were markedly depressed in tolerant animals. Interestingly, both donor-strain fetal liver cells and neonatal skin grafts were required to induce tolerance. These data suggest a period of hematopoietic "education" during and shortly after hematopoietic stem cell engraftment.

Animals↗
PubMed1996

Characteristics of the ventricular transient outward potassium current in genetic rodent models of diabetes.

The whole-cell configuration of the patch-clamp technique was employed to measure the transient outward potassium current in enzymatically isolated ventricular cells of spontaneously diabetic rats (BB/Wor) and mice (ob/ob). Healthy littermates (non-diabetic BB rats and lean mice) were used as controls. There was no significant difference between the non-diabetic and diabetic BB rats (Type I diabetes, IDDM) in the amplitude of either the current measured in the absence or the one found in the presence of 4-aminopyridine. The voltage dependence of the activation and steady-state inactivation was also similar in both populations, as no significant difference was observed in the rate of recovery from inactivation of Ito. The amplitudes of the total and 4-aminopyridine sensitive currents of lean and obese mice (Type II diabetes, NIDDM) were also similar. The voltage dependences of the activation and of the steady-state inactivation did not differ significantly, either. Our results might indicate certain limitations of the applicability of experiments carried out on genetically diabetic rats if the results are compared to those derived from the healthy littermates as controls.

Animals↗