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PubMed2007

Animal models of mood disorders: Recent developments.

PURPOSE OF REVIEW: The wide spectrum of disruptions that characterizes depression and bipolar illness highlights the difficulties researchers are posed with as they try to mimic these disorders in the laboratory. Nonetheless, numerous attempts have been made to create rodent models of mood disorders, or at least models of the symptoms of depression and bipolar illness. Despite many advances, however, there are no satisfactory animal models available. The need for improved animal models for identifying new antidepressants and providing insights into the neuropathology underlying the disease is critical. This review focuses on the attempts to improve current paradigms and also illustrates examples where current paradigms are used to uncover novel molecular targets of antidepressants. RECENT FINDINGS: Currently, there is a shift away from traditional animal models to a more focused research dealing with an endophenotype-style approach, genetic models and incorporation of new findings from human neuroimaging and genetic studies. SUMMARY: Endophenotype-based modelling of depression and bipolar illness is opening up more tractable avenues for understanding the neurobiological and genetic bases of these disorders. Further, advances in the clinical dissection of the psychiatric illnesses using molecular genetics, coupled with functional neuroimaging techniques, promises to yield better translational animal models and hence more fruitful therapeutic targets.

Animals↗
PubMed1989

Use of primary cultures of human hepatocytes in toxicology studies.

Often results from toxicological studies using rodent models cannot be directly extrapolated to probable effects in human beings. In order to examine the genotoxic potential of chemicals in human liver cells, a human hepatocyte DNA repair assay has been defined. Procedures were optimized to prepare primary cultures of human hepatocytes from discarded surgical material. On eight different occasions human hepatocyte cultures of sufficient viability to measure DNA repair were successfully prepared by collagenase perfusion techniques. The cells were allowed to attach to plastic or collagen substrata for periods of 1.5 to 24 h and subsequently incubated with [3H]thymidine and test chemicals for periods of 18 to 24 h. Chemically induced DNA repair, measured as unscheduled DNA synthesis, was quantitated autoradiographically. The following compounds were tested: 2-acetylaminofluorene, aflatoxin B1, 2-aminobenzyl alcohol, aniline, benzo(a)pyrene, carbon tetrachloride, chloroform, 2,4-diaminotoluene, 2,6-diaminotoluene, di(2-ethylhexyl)phthalate, dimethylnitrosamine, 1,6-dinitropyrene, 2,4-dinitrotoluene, 2,6-dinitrotoluene, methyl chloride, 5-methylchrysene, mono(2-ethylhexyl)phthalate, 2-methyl-2-P-(1,2,3,4-tetrahydro-1-naphthyl)phenoxypropionic acid (nafenopin), beta-naphthylamine, nitrobenzene, 2-nitrobenzyl alcohol, 2-nitrotoluene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, unleaded gasoline, and 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy-14,643). In only one of eight cases did some of the chemicals generally regarded as genotoxic fail to give a positive response. For purposes of comparison, all test chemicals were evaluated in the in vitro rat hepatocyte DNA repair assay. Individual-to-individual variation in the DNA repair response was far greater for the human cultures than for cultures derived from rats. For only three chemicals was there a qualitative difference in the response between the rodent and the human cells; beta-naphthylamine was positive in the rat but in none of the human cultures examined, whereas the opposite was seen for 2,6-diaminotoluene and 5-methylchrysene. Clofibric acid, mono(2-ethylhexyl)phthalate, and Wy-14,643 induced enzymes indicative of peroxisomal proliferation in primary rat hepatocyte cultures, but not in two human hepatocyte cultures. These results indicate that, in general, the in vitro rat hepatocyte DNA repair assay is a valid model for predicting potential genotoxic effects in human beings. However, rodent hepatocytes may not be appropriate for assessing the potential of chemicals to elicit nongenotoxic effects in human beings such as the induction of hepatocyte peroxisomal proliferation.

2-Acetylaminofluorene↗
PubMed1988

Diabetic embryopathy and fuel-mediated organ teratogenesis: lessons from animal models.

The growing recognition that faulty maternal metabolism during early organogenesis may be implicated in the increased incidence of birth defects in pregnancies complicated by diabetes has prompted worldwide efforts to institute improved preconceptional metabolic regulation. However, the failure to identify the periods of greatest risk for diabetic embryopathy, the mediating teratogen(s), and the underlying mechanisms have complicated attempts to establish precise therapeutic guidelines and targets. Some of the reported in vivo and in vitro experiences with rodent models have been reviewed to derive relevant insights. Substantial literature indicates that diabetes (experimental as well as spontaneous) in pregnant rats and mice is attended by retardation of growth and developmental delay during embryogenesis, and a variable incidence of birth defects. Poor metabolic regulation of the diabetic mother during early organogenesis may also be followed by subsequent resorption of the conceptus at the site of implantation. Vulnerability to diabetes-related resorptions and all other forms of embryopathy appears to begin during the early postimplantation period and is greatest near the onset of neurolation. Overall susceptibility is markedly influenced by genetic factors and may be modified by the antecedent metabolic exposures of the conceptus ("carry-over effects"). Mediation for the anomalous embryo development in pregnancies of diabetic rodents appears to be multifactorial; all the aberrant fuels and fuel-related components of "the diabetic state" (e.g. high glucose; ketones; somatomedin inhibitor(s); osmolality, etc.) which have been tested to date display dysmorphogenic potential ("fuel-mediated organ terato-genesis") in vitro. All tissues in the conceptus appear to be at risk. Dose-response relationships for the individual metabolic teratogens may be influenced by additive and synergistic interactions so that the integrated possibilities cannot be assessed fully by measurements confined to a single fuel or fuel-related component. In the context of the day-to-day variability in diabetes "control" of the poorly regulated mother, and the relatively longer duration of organogenesis, these multifactorial possibilities may account for the multiple birth defects that can occur in individual offspring, and the seemingly non-specific pattern of diabetic embryopathy. Insulin therapy diminishes the dysmorphogenic effects of "the diabetic state" in rodents with experimental or spontaneous diabetes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2002

Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration.

The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring (14)C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and V(d(ss)) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [(14)C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.

Animals↗
PubMed1997

Weight regulation, leptin and growth hormone.

Leptin, the product of the adipose tissue-specific ob gene, is a newly recognized hormone involved in the regulation of metabolism and body composition. Leptin appears to provide information to the central nervous system on the amount of energy stored in the adipose tissue. Serum leptin levels are highly correlated with body fat mass in adults, children and newborns. Obese individuals have significantly higher circulating leptin than normal, lean subjects. In addition, females have higher serum leptin than males with equivalent fat mass. Although leptin correlates with fat mass, circulating concentrations are altered by extremes in energy intake, such as fasting and overfeeding. Defects in leptin or its receptor in the hypothalamus lead to the development of obesity in several rodent models; however, no such deleterious defects have been identified in humans to date. Taken together, these observations suggest that humans may be resistant to their endogenous leptin levels. Despite this, studies in rodents demonstrating that leptin administration can cause weight loss in both ob/ob mice, and in normal weight controls suggest that leptin may be useful in the treatment of human obesity. This review will summarize the current understanding of leptin and its role in the regulation of body composition. In addition, the interaction of leptin with other metabolic hormones including growth hormone will be discussed.

Adult↗
PubMed2004

Dose-dependent neurochemical and functional protection afforded by encapsulated CNTF-producing cells.

Intracerebral delivery of hCNTF has shown considerable neuroprotective potential in animal models of Huntington's disease (HD). The present study describes the relationship between a range of hCNTF doses and the resulting behavioral and neurochemical (striatal ChAT and GAD activity) protection in a rodent model of HD. Encapsulated BHK delivering a range of hCNTF doses were implanted into the lateral ventricle ipsilateral to an intrastriatal quinolinic acid (QA) injection. Results demonstrated a dose-dependent effect of hCNTF with complete, partial, and no observable neuroprotection occurring with preimplant doses of hCNTF of 30.8, 8.6, and 0.8-2.1 ng hCNTF/24 h, respectively. These data continue to support the use of cellular delivery of hCNTF for HD and will facilitate the optimization of this approach in the clinical situation.

Animals↗
PubMed2001

Spontaneous remission of paroxysmal dystonia coincides with normalization of entopeduncular activity in dt(SZ) mutants.

Recent studies have shown a dramatically decreased spontaneous discharge rate of entopeduncular neurons in a unique animal model of idiopathic paroxysmal dystonia, the dt(sz) mutant hamster. These changes were found in animals at the age at which the most marked expression of dystonia is usually observed. In this rodent model, the age-dependent disappearance of stress-inducible dystonic attacks at an age of approximately 10 weeks allows investigations of the relevance of pathophysiological changes for the occurrence of dystonia by ontogenetic studies. Therefore, we examined the entopeduncular activity by extracellular single unit recordings in groups of dt(sz) mutants and nondystonic control hamsters at 17-22 weeks of age. In contrast to recent findings, after the complete remission of dystonia, the mean discharge rate of entopeduncular neurons in dt(sz) mutants (28.1 +/- 1.2 spikes/sec) was similar to that of age-matched nondystonic control hamsters (30.8 +/- 0.9 spikes/sec). Thus, the disappearance of paroxysmal dystonia is accompanied by a normalization of the entopeduncular activity in dt(sz) mutants. The present data clearly demonstrate the fundamental importance of a decreased basal ganglia output for the expression of paroxysmal dystonia.

Action Potentials↗
PubMed2004

Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes.

BACKGROUND: Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change. RESULTS: Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. CONCLUSIONS: Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified.

Animals↗
PubMed2003

Selection and reversal of Plasmodium berghei resistance in the mouse model following repeated high doses of artemether.

Artemether, a derivative of artemisinin, is effectively used for the treatment of malaria without any clinically relevant resistance to date. Artemether has also been developed as an antischistosomal agent, exhibiting highest activity against immature parasites. Here, we employ a rodent model and investigate whether the proposed artemether treatment schedule to prevent schistosome-attributable morbidity might select for Plasmodium berghei resistance. Mice infected with an ANKA strain of P. berghei were treated with artemether at either 47 mg/kg or 300 mg/kg. Once every 7-10 days, parasitized erythrocytes were passed to the next group of mice, receiving the same doses of artemether, for 50 passages. Resistance development was slow but increased considerably over the final ten passages. At the higher dose of artemether, the indices of resistance were 4.8 and 8.8 after 40 and 50 passages, respectively. Importantly, resistance was unstable, since sensitivity reverted to near-normal after five passages without drug pressure. A moderate index of P. berghei resistance and no apparent reversibility was found in comparative experiments employing pyronaridine. In conclusion, the pace of resistance development in P. berghei to repeated high doses of artemether is slow and reversible.

Animals↗
PubMed2005

Osteoclast diseases and dental abnormalities.

Tooth eruption depends on the presence of osteoclasts to create an eruption pathway through the alveolar bone. In diseases where osteoclast formation, or function is reduced, such as the various types of osteopetrosis, tooth eruption is affected. Diseases in which osteoclast formation or activity is increased, such as familiar expansile osteolysis and Paget's disease, are associated with dental abnormalities such as root resorption and premature tooth loss. Less is known about the origin of the dental problems in these conditions as there are no rodent models of these diseases as yet. In this short review, the genes currently known to be mutated in human osteoclast diseases will be reviewed and, where known, the effect of osteoclast dysfunction on dental development described. It will focus on human conditions and only mention rodent disease where no clear data in the human are available.

Alveolar Process↗
PubMed2005

Inducible immune regulation following autoimmune disease in the immune-privileged eye.

The immune-privileged eye has the potential to induce regulatory immunity along with local mechanisms of immunosuppression. Rodent models of human autoimmune uveoretinitis [experimental autoimmune uveoretinitis (EAU)] recover without spontaneous recurrence of uveitis, which differs from uveitis in some humans. This raises the possibility that the mechanism of immune privilege in the rodent eye can reimpose itself during autoimmune uveoretinitis and re-establish tolerance to autoantigen. To investigate this possibility, we examined the spleens of EAU-recovered mice for regulatory immunity. We detected regulatory immunity when we adoptively transferred post-EAU spleen cells into other mice immunized for EAU. We could not detect this regulatory immunity in enucleated mice nor in naive mice. Moreover, unlike the mechanisms of anterior chamber-associated immune deviation, the suppression was only mediated by post-EAU CD4+ T cells, which required activation with autoantigen presented by post-EAU spleen antigen-presenting cells (APC). Our results demonstrate that when the immune-privileged ocular microenvironment recovers from an autoimmune response, it has influenced systemic immunity to retinal autoantigen by affecting APC and mediating induction of potential regulatory CD4+ T cells laying in wait in the post-EAU spleen for restimulation.

Animals↗
PubMed2002

Canine prostate induces new bone formation in mouse calvaria: A model of osteoinduction by prostate tissue.

BACKGROUND: Osteoblastic metastases are common in patients with advanced prostate cancer. The pathophysiology of the new bone formation at metastatic sites is not currently known, but it is hypothesized that growth factors secreted by the prostate may be involved. Unfortunately, most rodent models of prostate cancer with metastasis to bone are osteolytic and not osteoblastic. Significant osteolysis by tumor cells at metastatic sites may also lead to fractures or bone instability. Misinterpretation of new periosteal bone due to bone instability as tumor-cell osteoinduction is another disadvantage of the osteolytic models. To circumvent these problems, we have developed a model system of new bone formation in the calvaria of nude mice stimulated by normal canine prostate tissue. METHODS: Collagenase-digested normal prostate tissue was implanted adjacent to the calvaria of nude mice. Calvaria were examined at 2 weeks post-implantation for changes in the bone microenvironment by histology, calcein uptake at sites of bone mineralization, and tartrate-resistant acid phosphatase staining for osteoclasts. RESULTS: The prostate tissue remained viable and induced abundant new woven bone formation on the adjacent periosteal surface. In some cases new bone formation also was induced on the distant or concave calvarial periosteum. The new bone stained intensely with calcein, which demonstrated mineralization of the bone matrix. The new bone formation on prostate-implanted calvaria significantly increased (1.7-fold) the thickness of the calvaria compared with control calvaria. New bone formation was not induced in calvaria of mice implanted with normal canine kidney, urinary bladder, spleen, or skeletal muscle tissue, or mice with surgically-induced disruption of the periosteum. Osteoclast numbers in the medullary spaces and periosteum of calvaria were mildly increased (61%) in mice with implanted prostate tissue. CONCLUSIONS: This animal model will be useful for investigating the roles of prostate-derived growth factors on new bone formation in vivo.

Animals↗
PubMed2002

5-HT(1B) mrna regulation in two animal models of altered stress reactivity.

BACKGROUND: Acute stress has profound effects on serotonergic activity, but it is not known whether alterations in the serotonin system can predispose individuals to exaggerated stress responses. We examined the regulation of 5-HT(1B) and 5-HT(1A) mRNA in two rodent models of differential sensitivity to stress: congenital learned helplessness (cLH) and handling and maternal separation (HMS). METHODS: 5-HT(1B) and 5-HT(1A) mRNAs in brain tissue sections were quantitated by in situ hybridization from control, stress-sensitive, and stress-resistant male rats in the HMS model and stress-sensitive and stress-resistant rats (both males and females) in the cLH model. Dorsal raphe nucleus, striatum, and hippocampus were examined. RESULTS: The main result was that dorsal raphe 5-HT(1B) mRNA was substantially elevated (63-73%) in male rats in the stress-resistant group of both models compared with stress-sensitive animals. 5-HT(1B) mRNA in female rats did not differ between groups in the cLH model. There were no differences in 5-HT(1A) mRNA between HMS groups. CONCLUSIONS: These findings suggest that 5-HT(1B) autoreceptor regulation is altered in animals with diminished stress reactivity. These results suggest that 5-HT(1B) autoreceptors in unstressed and acutely stressed animals differ, indicating the importance of state versus trait changes in serotonin function in animal models of anxiety and depression.

Analysis of Variance↗
PubMed2002

Vitamin D receptor-dependent antitumour effects of 1,25-dihydroxyvitamin D3 and two synthetic analogues in three in vivo models of prostate cancer.

OBJECTIVE: To determine the in vitro and in vivo effects of 1,25-dihydroxyvitamin D3 (calcitriol) and two newer less hypercalcaemic analogues, EB1089 and CB1093 (as the use of calcitriol as a therapeutic agent in humans has been limited by hypercalcaemia) in three rodent models of prostate cancer. MATERIALS AND METHODS: The highly metastatic MAT LyLu Dunning prostate model, PAIII tumours in Lobund-Wistar rats and LNCaP xenografts in nude mice were used. Vitamin D receptor (VDR) expression and binding were assessed in all cell lines. The effects of calcitriol, EB1089 and CB1093 on tumour growth, cell cycle and angiogenesis in vitro, and growth and serum calcium levels in vivo, were assessed. RESULTS: The growth of prostate adenocarcinoma was inhibited by calcitriol, EB1089 and CB1093 in the Dunning prostate model. Although both analogues increased serum calcium levels, the levels were significantly less than in rats treated with calcitriol. Tumour growth was also inhibited in male athymic nu/nu mice with LNCaP tumour xenografts. PAIII cells failed to express functional VDR and were insensitive to calcitriol and its analogues, either in vitro or in vivo. The analogues of calcitriol did not inhibit angiogenesis in a rat aorta assay. CONCLUSION: This is the first report comparing the actions of calcitriol and its analogues in different in vivo models. The results suggest that the newer less hypercalcaemic analogues of calcitriol may offer a novel therapeutic option for treating prostate cancer. VDR-dependent growth inhibition and not the inhibition of angiogenesis is the main mechanism of action of these compounds in vivo.

Adenocarcinoma↗
PubMed2003

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents.

1. Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer-enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. 3. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P < 0.05) more potent (ED(50) values 11 mg kg(-1), 46 mg kg(-1) and 57 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED(50) values 20 mg kg(-1), 73 mg kg(-1) and 81 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED(50) values 16 mg kg(-1), 20 mg kg(-1) and 19 mg kg(-1) respectively). 4. In the hippocampal kindled rat a dose of 40 mg kg(-1) of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg(-1). Racemic PID also significantly increased the seizure threshold in this model. 5. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. 6. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer-enantiomer interaction. 7. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer-enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.

Allylisopropylacetamide↗
PubMed1998

Genistein, a component of soy, inhibits the expression of the EGF and ErbB2/Neu receptors in the rat dorsolateral prostate.

BACKGROUND: Epidemiological reports suggest that Asians consuming a diet high in soy have a low incidence of prostate cancer. In animal models, soy and genistein have been demonstrated to suppress the development of prostate cancer. In this study, we investigate the mechanism of action, bioavailability, and potential for toxicity of dietary genistein in a rodent model. METHODS: Lobund-Wistar rats were fed a 0.025-1.0-mg genistein/g AIN-76A diet. The dorsolateral prostate was subjected to Western blot analysis for expression of tyrosine-phosphorylated proteins, and of the EGF and ErbB2/Neu receptors. Genistein concentrations were measured from serum and prostate using HPLC-mass spectrometry. Body and prostate weights, and circulating testosterone levels, were measured. RESULTS: Increasing concentrations of genistein in the diet inhibited tyrosine-phosphorylated proteins with molecular weights of 170,000 and 85,000 in the dorsolateral prostate. Western blot analysis revealed that the 1-mg genistein/g AIN-76A diet inhibited by 50% the expression of the EGF receptor and its phosphorylation. In rats fed this diet, serum-free and total genistein concentrations were 137 and 2,712 pmol/ml, respectively. The free and total genistein IC50 values for the EGF receptor were 150 and 600 pmol/g prostate tissue, respectively. Genistein in the diet also inhibited the ErbB2/Neu receptor. Body and dorsolateral prostate weights, and circulating testosterone concentrations, were not adversely effected from exposure to genistein in the diet for 3 weeks. CONCLUSIONS: We conclude that genistein in the diet can downregulate the EGF and ErbB2/Neu receptors in the rat prostate with no apparent adverse toxicity to the host. The concentration needed to achieve a 50% reduction in EGF receptor expression can be achieved by eating a diet high in soy products or with genistein supplementation. Genistein inhibition of the EGF signaling pathway suggests that this phytoestrogen may be useful in both protecting against and treating prostate cancer.

Animals↗
PubMed2003

Animal models in the investigation of anorexia.

Anorexia nervosa (AN) is an eating disorder of unknown origin that most commonly occurs in women and usually has its onset in adolescence. Patients with AN invariably have a disturbed body image and an intense fear of weight gain. There is currently no definitive treatment for this disease, which carries a 20% mortality over 20 years. Development of an appropriate animal model of AN has been difficult, as the etiology of this eating disorder likely involves a complex interaction between genetic, environmental, social, and cultural factors. In this review, we focus on several possible rodent models of AN. In our laboratory, we have developed and studied three different mouse models of AN based on clinical profiles of the disease; separation stress, activity, and diet restriction (DR). In addition, we discuss the spontaneous mouse mutation anx/anx and several mouse gene knockout models, which have resulted in an anorexic phenotype. We highlight what has been learned from each of these models and possibilities for future models. It is hoped that a combination of the study of such models, together with genetic and clinical studies in patients, will lead to more rational and successful prevention/treatment of this tragic, and often fatal, disease.

Adolescent↗
PubMed1998

Effects of omapatrilat in low, normal, and high renin experimental hypertension.

Combined inhibition of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) produces cardiovascular effects greater than those elicited by selective inhibition of either enzyme alone. Dual metalloprotease inhibitors are single molecules that inhibit both NEP and ACE and produce cardiovascular effects in animal models similar to those elicited by the combination of NEP and ACE inhibitors. The purpose of this study was to determined the duration of antihypertensive activity of the dual metalloprotease inhibitor omapatrilat in rodent models of hypertension. Omapatrilat inhibited NEP (Ki = 9 nmol/L) and ACE (Ki = 6 nmol/L) activities in vitro and inhibited the pressor response to angiotensin I in rats after intravenous administration with a potency and duration of action similar to those of the long acting ACE inhibitor fosinoprilat. After single dose administration, omapatrilat lowered mean arterial blood pressure (aortic catheter) in sodium depleted spontaneously hypertensive rats (high renin model) from 148+/-5 to 106+/-3 mm Hg (baseline to 24 h), in deoxycorticosterone acetate-salt hypertensive rats (low renin) from 167+/-4 to 141+/-5 mm Hg and in spontaneously hypertensive rats (normal renin) from 162+/-4 to 138+/-3 mm Hg (P < .05 at 24 h v vehicle in all models). After oral administration, omapatrilat (100 micromol/kg/day) persistently lowered systolic blood pressure (tail cuff) in spontaneously hypertensive rats during 11 days of treatment; at 24 h after dosing on day 12, mean arterial pressure (aortic catheter) was lower (P < .05) in the group receiving omapatrilat (133+/-5 mm Hg) than in the group receiving vehicle (149+/-2 mm Hg). The results indicate that omapatrilat is a potent dual metalloprotease inhibitor of NEP and ACE with long lasting, oral antihypertensive effects in low, normal, and high renin models of hypertension. Omapatrilat has the potential to be an effective, broad spectrum antihypertensive agent.

Angiotensin I↗