iturelix and Disease-Models--Animal

Though several studies have suggested that estradiol improves hippocampal-dependent spatial memory, the effects of other hormones in the hypothalamic-pituitary-gonadal axis on memory have largely been ignored. Estradiol and luteinizing hormone (LH) are generally inversely related and LH may significantly affect spatial memory. Ovariectomized (ovx) rats treated with Antide (a gonadotropin releasing hormone receptor antagonist) had low LH levels and showed enhanced spatial memory, comparable to treatment with estradiol. Antide-treated ovx females retained spatial memory longer than estradiol-treated ovx females. Deficits in spatial memory are a primary symptom of neurodegenerative disorders including Alzheimer's disease (AD). Treatment with Antide prevented spatial memory deficits in a neurotoxin-induced model typical of early AD. These data suggest that memory impairments seen in female rats after ovariectomy or women after menopause may be due to high LH levels and that a reduction in LH enhances memory. These results also implicate an LH lowering agent as a potential preventative therapy for AD.

Topics: Alzheimer Disease; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Female; Hormone Antagonists; Luteinizing Hormone; Memory; Memory Disorders; Oligopeptides; Ovariectomy; Rats; Rats, Sprague-Dawley; Spatial Behavior

Sex hormones regulate cholangiocyte hyperplasia in bile duct-ligated (BDL) rats. We studied whether follicle-stimulating hormone (FSH) regulates cholangiocyte proliferation. FSH receptor (FSHR) and FSH expression was evaluated in liver sections, purified cholangiocytes, and cholangiocyte cultures (NRICC). In vivo, normal female and male rats were treated with FSH or immediately after BDL with antide (a gonadotropin-releasing hormone antagonist blocking FSH secretion) or a neutralizing FSH antibody for 1 wk. We evaluated 1) cholangiocyte proliferation in sections and cholangiocytes and 2) changes in secretin-stimulated cAMP (functional index of cholangiocyte growth) levels, and ERK1/2 and Elk-1 phosphorylation. NRICC were stimulated with FSH before evaluation of proliferation, cAMP/IP(3) levels, and ERK1/2 and Elk-1 phosphorylation. To determine whether FSH regulates cholangiocyte proliferation by an autocrine mechanism, we evaluated the effects of 1) cholangiocyte supernatant (containing FSH) on NRICC proliferation and 2) FSH silencing in NRICC before measuring proliferation and ERK1/2 and Elk-1 phosphorylation. Cholangiocytes and NRICC express FSHR and FSH and secrete FSH. In vivo administration of FSH to normal rats increased, whereas administration of antide and anti-FSH antibody to BDL rats decreased 1) ductal mass and 2) secretin-stimulated cAMP levels, proliferation, and ERK1/2 and Elk-1 phosphorylation in cholangiocytes compared with controls. In NRICC, FSH increased cholangiocyte proliferation, cAMP levels, and ERK1/2 and Elk-1 phosphorylation. The supernatant of cholangiocytes increased NRICC proliferation, inhibited by preincubation with anti-FSH antibody. Silencing of FSH gene decreases cholangiocyte proliferation and ERK1/2 and Elk-1 phosphorylation. Modulation of cholangiocyte FSH expression may be important for the management of cholangiopathies.

Topics: Animals; Antibodies; Apoptosis; Autocrine Communication; Bile Ducts; Cell Proliferation; Cells, Cultured; Cholestasis; Culture Media, Conditioned; Cyclic AMP; Disease Models, Animal; ets-Domain Protein Elk-1; Female; Follicle Stimulating Hormone; Hepatocytes; Hormone Antagonists; Infusion Pumps, Implantable; Inositol 1,4,5-Trisphosphate; Ligation; Liver; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Oligopeptides; Phosphorylation; Rats; Rats, Inbred F344; Receptors, FSH; RNA Interference

The nonobese mouse model of autoimmune diabetes (NOD mouse) exhibits a strain-dependent preponderance of disease in females. Castration of male NOD mice leads to an increased incidence of diabetes, suggesting that testosterone directly modulates the expression of diabetes in the NOD mouse. However, castration also modulates hypothalamic and pituitary hormone production via removal of the negative feedback effects of testosterone. One hypothalamic hormone with immunomodulatory properties whose expression is increased by castration is GnRH. To test whether the increased incidence of diabetes in castrated male NOD mice is related to an increase in GnRH activity, we treated castrated male NOD mice with Antide, a GnRH receptor antagonist, to determine the effect on the incidence and timing of onset of diabetes. The prevalence of diabetes at 40 wk of age in male NOD mice was 50% in sham-operated mice, compared with an 83% prevalence in castrated males. Antide administration prevented the increased incidence of diabetes in the castrated male mice. Antide reduced total serum IgG levels, IL-6 cytokine expression in cultured splenocytes, and the lymphocytic infiltration of islets. GnRH administration exerted reciprocal effects, leading to earlier timing of onset of diabetes and increases in serum total IgG levels. We conclude that GnRH modulates the expression of diabetes in the NOD mouse independently of gonadal steroids.

Topics: Animals; Autoimmunity; Cells, Cultured; Diabetes Mellitus, Type 1; Disease Models, Animal; Feedback, Physiological; Gonadotropin-Releasing Hormone; Hormone Antagonists; Immunoglobulin G; Incidence; Interferon-gamma; Interleukin-6; Islets of Langerhans; Male; Mice; Mice, Inbred NOD; Oligopeptides; Orchiectomy; Spleen; Testosterone

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Endometriosis; Estradiol; Estrus; Female; Gonadotropin-Releasing Hormone; Oligopeptides; Rats; Rats, Inbred Strains