ABSTRACT
Activin is a member of the transforming growth factor-beta family that is involved in cell differentiation, hormone secretion, and regulation of neuron survival. The cellular responses to activin are mediated by phosphorylation of a downstream target, Smad2. The current study examines the influence of chronic electroconvulsive seizures (ECSs), as well as chemical antidepressants, on the expression of activin betaA and the phosphorylation of Smad2 in the rat hippocampus and frontal cortex. Chronic ECSs (10 d) resulted in a significant increase in activin betaA mRNA expression and Smad2 phosphorylation in both the hippocampus and frontal cortex. Chronic fluoxetine did not influence activin betaA expression, but fluoxetine as well as desipramine did increase Smad2 phosphorylation in the frontal cortex. The functional significance of increased activin was further tested by examining the effects of activin infusions into the hippocampus on a behavioral model of depression, the forced swim test (FST). A single bilateral infusion of activin A or activin B into the dentate gyrus of the hippocampus produced an antidepressant-like effect in the FST that was comparable in magnitude with fluoxetine. In contrast, infusion of the activin antagonist inhibin A did not influence behavior but blocked the effect of activin A. The results suggest that regulation of activin and Smad signaling may contribute to the actions of antidepressant treatment and may represent novel targets for antidepressant drug development.
Subject(s)
Activins/metabolism , Antidepressive Agents/pharmacology , Brain , Electroshock/methods , Inhibin-beta Subunits/metabolism , Smad2 Protein/metabolism , Activins/administration & dosage , Activins/genetics , Analysis of Variance , Animals , Behavior, Animal , Blotting, Western/methods , Brain/drug effects , Brain/metabolism , Brain/radiation effects , Depression/therapy , Desipramine/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Fluoxetine/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/radiation effects , Immunohistochemistry/methods , In Situ Hybridization/methods , Inhibin-beta Subunits/administration & dosage , Inhibin-beta Subunits/genetics , Inhibins/administration & dosage , Male , Motor Activity/drug effects , Motor Activity/radiation effects , Phosphorylation/drug effects , Phosphorylation/radiation effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
BACKGROUND: Activin A, the homodimer of the activin/inhibin betaA subunit, has been shown to participate in cutaneous wound healing. In this study we intended to determine its part in gastric ulceration. METHODS: Activin A expression was studied by immunohistochemistry and in situ hybridization in acetic-acid-induced chronic gastric ulcers in rat. The dynamics of this process were also assessed by quantitative real time RT-PCR and RNase protection assays (RPA). The effects of different doses of this cytokine on epithelial and mesenchymal cell proliferation were quantitated in vitro. RESULTS: Low amounts of activin A and its mRNA were expressed by epithelia, endothelia and fibroblasts in intact gastric tissue. Granulation tissue of gastric ulcers and gastric glands adjacent to the ulcer rim expressed markedly increased amounts of activin protein as well as activin/inhibin betaA mRNA. RPA and RT-PCR studies revealed a more than 3-fold increase in the relative abundance of this mRNA. Activin A did not affect the proliferation rate of fibroblasts and epithelial cells in vitro. CONCLUSIONS: Activin A participates in gastric ulcer healing in a similar fashion as in cutaneous wounding. Its expression on protein and mRNA level is markedly increased in ulcer base and rim.
Subject(s)
Activins/biosynthesis , Activins/genetics , Inhibin-beta Subunits/biosynthesis , Inhibin-beta Subunits/genetics , Stomach Ulcer/genetics , Stomach Ulcer/metabolism , Activins/administration & dosage , Animals , Biomarkers/analysis , Cell Count , Cell Division/drug effects , Cell Division/physiology , Disease Models, Animal , Dose-Response Relationship, Drug , Epithelial Cells/cytology , Epithelial Cells/metabolism , Extracellular Matrix/metabolism , Fibroblasts/cytology , Gastric Mucosa/cytology , Gastric Mucosa/metabolism , Gene Expression , Immunohistochemistry , In Situ Hybridization , Inhibin-beta Subunits/administration & dosage , Male , Mucous Membrane/cytology , Mucous Membrane/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar , Time FactorsABSTRACT
Activin A, a member of the TGF-b superfamily, is abundant in bone matrix, but little is known about its physiological role in bone metabolism. The present study was undertaken to determine whether topical activin A can increase the bone mass of isografted bone. The tibiae were bilaterally dissected from a donor C3H/HeJ mouse and transplanted subcutaneously in the dorsal region of a recipient mouse. One isografted tibia was topically infused for either 1, 2, 3, or 4 weeks with activin A, using an osmotic minipump at a dose of 0.02, 0.2, or 2 ng/hr. The other tibia was infused with 0.9% NaCl (control). The following results were obtained: (1) Topical activin A (2 ng/hr) stimulated periosteal bone formation after 2 or 3 weeks. The bone area in a standardized transverse section averaged 1.3 fold that in the control. (2) Numerous cuboidal or conical osteoblasts appeared on the surface of newly formed bone after the infusion of activin A for 2 or 3 weeks. Autoradiographic studies using 3H-proline revealed that the surface area of newly formed bone labelled with autoradiographic silver grains was greater in activin A-treated bone than in the control, suggesting an increased synthesis and secretion of collagen by osteoblasts. (3) Topical activin A increased the number of osteoclasts after 2 to 4 weeks. Furthermore, enhanced or increased bone resorption was observed in the projected anterior site of activin A-treated bone after 4 weeks. These results suggest that topical activin A increases the bone mass of isografted bone by increasing bone turnover.
