Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Mol Psychiatry ; 20(6): 744-54, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25330741

ABSTRACT

Major depressive disorder is often linked to stress. Although short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1 h per day for 7 days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-α1 (NF-α1; also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6 h per day for 21 days) CRS, mice show decreased hippocampal NF-α1 and FGF2 levels and depressive-like responses. In NF-α1-knockout mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior that is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reveal that NF-α1 treatment directly upregulates FGF2 expression through extracellular signal-regulated kinase-Sp1 signaling. Thus, during short-term CRS, hippocampal NF-α1 expression is upregulated and has a key role in preventing the onset of depressive-like behavior through enhanced FGF2-mediated neurogenesis. To evaluate the therapeutic potential of this pathway, we examined, rosiglitazone (Rosi), a PPARγ agonist, which has been shown to have antidepressant activity in rodents and humans. Rosi upregulates FGF2 expression in a NF-α1-dependent manner in hippocampal neurons. Mice fed Rosi show increased hippocampal NF-α1 levels and neurogenesis compared with controls, thereby indicating the antidepressant action of this drug. Development of drugs that activate the NF-α1/FGF2/neurogenesis pathway can offer a new approach to depression therapy.


Subject(s)
Carboxypeptidase H/metabolism , Depression/prevention & control , Hippocampus/cytology , Hypoglycemic Agents/therapeutic use , Neurogenesis/drug effects , Thiazolidinediones/therapeutic use , Animals , Carboxypeptidase H/genetics , Cells, Cultured , Depression/etiology , Depression/genetics , Disease Models, Animal , Doublecortin Domain Proteins , Food Preferences/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , Neuropeptides/metabolism , Rosiglitazone , Stress, Psychological/complications , Sucrose/administration & dosage , Sweetening Agents , Swimming/psychology , Up-Regulation/drug effects , Up-Regulation/genetics
2.
Endocrinology ; 154(9): 3284-93, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23825125

ABSTRACT

Prolonged chronic stress causing elevated plasma glucocorticoids leads to neurodegeneration. Adaptation to stress (allostasis) through neuroprotective mechanisms can delay this process. Studies on hippocampal neurons have identified carboxypeptidase E (CPE) as a novel neuroprotective protein that acts extracellularly, independent of its enzymatic activity, although the mechanism of action is unclear. Here, we aim to determine if CPE plays a neuroprotective role in allostasis in mouse hippocampus during chronic restraint stress (CRS), and the molecular mechanisms involved. Quantitative RT-PCR/in situ hybridization and Western blots were used to assay for mRNA and protein. After mild CRS (1 h/d for 7 d), CPE protein and mRNA were significantly elevated in the hippocampal CA3 region, compared to naïve littermates. In addition, luciferase reporter assays identified a functional glucocorticoid regulatory element within the cpe promoter that mediated the up-regulation of CPE expression in primary hippocampal neurons following dexamethasone treatment, suggesting that circulating plasma glucocorticoids could evoke a similar effect on CPE in the hippocampus in vivo. Overexpression of CPE in hippocampal neurons, or CRS in mice, resulted in elevated prosurvival BCL2 protein/mRNA and p-AKT levels in the hippocampus; however, CPE(-/-) mice showed a decrease. Thus, during mild CRS, CPE expression is up-regulated, possibly contributed by glucocorticoids, to mediate neuroprotection of the hippocampus by enhancing BCL2 expression through AKT signaling, and thereby maintaining allostasis.


Subject(s)
Allostasis , Carboxypeptidase H/biosynthesis , Hippocampus/metabolism , Neurons/metabolism , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Stress, Psychological/metabolism , Up-Regulation , Animals , CA3 Region, Hippocampal/metabolism , CA3 Region, Hippocampal/pathology , Carboxypeptidase H/genetics , Carboxypeptidase H/metabolism , Cells, Cultured , Embryo, Mammalian/cytology , Genes, Reporter/drug effects , Glucocorticoids/metabolism , Glucocorticoids/pharmacology , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/pathology , Male , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/cytology , Neurons/drug effects , Neurons/pathology , Promoter Regions, Genetic/drug effects , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/metabolism , Restraint, Physical , Severity of Illness Index , Stress, Physiological , Stress, Psychological/physiopathology , Up-Regulation/drug effects
3.
J Mol Endocrinol ; 48(2): 115-27, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22217803

ABSTRACT

We have previously demonstrated that measurement of tissue concentrations of the secretogranin II (SgII or SCG2 as listed in the HUGO database)-derived peptide EM66 may help to discriminate between benign and malignant pheochromocytomas and that EM66 represents a sensitive plasma marker of pheochromocytomas. Here, we investigated the gene expression and protein production of SgII in 13 normal adrenal glands, and 35 benign and 16 malignant pheochromocytomas with the goal to examine the molecular mechanisms leading to the marked variations in the expression of EM66 in tumoral chromaffin tissue. EM66 peptide levels were 16-fold higher in benign than in malignant pheochromocytomas and had an area under the receiver-operating characteristic curve of 0.95 for the distinction of benign and malignant tumors. Q-PCR experiments indicated that the SgII gene was significantly underexpressed in malignant tumors compared with benign tumors. Western blot analysis using antisera directed against SgII and SgII-derived fragments revealed lower SgII protein and SgII-processing products in malignant tumors. Western blot also showed that low p-cAMP-responsive element-binding (CREB) concentrations seemed to be associated with the malignant status. In addition, the prohormone convertase PC1 and PC2 genes and proteins were overexpressed in benign pheochromocytomas compared with malignant pheochromocytomas. Low concentrations of EM66 found in malignant tumors are associated with reduced expression and production of SgII and SgII-derived peptides that could be ascribed to a decrease in SgII gene transcription, probably linked to p-CREB down-regulation, and to lower PC levels. These findings highlight the mechanisms leading to lower concentrations of EM66 in malignant pheochromocytoma and strengthen the notion that this peptide is a suitable marker of this neuroendocrine tumor.


Subject(s)
Adrenal Gland Neoplasms/metabolism , Biomarkers, Tumor/metabolism , Peptide Fragments/metabolism , Pheochromocytoma/metabolism , Secretogranin II/metabolism , Adolescent , Adrenal Gland Neoplasms/genetics , Adrenal Gland Neoplasms/pathology , Adrenal Glands/pathology , Adrenal Glands/physiology , Adult , Aged , Biomarkers, Tumor/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Peptide Fragments/genetics , Pheochromocytoma/genetics , Pheochromocytoma/pathology , Proprotein Convertase 1/genetics , Proprotein Convertase 1/metabolism , Proprotein Convertase 2/genetics , Proprotein Convertase 2/metabolism , Secretogranin II/genetics , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL
...