ABSTRACT
Astrocyte is considered to be a type of passive supportive cells that preserves neuronal activity and survival. The dysfunction of astrocytes is involved in the pathological processes of major depression. Recent studies implicate sigma-1 receptors as putative therapeutic targets for current available antidepressant drugs. However, it is absent of direct evidences whether sigma-1 receptor could promote activation of astrocyte. In the present study, we took advantage of primary astrocyte culture and a highly selective agonist of sigma-1 receptor, (+)SKF-10047 to determine the effect of sigma-1 receptor on Brdu (bromodeoxyuridine) labeling positive cells, migration as well as GFAP (glial fibrillary acidic protein) expression of astrocyte. The results showed that (+)SKF-10047 notably increased the number of Brdu labeling positive cells, migration, and the expression of GFAP in primary astrocytes, which were blocked by antagonist of sigma-1 receptor. Moreover, we also found that (+)SKF-10047 increased the phosphorylation of ERK1/2 (extracellular signal-regulated kinases 1/2) and GSK3ß (glycogen synthase kinase 3ß) (ser 9) in the primary astrocytes. In addition, pharmacological inhibition of ERK1/2 and GSK3ß (ser 9) abolished sigma-1 receptor-promoted activation of astrocyte. Therefore, sigma-1 receptor could be considerate as a new pattern for modulating astrocytic function might emerge as therapeutic strategies.
Subject(s)
Astrocytes/drug effects , Glycogen Synthase Kinase 3 beta/metabolism , MAP Kinase Signaling System/drug effects , Phenazocine/analogs & derivatives , Receptors, sigma/agonists , Animals , Astrocytes/metabolism , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Gene Knockdown Techniques , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , Mice, Inbred C57BL , Phenazocine/pharmacology , Phosphorylation , Primary Cell Culture , Receptors, sigma/genetics , Signal Transduction , Sigma-1 ReceptorABSTRACT
AIMS: Sigma-1 receptors are involved in the pathophysiological process of several neuropsychiatric diseases such as epilepsy, depression. Allosteric modulation represents an important mechanism for receptor functional regulation. In this study, we examined antidepressant activity of the latest identified novel and selective allosteric modulator of sigma-1 receptor 3-methyl-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo[d]azepin-7-ol (SOMCL-668). METHODS AND RESULTS: A single administration of SOMCL-668 decreased the immobility time in the forced swimming test (FST) and tailing suspended test in mice, which were abolished by pretreatment of sigma-1 receptor antagonist BD1047. In the chronic unpredicted mild stress (CUMS) model, chronic application of SOMCL-668 rapidly ameliorated anhedonia-like behavior (within a week), accompanying with the enhanced expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of glycogen synthase kinase 3ß (GSK3ß) (Ser-9) in the hippocampus. SOMCL-668 also rapidly promoted the phosphorylation of GSK3ß (Ser-9) in an allosteric manner in vitro. In the cultured primary neurons, SOMCL-668 enhanced the sigma-1 receptor agonist-induced neurite outgrowth and the secretion of BDNF. CONCLUSION: SOMCL-668, a novel allosteric modulator of sigma-1 receptors, elicits a potent and rapid acting antidepressant effect. The present data provide the first evidence that allosteric modulation of sigma-1 receptors may represent a new approach for antidepressant drug discovery.
Subject(s)
Antidepressive Agents/therapeutic use , Benzazepines/therapeutic use , Receptors, sigma/metabolism , Stress, Psychological/drug therapy , Animals , Antidepressive Agents/pharmacology , Antipsychotic Agents/pharmacology , Anxiety/drug therapy , Anxiety/etiology , Benzazepines/pharmacology , Brain-Derived Neurotrophic Factor/pharmacology , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Hippocampus/cytology , Immobility Response, Tonic/drug effects , Male , Mice , Mice, Inbred C57BL , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Phenazocine/analogs & derivatives , Phenazocine/pharmacology , Signal Transduction/drug effects , Stress, Psychological/complications , Swimming/psychology , Time Factors , Venlafaxine Hydrochloride/pharmacology , Venlafaxine Hydrochloride/therapeutic use , Sigma-1 ReceptorABSTRACT
AIM: To investigate the expression of insulin-like growth factor-1 (IGF-1)/insulin-like growth factor-1 receptor (IGF-1R) in colorectal cancer (CRC) tissues and to analyze their correlation with lymphangiogenesis and lymphatic metastasis. METHODS: Immunohistochemistry was used to evaluate IGF-1 and IGF-1R expression and lymphatic vessel density (LVD) in 40 CRC specimens. The correlation between IGF-1/IGF-1R and LVD was investigated. Effects of IGF-1 on migration and invasion of CRC cells were examined using transwell chamber assays. A LoVo cell xenograft model was established to further detect the role of IGF-1 in CRC lymphangiogenesis in vivo. RESULTS: Elevated IGF-1 and IGF-1R expression in CRC tissues was correlated with lymph node metastasis (r = 0.715 and 0.569, respectively, P < 0.05) and tumor TNM stage (r = 0.731 and 0.609, P < 0.05). A higher LVD was also found in CRC tissues and was correlated with lymphatic metastasis (r = 0.405, P < 0.05). A positive correlation was found between LVD and IGF-1R expression (r = 0.437, P < 0.05). Transwell assays revealed that IGF-1 increased the migration and invasion of CRC cells. In vivo mouse studies showed that IGF-1 also increased LVD in LoVo cell xenografts. CONCLUSION: IGF-1/IGF-1R signaling induces tumor-associated lymphangiogenesis and contributes to lymphatic metastasis of CRC.
