ABSTRACT
Inflammatory responses are involved in mechanisms of neuronal cell damage in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). We investigated the mechanisms whereby inflammatory responses contribute to loss of dopaminergic neurons in fipronil (FPN)-treated rats. After stereotaxic injection of FPN in the substantia nigra (SN), the number of tyrosine hydroxylase (TH)-positive neurons and the levels of TH expression in the SN decreased at 7days, and a significant decrease was observed at 14days with a subsequent reduction in striatal TH expression. Decreases in dopamine (DA) levels, however, began at 3days post-injection, preceding the changes in TH expression. In contrast, glial fibrillary acidic protein (GFAP) expression was significantly increased at 3days and persisted for up to 14days post-lesion; these changes in GFAP expression appeared to be inversely correlated with TH expression. Furthermore, we found that FPN administration induced an inflammatory response characterized by increased levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), which was mediated by activated microglia following infusion of FPN unilaterally into the SN. Intranigral injection of FPN underwent an inflammatory response with a resultant ongoing loss of dopaminergic neurons, indicating that pesticides may have important implication for the study of PD.
Subject(s)
Dopaminergic Neurons/drug effects , Encephalitis/etiology , Neurotoxicity Syndromes/pathology , Pesticides/toxicity , Pyrazoles/toxicity , Striatonigral Degeneration/etiology , Substantia Nigra/drug effects , Animals , Biomarkers/metabolism , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Disease Progression , Dopamine/chemistry , Dopamine/metabolism , Dopaminergic Neurons/immunology , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Glial Fibrillary Acidic Protein/agonists , Glial Fibrillary Acidic Protein/metabolism , Injections, Intraventricular , Male , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/metabolism , Neurotoxicity Syndromes/immunology , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/physiopathology , Nitric Oxide Synthase Type II/chemistry , Nitric Oxide Synthase Type II/metabolism , Pyrazoles/administration & dosage , Random Allocation , Rats, Sprague-Dawley , Stereotaxic Techniques , Substantia Nigra/immunology , Substantia Nigra/metabolism , Substantia Nigra/pathology , Tumor Necrosis Factor-alpha/agonists , Tumor Necrosis Factor-alpha/metabolism , Tyrosine 3-Monooxygenase/antagonists & inhibitors , Tyrosine 3-Monooxygenase/metabolismABSTRACT
The poor therapeutic effect of traditional antiangiogenic therapy on glioblastoma multiforme (GBM) may be attributed to vasculogenic mimicry (VM), which was previously reported to be promoted by cancer stem-like cells (SLCs). All-trans retinoic acid (ATRA), a potent reagent which drives differentiation, was reported to be able to eradicate cancer SLCs in certain malignancies. The aim of the present study was to investigate the effects of ATRA on the VM formation ability of U87 glioblastoma SLCs. The expression of cancer SLC markers CD133 and nestin was detected using immunocytochemistry in order to identify U87 SLCs. In addition, the differentiation of these SLCs was observed through detecting the expression of glial fibrillary acidic protein (GFAP), ß-tubulin III and galactosylceramidase (Galc) using immunofluorescent staining. The results showed that the expression levels of GFAP, ß-tubulin III and Galc were upregulated following treatment with ATRA in a dose-dependent manner. Furthermore, ATRA significantly reduced the proliferation, invasiveness, tube formation and vascular endothelial growth factor (VEGF) secretion of U87 SLCs. In conclusion, the VM formation ability of SLCs was found to be negatively correlated with differentiation. These results therefore suggested that ATRA may serve as a promising novel agent for the treatment of GBM due to its role in reducing VM formation.
