Progressive loss of nigrostriatal dopaminergic neurons induced by inflammatory responses to fipronil.
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.
Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Hanyang Biomedical Research Institute, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
Jae Hyeon
JH
Park
Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Hanyang Biomedical Research Institute, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
Youn Sun
YS
Park
Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Hanyang Biomedical Research Institute, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea. Electronic address: hckoh@hanyang.ac.kr.
Hyun Chul
HC
Koh
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D018450:Disease Progression; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004660:Encephalitis / Q000209:etiology*; D005904:Glial Fibrillary Acidic Protein / Q000819:agonists / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000737:chemistry / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity*; D011720:Pyrazoles / Q000008:administration & dosage / Q000633:toxicity*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D013238:Stereotaxic Techniques; D020955:Striatonigral Degeneration / Q000209:etiology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D010575:Pesticides; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D014446:Tyrosine 3-Monooxygenase; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C082360:fipronil; D004298:Dopamine
Cyclooxygenase-2; Dopaminergic neuron; Fipronil; Inducible NO synthase; Inflammation