title: 4-Hydroxy TEMPO attenuates dichlorvos induced microglial activation and apoptosis.
abstract: Microglial cells have been implicated in various neurodegenerative diseases. Previous studies from our lab have shown that dichlorvos (an organophosphate) could induce Parkinson's like features in rats. Recently, we have shown that dichlorvos can induce microglial activation, and if not checked in time could ultimately induce neuronal apoptosis. However, this activation does not always pose a threat to the neurons. Activated microglia also secrete various neuronal growth factors, suggesting that they have beneficial roles in CNS repair. Therefore, it is essential to control their detrimental functions selectively. Here, we tried to find out how microglial cells behave when exposed to dichlorvos in either the presence or absence of potent nitric oxide scavenger and superoxide dismutase mimetic, 4-hydroxy TEMPO (4-HT). Wistar rat pups (1 day) were used to isolate and culture primary microglial cells. We found 4-HT pretreatment successfully attenuated the dichlorvos mediated microglial activation. Moreover, 4-HT pretreatment decreased the up-regulated levels of p53 and its downstream effector, p21. The expression of various cell cycle regulators such as Chk2, CDC25a, and cyclin A remained close to their basal levels when 4-HT pretreatment was given. DNA fragmentation analysis showed significant reduction in the DNA damage of 4-HT pretreated microglia as compared to dichlorvos treated cells. In addition to this, we found 4-HT pretreatment prevented the microglial cells from undergoing apoptotic cell death even after 48 h of dichlorvos exposure. Taken together, our results showed 4-HT pretreatment could successfully ameliorate the dichlorvos induced microglial cell damage.
authors.affiliation: Department of Biochemistry, Postgraduate Institute of Medical Education and Research , Chandigarh 160012, India.
authors.forename: Aditya
authors.initials: A
authors.lastname: Sunkaria
authors.forename: Deep Raj
authors.initials: DR
authors.lastname: Sharma
authors.forename: Willayat Yousuf
authors.initials: WY
authors.lastname: Wani
authors.forename: Kiran Dip
authors.initials: KD
authors.lastname: Gill
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D019925:Cyclin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects; D004249:DNA Damage; D004006:Dichlorvos / Q000494:pharmacology*; D016158:Genes, p53 / Q000187:drug effects; D019811:Hydroxylamine / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D003497:Cyclic N-Oxides; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007306:Insecticides; D017382:Reactive Oxygen Species; D019811:Hydroxylamine; D009569:Nitric Oxide; D004006:Dichlorvos; D064447:Checkpoint Kinase 2; C578632:Chek2 protein, rat; C517007:Cdc25a protein, rat; D020687:cdc25 Phosphatases; C505333:TEMPOL-H