title: In vitro toxicity of colistin on primary chick cortex neurons and its potential mechanism.
abstract: Colistin is increasingly used as the last-line therapy for infections caused by Gram-negative 'superbugs'. Although colistin neurotoxicity was reported in the literature, there has no data on its mechanism. In the present study, we examined the effect of colistin on primary chick neuron cells, which were treated with 0.83, 4.15 and 8.3μg/mL colistin for 6, 12 and 24h. Cell viability was evaluated with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assays after exposure to colistin. Formation of reactive oxygen species (ROS), nuclear morphology, caspase-3 activity and internucleosomal DNA fragmentation were examined. The results showed that, compared with the control, no significant change was observed in cell viability, ROS formation and caspase-3 activity in cells treated for 6, 12 and 24h with 0.83μg/mL colistin. However, in the 4.15 and 8.3μg/mL colistin-treated groups, the viability of chick primary neurons significantly decreased at 12 and 24h, respectively; caspase-3 activities were significantly increased to 5.1 and 7.4 fold at 6h, more earlier than the changes of ROS, which was significant increased to 124.5% and 143.5% (P<0.01) of control at 12h, respectively. The apoptosis of neuron cells was revealed by both nuclear morphological observations and internucleosomal DNA fragmentation in the 4.15 and 8.3μg/mL colistin-treated groups at 6, 12 and 24h. Our data demonstrated that colistin can induce apoptosis in primary chick cortex neurons through caspase-3 activation, which may be contributed with ROS-dependent and independent mechanism.
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Chongshan
authors.initials: C
authors.lastname: Dai
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China; College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang 110161, PR China.
authors.forename: Dexian
authors.initials: D
authors.lastname: Zhang
authors.affiliation: College of Life Science, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Ruixia
authors.initials: R
authors.lastname: Gao
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Facility for Anti-infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Electronic address: Jian.Li@monash.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China. Electronic address: lijichang828@yahoo.cn.
authors.forename: Jichang
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D002642:Chick Embryo; D002645:Chickens; D003091:Colistin / Q000633:toxicity*; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D017382:Reactive Oxygen Species; D053148:Caspase 3; D003091:Colistin
keywords: Apoptosis; Caspase-3 activity; Colistin; Neurotoxicity; ROS