title: Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress.
abstract: Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. The present study investigates the neuroprotective effect of the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity.
  
  
  
  The impact of minocycline pretreatment on colistin-induced apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated using cultured mouse neuroblastoma-2a (N2a) and primary cortical neuronal cells.
  
  
  
  Colistin-induced neurotoxicity in mouse N2a and primary cortical cells gives rise to the generation of reactive oxygen species (ROS) and subsequent cell death via apoptosis. Pretreatment of the neuronal cells with minocycline at 5, 10 and 20 μM for 2 h prior to colistin (200 μM) exposure (24 h), had an neuroprotective effect by significantly decreasing intracellular ROS production and by upregulating the activities of the anti-ROS enzymes superoxide dismutase and catalase. Minocycline pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis. Immunohistochemical imaging studies revealed colistin accumulates within the dendrite projections and cell body of primary cortical neuronal cells.
  
  
  
  To our knowledge, this is first study demonstrating the protective effect of minocycline on colistin-induced neurotoxicity by scavenging of ROS and suppression of apoptosis. Our study highlights that co-administration of minocycline kills two birds with one stone: in addition to its synergistic antimicrobial activity, minocycline could potentially ameliorate unwanted neurotoxicity in patients undergoing polymyxin therapy.
authors.affiliation: College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China.
authors.forename: Chongshan
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Ciccotosto
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.affiliation: College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Tang
authors.affiliation: College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China.
authors.forename: Xilong
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003091:Colistin / Q000494:pharmacology / Q000633:toxicity*; D004357:Drug Synergism; D004789:Enzyme Activation; D051379:Mice; D008911:Minocycline / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009447:Neuroblastoma; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D002374:Catalase; D013482:Superoxide Dismutase; D020169:Caspases; D008911:Minocycline; D003091:Colistin