title: Effects of colistin on amino acid neurotransmitters and blood-brain barrier in the mouse brain.
abstract: Neurotoxicity is one of the major potential side effects of colistin therapy. However, the mechanistic aspects of colistin-induced neurotoxicity remain largely unknown. The objective of this study was to examine the effects of colistin on the blood-brain barrier (BBB) and amino acid neurotransmitters in the cerebral cortex of mouse. Mice were divided into four groups (n=5) and were administrated intravenously with 15mg/kg/day of colistin sulfate for 1, 3 and 7days successively while the control group was administrated intravenously with saline solution. The permeability and ultrastructure of the BBB were detected using the Evans blue (EB) dye and transmission electron microscopy (TEM), and the expression of Claudin-5 were determined by real-time PCR examination and western blotting. The brain uptake of colistin was measured by high-performance liquid chromatography (HPLC). The effects of colistin on amino acid neurotransmitters and their receptors were also examined by HPLC and real-time PCR. The results of EB extravasation, TEM and expression of Claudin-5 showed that colistin treatment did not affect the BBB integrity. In addition, multiple doses of colistin could induce accumulation of this compound in the brain parenchyma although there was poor brain uptake of colistin. Moreover, colistin exposure significantly increased the contents of glutamate (Glu) and gamma aminobutyric acid (GABA), and enhanced the mRNA expression levels of gamma aminobutyric acid type A receptor (GABAAR), gamma aminobutyric acid type B receptor (GABABR), N-methyl-d-aspartate 1 receptor (NR1), N-methyl-d-aspartate 2A receptor (NR2A) and N-methyl-d-aspartate 2B receptor (NR2B) in the cerebral cortex. Our data demonstrate that colistin is able to accumulate in the mouse brain and elevate the levels of amino acid neurotransmitters. These findings may be associated with colistin-induced neurotoxicity.
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Meishuang
authors.initials: M
authors.lastname: Yi
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Chen
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Ishfaq
authors.initials: I
authors.lastname: Muhammad
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Fangping
authors.initials: F
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Xiangfang District, Harbin 150030, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
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: lijichang@neau.edu.cn.
authors.forename: Jichang
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D003091:Colistin / Q000633:toxicity*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D062507:Claudin-5; C491511:Cldn5 protein, mouse; D012333:RNA, Messenger; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D003091:Colistin
keywords: Accumulation; Blood-brain barrier; Colistin; Neurotoxicity; Neurotransmitters