Transcriptomic Mapping of Neurotoxicity Pathways in the Rat Brain in Response to Intraventricular Polymyxin B

• Published in: Molecular neurobiology 2023-03, Vol.60 (3), p.1317-1330
• Main Authors: Lu, Jing, Zhu, Yan, Parkington, Helena C., Hussein, Maytham, Zhao, Jinxin, Bergen, Phillip, Rudd, David, Deane, Mary A., Oberrauch, Sara, Cornthwaite-Duncan, Linda, Allobawi, Rafah, Sharma, Rajnikant, Rao, Gauri, Li, Jian, Velkov, Tony
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - toxicity; Biomedical and Life Sciences; Biomedicine; Brain; Cell Biology; Central nervous system; Dopamine; Dosage; Epinephrine; Gram-negative bacteria; Intracerebroventricular administration; Mass spectroscopy; Multidrug resistance; Neurobiology; Neuroimaging; Neurology; Neurosciences; Neurotoxicity; Neurotransmitters; Pharmacodynamics; Pharmacokinetics; Polymyxin B; Polymyxin B - chemistry; Polymyxin B - pharmacology; Polymyxins; Polymyxins - pharmacology; Rats; Receptors, GABA-A; Signal transduction; Spinal cord; Transcriptome - genetics; Transcriptomes; Transcriptomics; Ventricle; Ventricles (cerebral); γ-Aminobutyric acid
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-022-03140-7

Intraventricular or intrathecal administration of polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria caused infections in the central nervous system (CNS). However, our limited knowledge of the mechanisms underpinning polymyxin-induced neurotoxicity significantly hinders the development of safe and efficacious polymyxin dosing regimens. To this end, we conducted transcriptomic analyses of the rat brain and spinal cord 1 h following intracerebroventricular administration of polymyxin B into rat lateral ventricle at a clinically relevant dose (0.5 mg/kg). Following the treatment, 66 differentially expressed genes (DEGs) were identified in the brain transcriptome while none for the spinal cord (FDR ≤ 0.05, fold-change ≥ 1.5). DEGs were enriched in signaling pathways associated with hormones and neurotransmitters, including dopamine and (nor)epinephrine. Notably, the expression levels of Slc6a3 and Gabra6 were decreased by 20-fold and 4.3-fold, respectively, likely resulting in major perturbations of dopamine and γ-aminobutyric acid signaling in the brain. Mass spectrometry imaging of brain sections revealed a distinct pattern of polymyxin B distribution with the majority accumulating in the injection-side lateral ventricle and subsequently into third and fourth ventricles. Polymyxin B was not detectable in the left lateral ventricle or brain tissue. Electrophysiological measurements on primary cultured rat neurons revealed a large inward current and significant membrane leakage following polymyxin B treatment. Our work demonstrates, for the first time, the key CNS signaling pathways associated with polymyxin neurotoxicity. This mechanistic insight combined with pharmacokinetic/pharmacodynamic dosing strategies will help guide the design of safe and effective intraventricular/intrathecal polymyxin treatment regimens for CNS infections caused by MDR Gram-negative pathogens.