Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brain
There is a dearth of studies focused on understanding pharmacokinetics, pharmacodynamics and toxicodynamics of polymyxins following direct administration to the central nervous system (CNS). In this study, for the first time, untargeted metabolomics were employed to ascertain the perturbations of br...
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022004883 |
| _version_ | 1797978178813165568 |
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| author | Maytham Hussein Sara Oberrauch Rafah Allobawi Linda Cornthwaite-Duncan Jing Lu Rajnikant Sharma Mark Baker Jian Li Gauri G. Rao Tony Velkov |
| author_facet | Maytham Hussein Sara Oberrauch Rafah Allobawi Linda Cornthwaite-Duncan Jing Lu Rajnikant Sharma Mark Baker Jian Li Gauri G. Rao Tony Velkov |
| author_sort | Maytham Hussein |
| collection | DOAJ |
| description | There is a dearth of studies focused on understanding pharmacokinetics, pharmacodynamics and toxicodynamics of polymyxins following direct administration to the central nervous system (CNS). In this study, for the first time, untargeted metabolomics were employed to ascertain the perturbations of brain metabolism in the rat cerebral cortex following direct brain injection of 0.75 mg/kg polymyxin B (1 and 4 h) through the right lateral ventricle. In the right cortex metabolome, ICV polymyxin B induced a greater perturbation at 1 h compared to negligible effect at 4 h. Pathway enrichment analysis showed that sphingolipid, arginine, and histidine metabolism, together with aminoacyl-tRNA biosynthesis were significantly affected in the right cortex metabolome. Furthermore, intracerebroventricular (ICV) polymyxin B dysregulated the two arms (CDP-choline and CDP-ethanolamine) of the Kennedy pathway that governs the de novo biosynthesis of neuronal phospholipids. Importantly, the key intermediates of metabolic pathways that maintain cellular redox balance (e.g., glutathione metabolism) and mitochondrial function (e.g., electron transport chain) were markedly depleted. The abundance of key metabolites (e.g., N-acetyl-l-glutamate) associated with diverse CNS disorders (e.g., neurodegenerative disease) were also significantly perturbed. The biological significance of these metabolic perturbations on the CNS includes impaired oxidant-antioxidant balance, impaired neuronal lipid homeostasis and mitochondrial dysfunction. Furthermore, ICV polymyxin B caused a significant alteration in the abundance of several metabolic biomarkers associated with cerebral ischemia, oxidative stress as well as certain neurological disorders. These findings may facilitate the development of new pharmacokinetic/pharmacodynamic strategies to attenuate polymyxins ICV related CNS toxicities and stimulate the discovery of safer next-generation polymyxin-like lipopeptide antibiotics. |
| first_indexed | 2024-04-11T05:18:51Z |
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| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:18:51Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
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| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-cc10edd91d624340b9335629527d490a2022-12-24T04:54:59ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012060676077Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brainMaytham Hussein0Sara Oberrauch1Rafah Allobawi2Linda Cornthwaite-Duncan3Jing Lu4Rajnikant Sharma5Mark Baker6Jian Li7Gauri G. Rao8Tony Velkov9Department of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia; Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC 3800, AustraliaDepartment of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, AustraliaDepartment of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia; Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC 3800, AustraliaDepartment of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, AustraliaDepartment of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia; Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC 3800, AustraliaDivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USADiscipline of Biological Sciences, Priority Research Centre in Reproductive Biology, Faculty of Science and IT, University of Newcastle, University Drive, Callaghan, NSW 2308, AustraliaMonash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC 3800, Australia; Corresponding authors at: Department of Microbiology Monash Biomedicine Discovery Institute School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences19 Innovation Walk Monash University VIC 3800, Australia (T. Velkov).Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; Corresponding authors at: Department of Microbiology Monash Biomedicine Discovery Institute School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences19 Innovation Walk Monash University VIC 3800, Australia (T. Velkov).Department of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia; Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC 3800, Australia; Corresponding authors at: Department of Microbiology Monash Biomedicine Discovery Institute School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences19 Innovation Walk Monash University VIC 3800, Australia (T. Velkov).There is a dearth of studies focused on understanding pharmacokinetics, pharmacodynamics and toxicodynamics of polymyxins following direct administration to the central nervous system (CNS). In this study, for the first time, untargeted metabolomics were employed to ascertain the perturbations of brain metabolism in the rat cerebral cortex following direct brain injection of 0.75 mg/kg polymyxin B (1 and 4 h) through the right lateral ventricle. In the right cortex metabolome, ICV polymyxin B induced a greater perturbation at 1 h compared to negligible effect at 4 h. Pathway enrichment analysis showed that sphingolipid, arginine, and histidine metabolism, together with aminoacyl-tRNA biosynthesis were significantly affected in the right cortex metabolome. Furthermore, intracerebroventricular (ICV) polymyxin B dysregulated the two arms (CDP-choline and CDP-ethanolamine) of the Kennedy pathway that governs the de novo biosynthesis of neuronal phospholipids. Importantly, the key intermediates of metabolic pathways that maintain cellular redox balance (e.g., glutathione metabolism) and mitochondrial function (e.g., electron transport chain) were markedly depleted. The abundance of key metabolites (e.g., N-acetyl-l-glutamate) associated with diverse CNS disorders (e.g., neurodegenerative disease) were also significantly perturbed. The biological significance of these metabolic perturbations on the CNS includes impaired oxidant-antioxidant balance, impaired neuronal lipid homeostasis and mitochondrial dysfunction. Furthermore, ICV polymyxin B caused a significant alteration in the abundance of several metabolic biomarkers associated with cerebral ischemia, oxidative stress as well as certain neurological disorders. These findings may facilitate the development of new pharmacokinetic/pharmacodynamic strategies to attenuate polymyxins ICV related CNS toxicities and stimulate the discovery of safer next-generation polymyxin-like lipopeptide antibiotics.http://www.sciencedirect.com/science/article/pii/S2001037022004883Polymyxin BCNS toxicityMetabolomicsIntraventricular injection |
| spellingShingle | Maytham Hussein Sara Oberrauch Rafah Allobawi Linda Cornthwaite-Duncan Jing Lu Rajnikant Sharma Mark Baker Jian Li Gauri G. Rao Tony Velkov Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brain Computational and Structural Biotechnology Journal Polymyxin B CNS toxicity Metabolomics Intraventricular injection |
| title | Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brain |
| title_full | Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brain |
| title_fullStr | Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brain |
| title_full_unstemmed | Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brain |
| title_short | Untargeted metabolomics to evaluate polymyxin B toxicodynamics following direct intracerebroventricular administration into the rat brain |
| title_sort | untargeted metabolomics to evaluate polymyxin b toxicodynamics following direct intracerebroventricular administration into the rat brain |
| topic | Polymyxin B CNS toxicity Metabolomics Intraventricular injection |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022004883 |
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