NMR-Based Metabolic Profiling Reveals Neurochemical Alterations in the Brain of Rats Treated with Sorafenib
| Autor: | Chunyan Hu, Jueying Kong, Qian Zhao, Ruiming Zhu, Yan Li, Changman Du, Pengchi Deng, Huijuan Wang, Yinglan Zhao, Dengqi Fu, Xue Shao, Xiaobo Cen, Hailei Long, Li Luo, Hui Gu |
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| Rok vydání: | 2015 |
| Předmět: |
Sorafenib
Male Niacinamide medicine.medical_specialty Neuroscience(all) Striatum Pharmacology Biology urologic and male genital diseases Toxicology Antioxidants Rats Sprague-Dawley Neurochemical Metabolomics Internal medicine medicine Animals Neurochemistry Amino Acids Prefrontal cortex neoplasms Protein Kinase Inhibitors General Neuroscience Phenylurea Compounds Cell Membrane Neurotoxicity Brain medicine.disease Magnetic Resonance Imaging digestive system diseases Rats Endocrinology Histopathology Energy Metabolism medicine.drug |
| Zdroj: | Neurotoxicity research. 28(4) |
| ISSN: | 1476-3524 |
| Popis: | Sorafenib, an active multi-kinase inhibitor, has been widely used as a chemotherapy drug to treat advanced clear-cell renal cell carcinoma patients. In spite of the relative safety, sorafenib has been shown to exert a negative impact on cognitive functioning in cancer patients, specifically on learning and memory; however, the underlying mechanism remains unclear. In this study, an NMR-based metabolomics approach was applied to investigate the neurochemical effects of sorafenib in rats. Male rats were once daily administrated with 120 mg/kg sorafenib by gavage for 3, 7, and 28 days, respectively. NMR-based metabolomics coupled with histopathology examinations for hippocampus, prefrontal cortex (PFC), and striatum were performed. The (1)H NMR spectra data were analyzed by using multivariate pattern recognition techniques to show the time-dependent biochemical variations induced by sorafenib. Excellent separation was obtained and distinguishing metabolites were observed between sorafenib-treated and control rats. A total of 36 differential metabolites in hippocampus of rats treated with sorafenib were identified, some of which were significantly changed. Furthermore, these modified metabolites mainly reflected the disturbances in neurotransmitters, energy metabolism, membrane, and amino acids. However, only a few metabolites in PFC and striatum were altered by sorafenib. Additionally, no apparent histological changes in these three brain regions were observed in sorafenib-treated rats. Together, our findings demonstrate the disturbed metabonomics pathways, especially, in hippocampus, which may underlie the sorafenib-induced cognitive deficits in patients. This work also shows the advantage of NMR-based metabolomics over traditional approach on the study of biochemical effects of drugs. |
| Databáze: | OpenAIRE |
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