title: NMR-Based Metabolic Profiling Reveals Neurochemical Alterations in the Brain of Rats Treated with Sorafenib.
abstract: 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.
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Changman
authors.initials: C
authors.lastname: Du
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Shao
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Ruiming
authors.initials: R
authors.lastname: Zhu
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Dengqi
authors.initials: D
authors.lastname: Fu
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gu
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Jueying
authors.initials: J
authors.lastname: Kong
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Hailei
authors.initials: H
authors.lastname: Long
authors.affiliation: Analytical and Testing Center, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Pengchi
authors.initials: P
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China. xbcenalan@sina.com.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cen
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004734:Energy Metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D055432:Metabolomics; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib
chemical_list: D000596:Amino Acids; D000975:Antioxidants; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib
keywords: Metabolomic; NMR; Neurotoxicity; Sorafenib