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.
Highlights
Chemotherapeutic drugs are known to cause significant clinical neurotoxicity, which results in early cessation of treatment (Kuroi and Shimozuma 2004)
The results showed an apparent separation between sorafenibtreated brain tissues and normal controls on the scores plot of first two principal components PC (Fig. 3)
We identified that the metabonomics profiles in hippocampus, striatum, and prefrontal cortex (PFC) were modified by sorafenib
Summary
Chemotherapeutic drugs are known to cause significant clinical neurotoxicity, which results in early cessation of treatment (Kuroi and Shimozuma 2004). An orally active multi-kinase inhibitor that can cross the blood–brain barrier, has been widely used as a Neurotox Res (2015) 28:290–301 chemotherapy drug to treat advanced clear-cell renal cell carcinoma patients (Takimoto and Awada 2008). It selectively targets vascular endothelial growth factor receptor (VEGFR) 2/3, Raf, platelet-derived growth factor receptor, FLT-3, as well as c-Kit (Kane et al 2006). Effect sizes of cognitive dysfunction in patients using sorafenib were larger than patient controls (Mulder et al 2014). VEGF has been implicated to affect cognitive functioning through its effects on neurogenesis, cerebral blood flow, and/or modulation of long-term potentiation (Schanzer et al 2004; Ongali et al 2010; Fournier et al 2013), the neurochemical mechanism underlying such effects remains unknown (Kane et al 2006; Mulder et al 2014)
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