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. 2016 May;35(3):284-93.
doi: 10.1177/1091581815624397. Epub 2016 Feb 2.

2-Deoxy-d-Glucose (2-DG)-Induced Cardiac Toxicity in Rat: NT-proBNP and BNP as Potential Early Cardiac Safety Biomarkers

P S Terse  1 , P S Joshi  2 , N R Bordelon  3 , A M Brys  4 , K M Patton  4 , T P Arndt  5 , T P Sutula  6
Affiliations

2-Deoxy-d-Glucose (2-DG)-Induced Cardiac Toxicity in Rat: NT-proBNP and BNP as Potential Early Cardiac Safety Biomarkers

P S Terse et al. Int J Toxicol. 2016 May.

Abstract

2-Deoxy-d-glucose (2-DG) is being developed as a potential anticonvulsant and disease-modifying agent for patients with epilepsy; however, during preclinical development, cardiac toxicity has been encountered in rats. This study was performed to determine whether cardiac troponin (cTnI and cTnT), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and/or creatine kinase (CK) could be useful as indicators of 2-DG cardiac toxicity. In addition, this study also investigated the association of cardiac histopathological changes with these biomarkers. F344 rats (4/sex/group/sacrifice point) were gavaged with either vehicle or 2-DG (50, 125, or 375 mg/kg twice daily; total daily dose of 100, 250, or 750 mg/kg/d) for 7, 14, 21, or 45 days followed by a 15-day recovery. Dose-dependent increases in NT-proBNP and BNP plasma concentrations were observed. Following recovery period, the NT-proBNP and BNP concentrations returned to baseline levels. There were no remarkable increases in CK, ANP, cTnI, or cTnT concentrations. There were no gross cardiac lesions observed at the necropsy. Microscopic findings of vacuolar degeneration and hypertrophy of the endothelial cells of the endocardium were present in the heart at doses of 250 and 750 mg/kg/d. Microscopic findings, in general, were associated with increases in NT-proBNP levels. Cardiac toxicity appeared to be reversible. In conclusion, NT-proBNP and BNP are potential early biomarkers for 2-DG-induced cardiac toxicity that can be useful to monitor 2-DG therapy in clinical trials.

Keywords: 2-deoxy-d-glucose; BNP; NT-proBNP; vacuolar degeneration.

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Conflict of interest statement

DECLARATION OF CONFLICTING INTERESTS

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TPS holds a use patent for 2-DG.

Figures

Figure 4
Figure 4
Photomicrographs of sections of the cardiac atrium with H&E stain, 10 ; control (left) and high dose(right).
Figure 1
Figure 1
Plasma NT pro-BNP levels in Low Dose (100 mg/kg/day), Mid Dose (250 mg/kg/day), and High Dose (750mg/kg/day) rats. When N > 2, an asterisk (*) indicates a statistically (p ≤ 0.05) difference from the control group
Figure 2
Figure 2
Plasma BNP levels in Low Dose (100 mg/kg/day), Mid Dose (250 mg/kg/day), and High Dose (750mg/kg/day) rats. When N > 2, an asterisk (*) indicates a statistically (p ≤ 0.05) difference from the control group
Figure 3
Figure 3
Serum Creatine Kinase levels in Low Dose (100 mg/kg/day), Mid Dose (250 mg/kg/day), and High Dose (750mg/kg/day) rats. When N > 2, an asterisk (*) indicates a statistically (p ≤ 0.05) difference from the control group. Photomicrographs of sections of the cardiac atrium with H&E stain, 10X; control (left) and high dose (right).
See this image and copyright information in PMC

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