2- Deoxy–D-Glucose (2-DG) is being developed as a potential
anticonvulsant and disease-modifying agent for epilepsy patients; 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-deoxy-D-glucose (2-DG) cardiac toxicity. In addition,
this study also investigated the association of cardiac histopathological
changes with these biomarkers. F344 rats (four/sex/group/sacrifice point) were
gavaged with either vehicle or 2-DG (50, 125, or 375 mg/kg BID; total daily dose
of 100, 250 or 750 mg/kg/day) for 7, 14, 21, or 45 days followed by a 15 day
recovery. Dose dependent increases in NT pro-BNP and BNP plasma concentrations
were observed. Following recovery period, the NT pro-BNP 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/day. Microscopic findings, in general, were associated with
increases in NT pro-BNP 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.
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