2-Deoxy-d-Glucose (2-DG)–Induced Cardiac Toxicity in Rat

Abstract

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.

Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury

“…In our studies, we did not find evidence of chronic changes in animal health, systemic metabolism, or body temperature (Supplemental Figure 4) over the course of 2-DG treatment. This is important, as long-term exposure to 2-DG (>2 weeks) has been previously associated with cardiotoxicity (95,96) and hypothermia alone may be neuroprotective after TBI (97-99). 2-DG is already in use clinically to limit tumor growth in cancer patients (based on the Warburg effect, which describes increased glycolytic activity in neoplastic cells), and short-term treatments are well tolerated in humans (75).…”

Metabolic Profiling Analysis of Patients With Coronary Heart Disease Undergoing Xuefu Zhuyu Decoction Treatment

“…In addition, 2-DG possessed a mannose-like property, which competed with mannose during the initial steps of N-linked glycosylation, resulting in protein misfolding and endoplasmic reticulum stress (Xi et al, 2014). In rat models, 2-DG was encountered as cardiac toxicity, with microscopic findings of vacuolar degeneration and hypertrophy of the endothelial cells of the endocardium (Terse et al, 2016). Studies in tumors have found that at low doses, 2-DG mainly interfered with N-linked glycosylation, resulting in endoplasmic reticulum stress, apoptosis, and autophagy.…”

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

“…The theoretically optimum 2-DG dose may be at the intersection of the two curves, where~70% slices will stop bursting and remain viable (horizontal dashed line), corresponding to~2.7 mM 2-DG (vertical dashed line). monitored and averted by following brain natriuretic peptide levels (Terse et al 2016). Therefore, 2-DG represents a unique compound with antiseizure and antiepileptic actions.…”