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

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.

Gene expression profiling in lung tissues from mice exposed to cigarette smoke, lipopolysaccharide, or smoke plus lipopolysaccharide by inhalation.

The purpose of this study was to investigate whether coexposure to lipopolysacchride (LPS) will heighten the inflammatory response and other pulmonary lesions in mice exposed to cigarette smoke, and thus to evaluate the potential use of this LPS-compromised mouse model as a model for chronic obstructive pulmonary disease (COPD) investigation. AKR/J male mice were exposed to HEPA-filtered air (sham control group), cigarette smoke (smoke group), LPS (LPS group), or smoke plus LPS (smoke-LPS group) by nose-only inhalation. Lungs were collected at the end of the 3-wk exposure and processed for microarray analysis. Clustering and network analysis showed decreased heat-shock response and chaperone activity, increased immune and inflammatory response, and increased mitosis in all three exposed groups. Two networks/function modules were exclusively found in the smoke-LPS group, that is, the downregulated muscle development/muscle contraction process and the upregulated reactive oxygen species production process. Notably, the number of genes and function modules/networks associated with inflammation was reduced in the smoke-LPS group compared to the LPS group. The most upregulated gene in the smoke group, MMP12, is a matrix metalloproteinase that preferentially degrades elastin and has been implicated in COPD development. NOXO1, which was upregulated in all three treatment groups, positively regulates the expression of a subunit of NADPH oxidase (NOX1), a major source of reactive oxygen species, and may play an important role in the pathogenesis of COPD. Serum amyloid A1, which is an acute-phase systemic inflammation marker and can be induced by LPS exposure, was significantly upregulated in the LPS and smoke-LPS groups. MARCO, a scavenger receptor expressed in macrophages that may play a significant role in LPS-induced inflammatory response, was upregulated in the LPS group and the smoke-LPS group, but not in the smoke group. In conclusion, gene expression profiling identified genes and function modules that may be related to COPD pathogenesis and may be useful as biomarkers to monitor COPD progression. In addition, an LPS-compromised mouse model showed potential as a useful tool for studying cigarette smoke-associated COPD.