Qualification of Cardiac Troponin I Concentration in Mouse Serum Using Isoproterenol and Implementation in Pharmacology Studies to Accelerate Drug Development

Abstract

Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. Additional attributes, including low cost and rapid turnaround time, made cTnI concentration in serum invaluable for detecting cardiotoxicity, exploring structureactivity relationships, and prioritizing development of compounds with improved safety profiles early in drug discovery.

ATP-binding cassette transporter Abcg2 lineage contributes to the cardiac vasculature after oxidative stress

“…This chemical was chosen as a simple and effective agent for generating cellular oxidative stress levels without concomitant tissue injury. To date, there has not been a suitable alternative for an in vivo oxidative stress model without tissue injury (1,3,6,8,12,29,32,38). As reported in previous studies (2, 4) using PQ to generate high-level ROS to mimic disease systems, we observed a significant increase in oxidative stress markers in cardiac tissue within hours of treatment.…”

Beta-Adrenoreceptor Agonism Influences Retinal Responses to Hypoxia in a Model of Retinopathy of Prematurity

“…16 In the present study, isoproterenol was given at low doses (0.1 and 0.5 mg kg À1 dose À1 ) to reduce the incidence of cardiovascular side effects. 19,20 In addition, the mouse strain used in the present study has been reported to be resistant to isoproterenolinduced cardiac damage. 26 In OIR mice, isoproterenol, dissolved in sterile saline, was given two times a day subcutaneously from PD12 to PD16.…”

“…Isoproterenol was subcutaneously administered according to previous studies in mice. 19,20 In this respect, subcutaneous delivery of noradrenergic drugs seems to be effective in influencing hypoxia-induced retinal neovascularization. 9 On the other hand, isoproterenol can induce cardiovascular alterations, 21 which, in turn, may influence retinal angiogenesis.…”

The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of pancreatic toxicity in the rat and dog

“…Additional markers of hepatotoxicity are currently under investigation [6]. Cardiac troponin I is a sensitive and specific serum based biomarker of cardiac injury in humans and mice and has been employed to mitigate cardiac toxicity in mouse toxicology studies with novel kinase inhibitors [7]. Urine based biomarkers for evaluation of renal toxicity include BUN (blood urea nitrogen), creatinine, urinary albumin, KIM-1 (kidney injury molecule-1), NGAL (neutrophil gelatinase associated lipocalin) and cystatin C [8].…”