RESUMO
Identifying compounds that are neurotoxic either toward the central or the peripheral nervous systems (CNS or PNS) would greatly benefit early stages of drug development by derisking liabilities and selecting safe compounds. Unfortunately, so far assays mostly rely on histopathology findings often identified after repeated-dose toxicity studies in animals. The European NeuroDeRisk project aimed to provide comprehensive tools to identify compounds likely inducing neurotoxicity. As part of this project, the present work aimed to identify diagnostic non-invasive biomarkers of PNS toxicity in mice. We used two neurotoxic drugs in vivo to correlate functional, histopathological and biological findings. CD1 male mice received repeated injections of oxaliplatin or paclitaxel followed by an assessment of drug exposure in CNS/PNS tissues. Functional signs of PNS toxicity were assessed using electronic von Frey and cold paw immersion tests (oxaliplatin), and functional observational battery, rotarod and cold plate tests (paclitaxel). Plasma concentrations of neurofilament light chain (NF-L) and vascular endothelial growth factor A (VEGF-A) were measured, and histopathological evaluations were performed on a comprehensive list of CNS and PNS tissues. Functional PNS toxicity was observed only in oxaliplatin-treated mice. Histopathological findings were observed dose-dependently only in paclitaxel groups. While no changes of VEGF-A concentrations was recorded, NF-L concentrations were increased only in paclitaxel-treated animals as early as 7 days after the onset of drug administration. These results show that plasma NF-L changes correlated with microscopic changes in the PNS, thus strongly suggesting that NF-L could be a sensitive and specific biomarker of PNS toxicity in mice.
RESUMO
The aim of this study was to further investigate the mechanism of development of cardiac lesions occurring under treatment with milrinone in dogs, by using echocardiography for assessing the effects of this drug on cardiac function. Milrinone is a cAMP phosphodiesterase 3 inhibitor having positive inotropic and vasodilatory effects. We treated groups of three dogs with milrinone at a single dose of 0.5 or 1 mg/kg and recorded M-mode and Doppler parameters at different time points before and after treatment. The hearts of the high-dose animals were histopathologically examined. The treatment with milrinone at 1 mg/kg produced mild cardiac lesions at two different locations. In the left ventricle, haemorrhages in the subendocardium and myocardium occurred in all three dogs. In the right atrium, subepicardial haemorrhages occurred in one dog and inflammation of the epicardium was observed in two dogs. These lesions were considered to be related to changes in the cardiac function, which were investigated by echocardiography. Milrinone treatment produced a moderate tachycardia and changes in M-mode parameters indicating an increase in contractility, in particular, a decrease in end-systolic volume, an increase in ejection fraction and an increase in the rate of circumferential fiber shortening. In addition, there was an increase in the maximal aortic flow velocity evaluated by Doppler measurements, which is thought to represent a haemodynamic correlate of an increase in left ventricular contractility. This increase in myocardial work is considered to play a key role in the development of the lesions observed in the left ventricle. Doppler measurements also revealed changes in the right atrioventricular flow, probably resulting from cardiac stimulation produced by milrinone. In particular, there was an increase in the Vmax of the A-wave of the tricuspid flow, suggesting an increase in contractility of the right atrium. This change, by increasing blood flow in atrial wall, may be involved in the induction of the lesions observed in the right atrium. In conclusion, Doppler and M-mode echocardiography are useful tools to assess haemodynamic changes occurring upon treatment with vasodilators or cardiac stimulants in order to further understand the mechanism of development of cardiac lesions produced by such compounds.
