Toxicological Sciences | October 22, 2021

Sano T, Masuda Y, Yasuno H, Shinozawa T, Watanabe T and Kakehi M

Toxicol Sci. 2021

https://doi.org/10.1093/toxsci/kfab122

Abstract

Neurotoxicity is a principal concern in nonclinical drug development. However, standardized and universally accepted fluid biomarkers for evaluating neurotoxicity are lacking. Increasing clinical evidence supports the potential use of neurofilament light chain (NfL) as a biomarker of several neurodegenerative diseases; therefore, we investigated changes in the cerebrospinal fluid (CSF) and serum levels of NfL in SD rats treated with central nervous system (CNS) toxicants [trimethyltin (TMT, 10 mg/kg p.o., single dose), kainic acid (KA, 12 mg/kg s.c., single dose), MK-801 (1 mg/kg s.c., single dose)], and a peripheral nervous system (PNS) toxicant (pyridoxine, 1200 mg/kg/day for 3 days). Animals were euthanized 1 (Day 2), 3 (Day 4), or 7 days after administration (Day 8). Increased serum NfL was observed in TMT- and KA-treated animals, which indicated neuronal cell death in the brain on Day 2, 4, and/or 8. MK-801-treated animals exhibited no changes in the serum and CSF levels of NfL and no histopathological changes in the brain at any time point. Pyridoxine induced chromatolysis of the dorsal root ganglion on Day 2 and degeneration of peripheral nerve fiber on Day 4; additionally, serum NfL was increased. A strong correlation was observed between the serum and CSF levels of NfL and brain lesions caused by TMT and KA, indicating that NfL could be a useful biomarker for detecting CNS toxicity. Additionally, PNS changes were correlated with serum NfL levels. Therefore, serum NfL could serve as a useful peripheral biomarker for detecting both CNS and PNS toxicity in rats.