Blood Neurofilament Light Chain as a Potential Biomarker for Central and Peripheral Nervous Toxicity in Rats

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.

Comparative analysis of neurofilament light chain levels in the serum and cerebrospinal fluid in rats subjected to partial sciatic nerve ligation

“…However, these studies lacked a comparison of peripheral nerve damage, including DRG lesions, to CSF NfL levels, especially from the perspective of the effects of DRG lesions on NfL levels. Conversely, we previously reported that a pyridoxine-induced sensory neuropathy model showed DRG and peripheral nerve changes, with apparent increased NfL levels in both the serum and CSF 5 . NfL is abundant in the axon and DRG 7,8 , and the DRG and its surrounding nerve fibers potentially communicate directly with the CSF in the subarachnoid space in rats 9 .…”

Circulating neurofilament light chain as a promising biomarker of AAV-induced dorsal root ganglia toxicity in nonclinical toxicology species

“…However, previous studies report increased NF-L in rats treated with various neurotoxicants (e.g., chloropropionic acid, acrylamide, trimethyltin, kainic acid), as well as rodent models of Huntington’s disease and pneumococcal meningitis. 33 , 34 , 35 , 36 Moreover, circulating NF-L was elevated in patients with traumatic brain injury (TBI) 37 , 38 , 39 and several neurodegenerative diseases including multiple sclerosis, Alzheimer’s disease, ALS, spinal muscular atrophy, and Guillain-Barré syndrome. 40 , 41 , 42 , 43 In each of these studies, NF-L was elevated in CSF as well as blood-derived biofluids.…”

Serum neurofilament light chain: a novel biomarker for early diabetic sensorimotor polyneuropathy

“…The efficacy of serum NFL as a biomarker of neuroaxonal damage emerged initially in multiple sclerosis, where it serves for prognosis and treatment monitoring [ 10 , 11 ]. Currently, there is growing scientific evidence associating serum NFL with other neurodegenerative diseases [ 12 ] and peripheral neuropathies in humans [ 13 – 25 ] and animals [ 26 – 28 ]. However, evidence of a potential association between NFL and DSPN is scarce.…”