title: Initial biological qualification of SBDP-145 as a biomarker of compound-induced neurodegeneration in the rat.
abstract: Detection of compound-related neurodegeneration is currently limited to brain histopathology in veterinary species and functional measurements such as electroencephalography and observation of clinical signs in patients. The objective of these studies was to investigate whether concentrations of spectrin breakdown product 145 (SBDP-145) in cerebrospinal fluid (CSF) correlate with the severity of neurodegeneration in rats administered neurotoxic agents, as part of a longer term objective of developing in vivo biomarkers of neurotoxicity for use in non-clinical and clinical safety studies. Non-erythroid alpha-II spectrin is a cytoskeletal protein cleaved by the protease calpain when this enzyme is activated by dysregulation of calcium in injured cells. Calcium dysregulation is also associated with some toxicological responses in animals, and may be sufficient to activate neuronal calpain and produce SBDPs that can be released into CSF. Neurotoxicants (kainic acid, 2-chloropropionic acid, bromethalin, and pentylenetetrazole) known to affect different portions of the brain were administered to rats in dose-response and time-course studies in which neurodegeneration was measured by histopathology and SBDP-145 concentrations in CSF were measured by ELISA. We consistently observed >3-fold increases in SBDP-145 concentration in rats with minimal to slight neurodegenerative lesions, and 20 to 150-fold increases in animals with more severe lesions. In contrast, compounds that caused non-degenerative changes in central nervous system (CNS) did not increase SBDP-145 in CSF. These data support expanded use of SBDP-145 as a biomarker for monitoring compound-induced neurodegeneration in pre-clinical studies, and support the investigation of clinical applications of this biomarker to promote safe dosing of patients with compounds that have potential to cause neurodegeneration.
authors.affiliation: Toxicology and Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana 46285 pritt_michael_l@lilly.com.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pritt
authors.affiliation: Toxicology and Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana 46285.
authors.forename: D Greg
authors.initials: DG
authors.lastname: Hall
authors.affiliation: Vet Path Services Inc., Mason, Ohio 45040.
authors.forename: William H
authors.initials: WH
authors.lastname: Jordan
authors.affiliation: Toxicology and Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana 46285.
authors.forename: Darryl W
authors.initials: DW
authors.lastname: Ballard
authors.affiliation: Center for Neuroproteomics & Biomarkers Research, Department of Psychiatry, University of Florida, Gainesville, Florida 32611.
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Wang
authors.affiliation: Neoclone, Madison, Wisconsin 53713.
authors.forename: Uwe R
authors.initials: UR
authors.lastname: Müller
authors.affiliation: Toxicology and Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana 46285.
authors.forename: David E
authors.initials: DE
authors.lastname: Watson
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D009410:Nerve Degeneration / Q000134:cerebrospinal fluid / Q000139:chemically induced* / Q000175:diagnosis*; D020258:Neurotoxicity Syndromes / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000209:etiology*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D011237:Predictive Value of Tests; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012720:Severity of Illness Index; D013049:Spectrin / Q000134:cerebrospinal fluid*; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; D013049:Spectrin
keywords: SBDP-145; biomarker; calpain; neurodegeneration; α-2-spectrin