TY - JOUR
T1 - Neurotoxic Effects of Zoniporide
T2 - A Selective Inhibitor of the Na+/H+ Exchanger Isoform 1
AU - Pettersen, John C.
AU - Chouinard, Luc
AU - Kerlin, Roy L.
AU - Groom, Simon N.
AU - Botts, Suzanne
AU - Arezzo, Joseph C.
AU - Boucher, Mary A.
AU - Frazier, Donald E.
AU - Buchholz, Allan R.
PY - 2008/6
Y1 - 2008/6
N2 - Zoniporide, an inhibitor of the Na+-H+ exchanger-1, was administered by continuous intravenous infusion to rats and dogs for up to 1 month. In 1-month studies, histological and functional changes were observed in select portions of the peripheral nervous system; however, these findings were not detected in 2-week studies at similar or higher doses. In the 1-month rat study, there was dose-dependent, minimal, focal, or multifocal nerve fiber (axonal) degeneration in the spinal cord and/or sciatic nerve. In a follow-up rat study, findings included slowing of caudal nerve conduction velocity and axonal degeneration in the spinal cord (dorsal funiculus), dorsal roots, dorsal root ganglia (DRG), radial, sciatic, and tibial nerves. In the 1-month dog study, there was impairment of the patellar reflex and associated postural reaction changes, minimal to marked proximal nerve fiber degeneration in the DRG, and minimal nerve fiber degeneration in the dorsal roots and funiculi of the spinal cord. Minimal nerve fiber degeneration of equivocal significance was noted in various peripheral nerves. Taken together, these findings were consistent with a specific effect on peripheral sensory nerve fibers. These studies demonstrated that zoniporide produces clinical, electrophysiologic, and microscopic evidence of peripheral sensory axonopathy and establishes the importance of careful preclinical evaluation of neurological function.
AB - Zoniporide, an inhibitor of the Na+-H+ exchanger-1, was administered by continuous intravenous infusion to rats and dogs for up to 1 month. In 1-month studies, histological and functional changes were observed in select portions of the peripheral nervous system; however, these findings were not detected in 2-week studies at similar or higher doses. In the 1-month rat study, there was dose-dependent, minimal, focal, or multifocal nerve fiber (axonal) degeneration in the spinal cord and/or sciatic nerve. In a follow-up rat study, findings included slowing of caudal nerve conduction velocity and axonal degeneration in the spinal cord (dorsal funiculus), dorsal roots, dorsal root ganglia (DRG), radial, sciatic, and tibial nerves. In the 1-month dog study, there was impairment of the patellar reflex and associated postural reaction changes, minimal to marked proximal nerve fiber degeneration in the DRG, and minimal nerve fiber degeneration in the dorsal roots and funiculi of the spinal cord. Minimal nerve fiber degeneration of equivocal significance was noted in various peripheral nerves. Taken together, these findings were consistent with a specific effect on peripheral sensory nerve fibers. These studies demonstrated that zoniporide produces clinical, electrophysiologic, and microscopic evidence of peripheral sensory axonopathy and establishes the importance of careful preclinical evaluation of neurological function.
KW - Na/H exchanger
KW - nerve conduction velocity
KW - nerve fiber degeneration
KW - neurological examination
KW - neurotoxicity
KW - patellar reflex
KW - zoniporide
UR - http://www.scopus.com/inward/record.url?scp=49749084733&partnerID=8YFLogxK
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U2 - 10.1177/0192623308318215
DO - 10.1177/0192623308318215
M3 - Article
C2 - 18467682
AN - SCOPUS:49749084733
SN - 0192-6233
VL - 36
SP - 608
EP - 619
JO - Toxicologic pathology
JF - Toxicologic pathology
IS - 4
ER -