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Neurotoxic Effects of Zoniporide: A Selective Inhibitor of the Na⁺/H⁺ Exchanger Isoform 1

¹ Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Groton, Connecticut, USA
² Charles River Laboratories, Preclinical Services, Montréal, Quebec, Canada
³ GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA
⁴ Albert Einstein College of Medicine, Departments of Neuroscience and Neurology, Bronx, New York, USA
⁵ Neurogen Corporation, Branford, Connecticut, USA

Correspondence: John C. Pettersen, Pfizer Global Research and Development, Groton/New London Laboratories, Drug Safety Research and Development, MS 8274–1254, Eastern Point Road, Groton, CT 06340, USA; e-mail:john.c.pettersen{at}pfizer.com

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.

Key Words: zoniporide • Na⁺/H⁺ exchanger • neurotoxicity • nerve fiber degeneration • nerve conduction velocity • patellar reflex • neurological examination

Abbreviations: NHE, sodium hydrogen exchanger • NHE-1, sodium hydrogen exchanger-1 • FOB, functional observational battery • NCV, nerve conduction velocity • CMAP, compound muscle action potential • CNS, central nervous system • PNS, peripheral nervous system • iv, intravenous • im, intramuscular • SEP, somatosensory evoked potential

This version was published on June 1, 2008

Toxicologic Pathology, Vol. 36, No. 4, 608-619 (2008)
DOI: 10.1177/0192623308318215


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