Brain Research, 483 (1989) 1-11 1 Elsevier BRE 14327 Research Reports Effect of exogenous pyruvate on acrylamide neuropathy in rats Mohammad I. Sabri I , Wallace Dairman 2, Monica Fenton I , Laslo Juhasz 2, Thomas Ng 3 and Peter S. Spencer 1 1Center for Research and Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland, OR 97201 (U. S.A.), 2Department of Toxicology and Experimental Pathology, Hoffmann-La Roche, Nutley, NJ 07110 (U.S.A.) and 3Department of Neurology, New York University Medical Center, New York, NY lO032 (U.S.A.) (Accepted 23 August 1988) Key words: Acrylamide; Neuropathy; Neurotoxicity; Retrograde axonal transport The protective effect of exogenous sodium pyruvate on the distal-proximal progression of experimental acrylamide neuropathy in rats was examined. Incorporation of 2% (w/w) sodium pyruvate powder in the diet of rats receiving subcutaneous injections of an aqueous solution of acrylamide (35 mg/kg/day, 5 days/week) retarded the onset and development of functional, morphological, and biochemical measures of acrylamide neuropathy. Pyruvate supplementation did not alter hexobarbital sleep time or zoxazolamine pa- ralysis time, two in vivo measures of microsomal mixed-function oxidase activity, and the disposition of radioactivity in plasma or sci- atic nerve following subcutaneous injection of [14C]acrylamide. Although acrylamide can interfere with energy metabolism at a vari- ety of sites where pyruvate can rescue neurons (axons), the data of this study are consistent with our earlier hypothesis that acrylamide neuropathy may be associated with a glycolytic deficit. The exact site of pyruvate protection is unknown. Exogenous pyruvate is per- haps utilized by axons to circumvent toxin-induced glycolytic inhibition and provide chemical energy for fast axonal transport. INTRODUCTION Repeated exposure to acrylamide, a reactive vinyl monomer of the commercially important polymer, polyacrylamide, is known to produce peripheral neu- ropathy in humans 9'16'35. Neuropathological studies of experimental acrylamide neuropathy have re- vealed distal axonal degeneration of long fibers in pe- ripheral nerves and spinal cord of laboratory ani- mals 8'23'29'37. The mechanisms underlying this and other types of central-peripheral distal axonopathy are unknown 2°'33'36, although disruption of the ener- gy-dependent axonal transport system has been pro- posed 34. Several investigators have shown that acryl- amide selectively inhibits certain glycolytic enzymes, both in vitro and in vivo 11-13,24, but it is unclear whether enzyme inhibition precedes or merely ac- companies axonal degeneration. Others have re- ported that acrylamide fails to inhibit glycolytic en- zymes 3'39, and instead produces specific inhibition of oxidative enzymes 3°. Thus, the mechanism by which acrylamide dose-dependently impairs retrograde ax- onal transport 14,18-21 as well as anterograde trans- port, and induces distal axonal degeneration, re- m a i n s o b s c u r e 4'10'27'31'32'40'41. In vitro studies have shown that inhibition of glyc- eraldehyde-3-phosphate dehydrogenase (GAPDH) by iodoacetate perturbs fast axonal transport as a function of declining levels of adenosine triphosphate (ATP) and creatine phosphate (Cp)26; supplementa- tion with pyruvate allows the nerve to bypass the blockade in energy transformation pathways and re- store axonal transport by providing an alternative substrate for the generation of ATP and C P 22'26. Thus, if acrylamide perturbs axonal transport and causes neuropathy by disrupting glycolysis, exo- genous pyruvate might arrest or retard the develop- ment of acrylamide neuropathy by acting as an alter- native substrate of oxidative metabolism. We have examined the effect of dietary pyruvate on the course Correspondence: M.I. Sabri, Center for Research and Occupational and Environmental Toxicology, Oregon Health Sciences Uni- versity, 3181 S.W. Sam Jackson Park Road, L474, Portland, OR 97201, U.S.A. 0006-8993/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)