Selective vulnerability of axonal systems to acrylamide and 2,5-hexanedione toxicity

Abstract

Studies were conducted to determine if a selectjv~ vulnerability irrespective of axonal size occurs in the CNS with acrylamide {ACR} and in the PNS with another toxicant, 2,5-hexanedione {HD). In these studies two new and effective HD cat models have been introduced, the osmotic minipump and the subcutaneous injection models.. These models have an advantage ove~ the drinking water model previously used in that the rate of toxicant administration can be tightly controlled. By studying the behavioral consequences of HD intoxication it was. determined that the rate of toxicant administration is important in attaining a given behavioral deficit~ This contradicts previous reports. whi<:h. suggest that total HD dose,, and not the rate of toxicant administration, was the factor responsible for the behavioral and morphological changes· observed in HP toxicity •. These studies have added to the growing body of evidence. which directly opposes the classical hypothesis of selective vulnerability of axons in DA by suggesting that the largest diameter axons are not the most vulnerable to toxicant-induc·ed DA. In these studies smaller diameter axons were shown to be more vulnerable than the.largest diameter axons in the CNS utilizing ACR as the model toxicant, and in the peripheral nervous system utilizing HD. ACR impaired the ability to evoke a dorsal root reflex from the sural nerve {medium diameter) but not from the medial gastrocnemious nerve {largest diameter). HD affected the lengthfrequency response relationship. of secondary muscle spindle {Group II) to a greater extent than the primary muscle spindle (Group I). In addition, electron microscopic investigation of peripheral nerves from animals intoxicated with HD showed that unmyelinated fibers were undergoing degenerative changes at the same doses as myelinated axons of all diameters. An alternate hypothesis of selective vulnerability of slowly adapting systems in preference to rapidly adapting systems was also investigated. In these studies of primary muscle spindle afferent function (position and velocity sensitivity) and differential effect of HD on these two systems was not found. These data also suggested that a defect in muscle spindle afferent activity was not the genesis ·of the ataxia and motor incoordination induced by HD toxicity as was previously thought.