Cytoskeletal disorganization induced by local application of β,β′‐iminodipropionitrile and 2,5‐hexanedione

β,β′‐Iminodipropionitrile and 2,5‐hexanedione are neurotoxins that produce neurofilamentous axonal swellings. The swellings produced experimentally with these agents are similar in structure but different in distribution. Neither the relationships between these agents nor the mechanisms of action are known. In this study local effects on nerve fibers were compared following injection of β′‐iminodipropionitrile and 2,5‐hexanedione beneath the perineurium of rat sciatic nerves. Soon after injection, 2,5‐hexanedione reproduced the distinctive cytoskeletal disorganization previously described with β′‐iminodipropionitrile: microtubules collected into a central channel, with neurofilaments segregated in a surrounding subaxolemmal ring. Later, the β′‐iminodipropionitrileinjected nerves developed local neurofilament accumulations, reproducing the neurofilamentous axonal swellings characteristic of systemic intoxication with these agents. The results indicate that both these agents have direct local effects on the axonal cytoskeleton and probably are similar in mechanism of action. Both these agents appear to segregate neurofilaments from the rest of the axonal cytoskeleton. This segregation may prevent the normal proximal‐to‐distal transport of neurofilaments, resulting in the formation of neurofilamentous axonal swellings.