Structural basis of γ-diketone neurotoxicity: Non-neurotoxicity of 3,3-dimethyl-2,5-hexanedione, a γ-diketone incapable of pyrrole formation

The chronic exposure to γ-diketones results in the formation of giant neurofilament (NF)-containing axonal enlargements, followed by axonal degeneration in peripheral axons. Based on the specific ability of γ-diketones to react with primary amino groups to form pyrroles, and the observation of such reaction with NF protein in vitro and with other proteins in vivo , it has been proposed that pyrrole formation at primary amino groups of NF protein is responsible for the neurotoxicity of γ-diketones. We have tested this hypothesis through an investigation of the neurotoxicity in rats of 3,3-dimethyl-2,5-hexanedione (3,3-DMHD), a γ-diketone which is incapable of forming pyrroles. 3,3-DMHD was found to produce only a slight alteration of axonal caliber and no clinical neurotoxicity after up to 12 weeks of administration, at a dose over 20 times that for which its isomer 3,4-dimethyl-2,5-hexanedione (3,4-DMHD) produced massive focal NF-containing axonal enlargements and complete paralysis in 4 weeks. These results support the view that the pyrrole-forming capability of γ-diketones is the initial molecular event in the pathogenesis of γ-diketone neurotoxicity.