dl- versus meso-3,4-dimethyl-2,5-hexanedione: a morphometric study of the proximo-distal distribution of axonal swellings in the anterior root of the rat.
The neurotoxicity of the dl and meso diastereomers of the gamma-diketone 3,4-dimethyl-2,5-hexanedione (DMHD) was studied to determine if the difference in rates of pyrrole derivatization would influence the clinical and morphological appearance of the neuropathy associated with these gamma-diketones. Two groups of rats received 0.2 mmol/kg/day intraperitoneal injections of their respective diastereomer, and two groups of control rats received comparable volumes of water. The dl-DMHD treated group reached the clinical end-point of hindlimb paralysis in a period of time threefold shorter than the meso-DMHD treated group, paralleling the in vitro kinetics of pyrrole formation with a model amine. A computerized morphometric analysis of cross-sectional axonal areas along the lengths of L4 and L5 anterior roots revealed that the dl-DMHD treated rats had axonal swellings more proximal and of smaller caliber than the meso-DMHD treated rats. 14C-labeled dl and meso diastereomers were synthesized and used to determine relative ability of the diastereomers to gain access to the nervous system. There was approximately 25% more dl-DMHD in the brain after 2 hr. The brain:serum ratios of the diastereomers, however, were equivalent. The more distal location of the neurofilament-filled swellings after meso-DMHD intoxication corroborates previous findings regarding toxicant potency and location of axonal swellings and suggests that the rate of neurofilament crosslinking determines the location of swellings along the length of the axon in the neurofilamentous axonopathies.
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000648:ultrastructure; D005727:Ganglia, Spinal / Q000187:drug effects*; D006588:Hexanones / Q000633:toxicity*; D007536:Isomerism; D007659:Ketones / Q000633:toxicity*; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D006588:Hexanones; D007659:Ketones; C039195:3,4-dimethyl-2,5-hexanedione