Evidence for multiple mechanisms responsible for 2,5-hexanedione-induced neuropathy.
Lapadula-DM; Suwita-E; Abou-Donia-MB
Brain Res 1988 Aug; 458(1):123-131
The roles of protein crosslinking and phosphorylation in 2,5- hexanedione (110134) (25HD) induced neuropathy were studied in rats. Male Sprague-Dawley-rats were administered 0.1, 0.25, 0.50, or 1% 25HD in their drinking water for up to 70 days. They were observed for clinical signs of toxicity. Surviving animals were killed at the end of the study and the spinal cords were removed. The neurofilament proteins were isolated and examined by two dimensional polyacrylamide gel electrophoresis, histochemical techniques, and immunoblotting using antineurofilament protein antibodies to evaluate changes in neurofilament protein expression and crosslinking. The extent of phosphorylation was determined by a radioimmunoassay technique. 25HD at 1% caused hindlimb paralysis and 90% mortality. The 0.25 and 0.5% doses caused mild to severe ataxia. The 0.1% dose did not cause any overt signs of toxicity. 25HD at 0.25 to 1% caused significant decreases in staining for neurofilament proteins having molecular weights of 210, 160, and 70 kilodaltons (kDa). The 210kDa protein was affected the most. Significant protein crosslinking was induced by all 25HD doses. The extent of protein phosphorylation was significantly decreased in a dose dependent manner. All neurofilament proteins appeared to be shifted to an isoelectric point indicative of greater basicity. 25HD decreased the concentrations of low molecular weight immunoreactive proteins, indicating that neurofilament proteolysis was inhibited. The authors conclude that 25HD induced neuropathy appears to involve decreased neurofilament protein phosphorylation, decreased neurofilament proteolysis, and enhanced neurofilament crosslinking. Protein dephosphorylation probably occurs prior to crosslinking.
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Ketones; Spinal-cord; In-vivo-studies; Laboratory-animals; Drinking-water; Protein-chemistry; Nerve-fibers; Immunochemistry
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
Neurotoxic Disorders; Neurotoxic-effects
Duke University, Durham, North Carolina