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Evidence for multiple mechanisms responsible for 2,5-hexanedione-induced neuropathy.

Authors
Lapadula-DM; Suwita-E; Abou-Donia-MB
Source
Brain Res 1988 Aug; 458(1):123-131
NIOSHTIC No.
00213648
Abstract
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.
Keywords
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Ketones; Spinal-cord; In-vivo-studies; Laboratory-animals; Drinking-water; Protein-chemistry; Nerve-fibers; Immunochemistry
Contact
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
CODEN
BRREAP
CAS No.
110-13-4
Publication Date
19880616
Document Type
Journal Article
Funding Amount
1567389
Funding Type
Grant
Fiscal Year
1988
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-00823
Issue of Publication
1
ISSN
0006-8993
Priority Area
Neurotoxic Disorders; Neurotoxic-effects
Source Name
Brain Research
State
NC
Performing Organization
Duke University, Durham, North Carolina
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