Neurotoxicity of glycidamide, an acrylamide metabolite, following intraperitoneal injections in rats.
Acrylamide (2-propenamide) monomer produces central-peripheral distal axonopathy in humans and some animal species. Its neurotoxicity is characterized by abnormal sensation, decreased motor strength, and ataxia. Acrylamide forms adducts with glutathione, proteins, and DNA. Recent studies demonstrated that acrylamide is metabolized to its epoxide, glycidamide (2,3-epoxy-1-propanamide). We studied the neurotoxicity potential of glycidamide in male Sprague-Dawley rats. Animals (groups of 6) were injected ip daily with either aqueous acrylamide or glycidamide at an acrylamide-equivalent dose of 50 mg/kg (0.70 mmol/kg). Both treatments resulted initially in the rats circling, which was followed by the onset of ataxia at 7-9 d and hindlimb paralysis at 12-14 d. Treated animals showed muscle wasting. At termination, acrylamide- and glycidamide-treated rats weighed 105% and 86% of initial weight, respectively, compared to 145% for controls. Animals were anesthetized and perfused with 10% neutral phosphate-buffered formalin 12 or 14 d after beginning of treatment. Both treatment groups exhibited similar neuropathologic changes in the central and peripheral nervous systems. More severe lesions were produced by glycidamide. A marked increase in the number of affected Purkinje cells in the cerebellum, which exhibited changes ranging from pyknosis to cell death, were present. The brainstem exhibited axonal degeneration with chromatolytic necrosis in midbrain medial and lateral reticular nuclei. The spinal cord was characterized by spongy form changes with vacuoles of different sizes in various levels. These results suggest that glycidamide is an active neurotoxic metabolite of acrylamide.
Abou-Donia
M B
MB
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
Ibrahim
S M
SM
Corcoran
J J
JJ
Lack
L
L
Friedman
M A
MA
Lapadula
D M
DM
D020106:Acrylamide; D000178:Acrylamides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology*
D000178:Acrylamides; D004852:Epoxy Compounds; D020106:Acrylamide; C071834:glycidamide