Development of encephalopathic features similar to Reye syndrome in rabbits.
The progression of neurological abnormalities through four or five clinically distinguishable levels of deepening coma and the development of a fatty liver are the hallmarks of Reye syndrome. A number of animal models have been described that result in fatty liver formation with minimal, static, or catastrophic neurological changes. In this study, we attempted to produce neurological features in rabbits that reflected a rostral-caudal progression of abnormalities that could be categorized into clinically distinguishable levels reminiscent of Reye syndrome. This was accomplished by the intracisternal administration of 0.5-25 mg of 11,14-icosadienoic acid (20:2 omega 6) suspended in a mixture of rabbit serum and isotonic saline solution. A reproducible, dose-titratable spectrum of at least four levels of deepening coma could be produced at will. Increases in serum glutamate-oxaloacetate transaminase and creatine kinase and changes in serum glucose resulted 1-2 hr after the neurological abnormalities were evoked. Other unsaturated fatty acids produced similar responses. Those tested included 18:1 omega 9, 18:2 omega 6, 18:3 omega 3, 20:3 omega 6, 20:4 omega 6, and 22:4 omega 6 fatty acids. Saturated fatty acids, including 6:0, 8:0, 16:0, 18:0, and 20:0, failed to elicit these effects. The abnormalities were sustained for 30-120 min after a single dose. Full recovery was observed in some animals that had not reached the fourth level of our grading system for coma. Pretreatment of the rabbits with aspirin modulated the neurological abnormalities. Twenty micrograms of bee venom melittin, which activates endogenous phospholipase A2, administered intracisternally into rabbits also produced signs of level 3 (our grading system) coma for several hours. These findings suggest a possible role for polyunsaturated fatty acids in the development of Reye syndrome and offer a means of producing the neurological components of that syndrome in a laboratory animal.
D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000633:toxicity; D005231:Fatty Acids, Unsaturated / Q000633:toxicity; D008297:Male; D009420:Nervous System / Q000503:physiopathology; D011187:Posture; D011817:Rabbits; D012202:Reye Syndrome / Q000503:physiopathology*; D012640:Seizures / Q000503:physiopathology
D005230:Fatty Acids, Nonesterified; D005231:Fatty Acids, Unsaturated; D000082:Acetaminophen; D001241:Aspirin