Development of encephalopathic features similar to Reye syndrome in rabbits.

Abstract

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 (20:2wo6) 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 18:1w9, 18:2w6, 18:3a3, 20:3w6, 20:4o6, and 22:4w6 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.Reye syndrome is a rare but clinically important childhood encephalopathy of unknown origin associated with fatty visceral changes and complex metabolic abnormalities (1, 2). The encephalopathy is a progressive one with four or five stages "each correlating with progressive rostral-caudal central nervous system involvement" as first recognized by Several animal models have been proposed, including the use of a specific inhibitor of fatty acid oxidation (7), the infusion of those metabolites that are found in increased concentrations in the blood of affected patients (8, 9), and the inoculation of animals with viruses, either alone or in conjunction with special diets or prior exposure of the animals to chemicals (10-13). Fatty liver formation and biochemical evidence of liver dysfunction have been observed in each of these models. However, from the neurological point of view, only minimal, nonprogressive changes or, alternatively, collapse and death have been reported. In some instances, the infusion of glucose reversed or prevented these neurological abnormalities (7). Such features are in contrast to t...

Erythrocyte Lipid Abnormalities in Reye's Syndrome

“…There were several notable differences in RBC phospholipid fatty acids between RS patients (nos. [8][9][10][11][12][13][14] and ICU controls during the first 48 h of hospital admission. In …”

“…In vitro and in vivo experiments in animals have demonstrated that polyunsaturated fatty acids can cause cerebral edema ( 6 4 , a cardinal clinical feature of RS. In a rabbit model of RS, Kang et al (9) have shown that intracisternal injection of free PUFA leads to a reproducible dose-titratable encephalopathy; they and others have proposed that PUFA may be acting as toxins in RS. There have been no attempts to measure the lipid profile of any tissue during acute RS. Since the majority of PUFA in the cells is in phospholipids, we believe tissue lipid analysis could add to the understanding of the role of PUFA in this syndrome.…”

Octanoic Acid Inhibits Astrocyte Volume Control: Implications for Cerebral Edema in Reye's Syndrome

“…Pathological changes in the brain and liver and a poor neurological outcome are correlated with elevations in levels of serum fatty acids and ammonia (DeLong and Glick, 1982;Heubi et al, 1984;Dezateux et al, 1986). In animal models, administration of octanoic acid, other short-to medium-chain-length fatty acids, or polyunsaturated fatty acids can mimic the neuropathological changes of Reye's syndrome (Glasgow and Chase, 1975;Trauner, 1982;Kang et al, 1984).…”