Animal Models for Reye’s Syndrome

  • M. G. Murphy
  • S. C. Digout
  • J. F. S. Crocker
Part of the Neuromethods book series (NM, volume 22)


Reye’s Syndrome (RS) was first documented by Douglas Reye and colleagues in 1963 as an “encephalopathy with fatty degeneration of the viscera,” a rare entity, but one that at that time was associated with an 80% mortality rate (Reye et al., 1963). Although the apparent incidence and outcome of the disease have improved, it continues to be one of the major causes of noninflammatory neurologic death after a viral illness in children (Sullivan-Boylai and Corey, 1981; Heubi et al., 1987).


Octanoic Acid Viral Illness Serum Free Fatty Acid Serum Glutamic Oxaloacetic Transaminase Carbamyl Phosphate 
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  1. Brown R. E. and Forman D. T. (1982) The biochemistry of Reye’s Syndrome. CRC Crit. Rev. Clin. Lab. Sci. 17, 247–296.CrossRefGoogle Scholar
  2. Bourgeois C. H., Shank R. C., Grossman R. A., Johnsen D. O., Wooding W. L., and Chandavimol P. (1971) Acute aflatoxin B1 toxicity in the macaque and its similarity to Reye’s Syndrome. Lab. Invest. 24, 206–216.PubMedGoogle Scholar
  3. Brownstein D. G., Johnson E. A., and Smith A. L. (1984) Spontaneous Reye’s like syndrome in BALB/cByJ mice. Lab. Invest. 51, 386–395.PubMedGoogle Scholar
  4. Colon A. R., Ledesma B. S., Pardo V., and Sandberg D. H. (1974) Viral potentiation of chemical toxins in the experimental syndrome of hypoglycemia, encephalopathy, and visceral fatty degeneration. Am J. Dig. Dis. 19, 1091–1101.PubMedCrossRefGoogle Scholar
  5. Crocker J. F. S., Rozee K. W., Ozere R. L., Digout S. C., and Hutzinger O. (1974) Insecticide and viral interactions as a cause of fatty visceral changes and encephalopathy in the mouse. Lancet 2, 22–24.PubMedCrossRefGoogle Scholar
  6. Crocker J. F. S., Ozere R. L., Safe S. H., Digout S. C., Rozee K. R., and Hutzinger O. (1976) Lethal interaction of ubiquitous insecticide carriers with virus. Science 192, 1351–1353.PubMedCrossRefGoogle Scholar
  7. Crocker J. F. S. and Ozere R. L. (1979) The incidence and etiology of Reye’s Syndrome in eastern Canada, in Reye’s Syndrome II, (Crocker J. F. S., ed.), Grune and Stratton, NY, pp. 3–12.Google Scholar
  8. Crocker J. F. S. and Bagnell P. C. (1981) Reye’s syndrome: Clinical review. Can. Med Assoc. J. 124, 375–382.PubMedGoogle Scholar
  9. Crocker J. F. S. (1982) Reye’s Syndrome. Semin. Liver Dis. 2, 340–352.PubMedCrossRefGoogle Scholar
  10. Crocker J. F. S., Fung D., Hudson R., and Safe S. H. (1985) Examination of the role of surfactants in Reye’s Syndrome, in Reye’s Syndrome IV (Pollack J. D., ed.), The National Reye’s Syndrome Foundation, OH, pp. 135–140.Google Scholar
  11. Crocker J. F. S., Renton K. W., Lee S. H., Rozee K. R., Digout S. C., and Malatjalian D. A. (1986) Biochemical and morphological characteristics of a mouse model of Reye’s Syndrome induced by the interaction of influenza virus and a chemical emulsifier. Lab. Invest. 54, 32–40.PubMedGoogle Scholar
  12. Crocker J. F. S. (1988) Role of exogenous agents in Reye’s Syndrome in “Reye Syndrome” Royal Society of Medical Services. Round Table Series, No. 8, Oxford, England, pp. 45–52.Google Scholar
  13. Crocker J. F. S., Lee S. H. S., Love J. A., Malatjalian D. A., Renton K. W., Rozec K. R., and Murphy M. G. (1991) Surfactant-potentiated increases in intracranial pressure in a mouse model of Reye’s Syndrome. Exp. Neurol. 111, 95–97.PubMedCrossRefGoogle Scholar
  14. Daugherty C. C., Gartside P. S., Heubi J. E., Saalfeld K., and Snyder J. (1987) A morphometric study of Reye’s Syndrome. Correlation of reduced mitochondrial numbers and increased mitochondrial size with clinical manifestations. Am. J. Pathol. 129, 313–326.PubMedGoogle Scholar
  15. Davis L. E., Cole L. L., Lockwood S. J., and Kornfeld M. (1983) Experimental influenza B virus toxicity in mice. A possible model for Reye’s Syndrome. Lab. Invest. 48, 140–147.PubMedGoogle Scholar
  16. Davis L. E., Green C. L., and Wallace J. M. (1985) Influenza B virus model of Reye’s Syndrome in mice: The effect of aspirin. Ann. Neurol. 18, 556–559.PubMedCrossRefGoogle Scholar
  17. Davis L. E. (1986) Influenza B virus model of Reye’s Syndrome in mice: Review of clinical, biochemical and pathologic studies. J. Natl. Reye’s Synd. Found. 6, 43–50.Google Scholar
  18. Davis L. E. and Kornfeld M. (1986) Mouse influenza B virus model of Reye’s Syndrome. Encephalopathy and microvesicular fatty metamorphosis of the liver by influenza B virus following intravenous administration in mice. Am. J Physiol. 122, 190–192.Google Scholar
  19. Davis L. E. (1987) Influenza B virus model of Reye’s Syndrome. Evidence for a nonpermissive infection of liver and brain. Lab. Invest. 56, 32–36.PubMedGoogle Scholar
  20. DeLong G. R. and Glick T, H. (1982) Encephalopathy of Reye’s Syndrome: A review of pathogenic hypotheses. Pediatrics 69, 53–63.PubMedGoogle Scholar
  21. Deshmukh D. R., Maassab H. F., and Mason M. (1982) Interactions of aspirin and other potential etiologic factors in an animal model of Reye syndrome. Proc. Natl. Acad. Sci. 79, 7557–7560.PubMedCrossRefGoogle Scholar
  22. Deshmukh D. R., Deshmukh G. D., Shope T. C., and Radin N. S. (1983) Free fatty acids in an animal model of Reye’s Syndrome. Biochim. Biophys. Acta. 753, 153.PubMedGoogle Scholar
  23. Deshmukh D. R. and Thomas P. E. (1985) Arginine deficiency, hyperammonemia and Reye’s Syndrome in ferrets. Lab. Anim. Sci. 35, 242–245.PubMedGoogle Scholar
  24. Deshmukh D. R. (1985) Animal models of Reye’s Syndrome. Rev.Infect. Dis. 7, 31–40.PubMedCrossRefGoogle Scholar
  25. De Vivo D. C. (1984) Do animals develop Reye Syndrome? Lab. Invest. 51, 367–372.PubMedGoogle Scholar
  26. De Vivo D. C. (1986) Do animals develop Reye’s Syndrome? J. Natl. Reye’s Synd. Found. 6, 17–37.Google Scholar
  27. Ennis F. A., Well M. A., Barry D. W., Daniel S., and Manechevitz J. (1976) Host defence mechanisms against influenza infection. II. Protection of mice with vaccines against A/Port Chalmers/1/73 and B. Hong Kong/ S/72. Post Grad. Med. J. 52, 338–344.CrossRefGoogle Scholar
  28. Faraj B. A., Caplan D. B., Newman S. L., Ahmann P. A., Camp V. M., and Kutner M. (1984) Hypercatecholaminemia in Reye’s Syndrome. Pediatrics 73, 481–488.PubMedGoogle Scholar
  29. Frewen T. C. and Kisson N. (1987) Cerebral blood flow and brain oxygen extraction in Reye syndrome. J. Pediatr. 110, 903–905.PubMedCrossRefGoogle Scholar
  30. Gauthier M. D., Guay J., Lacroix J., and Lortie A. (1989) Reye’s syndrome: A reappraisal of diagnosis in 48 presumptive cases. Am. J. Dis. Child. 143, 1181–1185.PubMedGoogle Scholar
  31. Glasgow A. W. and Chase H. P. (1975) Production of the features of Reye’s Syndrome in rats with 4-pentenoic acid. Pediatr. Res. 9, 133–138.PubMedCrossRefGoogle Scholar
  32. Greene C. L., Blitzer M., and Shapira E. (1988) Inborn errors of metabolism and Reye Syndrome: Differential diagnosis. J Pediatr. 113, 156–159.PubMedCrossRefGoogle Scholar
  33. Hart M. A., Swisher J. A., and Caspers M. L. (1989) Alterations in plasma amino acids and hepatic enzymes in the 4-pentenoic acid model of Reye’s syndrome. Biochem. Pharmacol. 38, 1696–1698.PubMedCrossRefGoogle Scholar
  34. Heubi J. E., Partin J. C., Partin J. S., and Schubert W. K. (1987) Reye’s Syndrome: Current concepts. Hepatology 7, 155–164.PubMedCrossRefGoogle Scholar
  35. Hug G., Bosken J., Bove K., Linnemann C. C. Jr., and McAdams L. (1981) Reye’s Syndrome simulacra in liver of mice after treatment with chemical agents and encephalomyocarditis virus. Lab. Invest 45, 89–109.PubMedGoogle Scholar
  36. Hurwitz E. S. (1988) The changing epidemiology of Reye’s syndrome in the United States: Further evidence for a public health success. Am. Med. Assoc. 260, 3178–3180.CrossRefGoogle Scholar
  37. Kang E. S., Gates R. E., and Wrenn E. L. Jr. (1982) Abnormal cellular regulation of lipolysis and phosphorylation in Reye’s Syndrome. Biochem. Med. 27, 180–194.PubMedCrossRefGoogle Scholar
  38. Kang E. S., Olson G., Jabbour J. T., Solomon S. S., Heimberg M., Sabesin S., and Griffith J. F. (1984) Development of encephalopathic features similar to Reye Syndrome in rabbits. Proc. Natl. Acad. Sci. USA 81, 6169–6173.PubMedCrossRefGoogle Scholar
  39. Kilpatrick L. E., Polin R. A., Douglas S. D., and Corkey B. E. (1989) Hepatic metabolic alterations in rats treated with low-dose endotoxin and aspirin: An animal model of Reye’s Syndrome. Metabolism 38, 73–77.PubMedCrossRefGoogle Scholar
  40. Koga Y., Yoshida I., Kimura M., Yamashita F., and Sinniah D. (17) Inhibition of mitochondrial functions by margosa oil: Possible implications in the pathogenesis of Reye’s Syndrome. Pediatr. Res. 22, 184–187.CrossRefGoogle Scholar
  41. La Montagne J. R. (1983) Summary of a workshop on disease mechanisms and prospects for prevention of Reye’s Syndrome. J. Infect. Dis. 148, 943–950.PubMedGoogle Scholar
  42. Linnemann C. C. Jr., Ueda K., Hug G., Schaeffer, A., Clark A., and Schiff G. M. (1979) Salicylate intoxication and influenza in ferrets. Pediatr. Res. 13, 44–47.PubMedCrossRefGoogle Scholar
  43. Mamunes P., DeVries C. H., Miller C. O., and David R. B. (1975) Fatty acid quantitation in Reye’s Syndrome, in Reye’s Syndrome (Pollack J. D, ed.), Grune and Stratton, New York, pp. 245–254.Google Scholar
  44. McWilliam R. C. and Stephenson J. B. P. (1985) Life-threatening intracranial hypertension in Reye’s syndrome treated with intravenous thiopentone. Eur. J. Pediatr. 144, 383–384.PubMedCrossRefGoogle Scholar
  45. Mowat A. P. (1983) Reye’s Syndrome: 20 years on. Br. Med. J. 286, 1999–2001.CrossRefGoogle Scholar
  46. Murphy M.G., Archambault-Schertzer L., Ackman R. G., and Crocker J. F. S. (1986) Serum lipid abnormalities in a chemical/viral mouse model for Reye’s Syndrome. Lipids 21, 378–382.PubMedCrossRefGoogle Scholar
  47. Murphy M. G., Archambault-Schertzer L., VanKessel J., Digout S. C., Malatjalian D. A., and Crocker J. F. S. (1987) Hepatic lipid abnormalities in a chemical/viral mouse model for Reye’s Syndrome. Lipids 22, 217–223.PubMedCrossRefGoogle Scholar
  48. Murphy M. G., Digout S. C., and Crocker J. F. S. (1989) Encephalopathy of Reye Syndrome. Studies of the pathogenetic process in animal models, in Hepatic Encephalopathy. (Butterworth R. F. and Pomier Layrargves G., eds.), Humana Press, Clifton, NJ, pp. 245–259.Google Scholar
  49. Nara T., Tsukiyama T., and Nishimoto H. (1988) The neuron-specific enolase as a marker of brain destruction in a case of Reye’s Syndrome: Related to the treatment of brain edema. Acta Paediatr. Scand. 77, 912, 913.PubMedCrossRefGoogle Scholar
  50. Ogbum P. L. Jr. (1976) Medium and long chain serum free fatty acids in a case of Reye’s Syndrome. South. Med. J. 69, 632, 633.Google Scholar
  51. Ogbum P. L. Jr., Sharp H., Lloyd-Still J. D., Johnson S. B., and Holman R. T. (1982) Abnormal polyunsaturated fatty acid patterns of serum lipids in Reye’s syndrome. Proc. Natl. Acad. Sci. USA 79, 908–911.CrossRefGoogle Scholar
  52. Partin J. S., McAdams A. J., Partin J. C., Schubert W. K., and McLaurin R. L. (1978) Brain ultrastructure in Reye’s Syndrome. Acute injury and recovery processes in three children. Neuropathol. Exp. Neurol. 37, 796–819.CrossRefGoogle Scholar
  53. Pranzatelli M. R. and De Vivio D. C. (1987) Pharmacology of Reye Syndrome. Clin. Neuropharmacol. 10, 96–125.PubMedCrossRefGoogle Scholar
  54. Quint P. A. K. and Allman F. D. (1984) Differentiation of chronic salicylism from Reye Syndrome. Pediatrics 74, 1117–1119.PubMedGoogle Scholar
  55. Rarey K. E., Davis J. A., and Deshmukh D. R. (1987) Response of epithelial cells of the choroid plexus in the ferret model for Reye’s Syndrome. Lab. Invest. 56, 249–255.PubMedGoogle Scholar
  56. Reye B. D. K., Morgan G., and Baral J. (1963) Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood. Lancet 2, 749.PubMedCrossRefGoogle Scholar
  57. Robinson B. H., Taylor J., Cutz E., and Gall D. G. (1978) Reye’s Syndrome: Preservation of mitochondrial enzymes in brain and muscle compared with the liver. Pediatr. Res. 12, 1045–1047.PubMedCrossRefGoogle Scholar
  58. Roe C. (1988) Metabolic disorders producing a Reye-like Syndrome in “Reye’s Syndrome” (C. Wood, ed.) Round Table Series No. 8, Royal Society of Medical Services, Oxford, England, pp. 85–101.Google Scholar
  59. Rogan W. J., Yang G. C., and Kimbrough R. D. (1985) Aflatoxin and Reye’s Syndrome: A study of livers from deceased cases. Arch. Environ. Health 40, 91–95.PubMedGoogle Scholar
  60. Romshe C. A., Hilty M. D., McClung H. J., Kerzner B., and Reiner C. E. (1981) Amino acid pattern in Reye Syndrome: Comparison with clinically similar entities. J. Pediatr. 98, 788–790.PubMedCrossRefGoogle Scholar
  61. Rozee K. R., Lee S. H. S., Crocker J. F. S., and Safe S. (1978) Enhanced virus replication in mammalian cells exposed to commercial emulsifiers. Appl. Environ. Microbiol. 35, 297–300.PubMedGoogle Scholar
  62. Schwarz K. B., Larroya S., Kohlman L., and Morrison A. (1987) Erythrocyte lipid abnormalities in Reye’s Syndrome. Pediatr. Res. 21, 352–356.PubMedCrossRefGoogle Scholar
  63. Sinniah D., Baskaran G., and Leong K. L. (1981) Detoxification of margosa oil causing Reye’s syndrome. IRCS Med. Sci. 9, 369.Google Scholar
  64. Sinniah D. and Baskaran G. (1981) Margosa oil poisoning as a cause of Reye’s syndrome. Lancet 1, 487–489.PubMedCrossRefGoogle Scholar
  65. Sinniah D., Baskaran G., Looi L. M., and Leong K. L. (1982) Reye-like syndrome due to margosa oil poisoning: Report of a case with postmortem findings. Am. J. Gastroenterol 77, 158–161.PubMedGoogle Scholar
  66. Sinniah D., Schwartz P. H., Mitchell R. A., and Arcinue E. L. (1985) Investigation of an animal model of a Reye-like syndrome caused by margosa oil. Pediatr. Res. 19, 1346–1355.PubMedCrossRefGoogle Scholar
  67. Sullivan-Boylai J. Z. and Corey L. (1981) Epidemiology of Reye’s Syndrome. Epidemiol. Rev. 3, 1–26.Google Scholar
  68. Tanaka K., Isselbacher K. J., and Sheh V. (1972) Isovaleric and alpha-methylbutyric acidemias induced by hypoglycin A: Mechanism of Jamaican vomiting sickness. Science 175, 69–71.PubMedCrossRefGoogle Scholar
  69. Tang T. T., Siegesmund K. A., Sedmak G. V., Casper J. T., Varma R. R., and McCreadie S. R. (1975) Reye Syndrome. A correlated electron-microscopic, viral, and biochemical observation. Am. Med. Assoc. 232, 1339–1346.CrossRefGoogle Scholar
  70. Taubman B., Hale D. E., and Kelley R. I. (1987) Familial Reye-like Syndrome: A presentation of medium-chain acyl-coenzyme A dehydrogenase deficiency. Pediatrics 79, 382–385.PubMedGoogle Scholar
  71. Taylor D. A., Bagnell P. C., Renton K. W., and Crocker J. F. S. (1979) Intracellular changes induced by emulsifier-virus interaction in vivo and in vitro in the mouse, in Reye’s Syndrome II (Crocker J. F. S., ed.), Grune and Stratton, New York, pp. 459–472.Google Scholar
  72. Thayer W. S. (1984) Inhibition of mitochondrial fatty acid oxidation in pentenoic acid-induced fatty liver. A possible model for Reye’s Syndrome. Biochem. Pharmacol. 33, 1187–1194.PubMedCrossRefGoogle Scholar
  73. Thurlow P. M., Desau R. K., Newberne P. M., and Brown H. (1980) Aflatoxin B1 acute effects on three hepatic urea cycle enzymes using semi-automated methods: A model for Reye’s syndrome. Toxicol. Appl Pharmacol. 53, 293–298.PubMedCrossRefGoogle Scholar
  74. Tonsgard J. H. (1989) Effect of Reye’s Syndrome serum on the ultrastructure of isolated liver mitochondria. Lab Invest. 60, 568–573.PubMedGoogle Scholar
  75. Trauner D. A., Nyhan W. L., and Sweetman L. (1975) Short-chain organic acidemia and Reye’s Syndrome. Neurology 25, 296–298.PubMedGoogle Scholar
  76. Trauner D. A. and Huttenlocher P. R. (1978) Short-chain fatty acid induced central hyperventilation in rabbits. Neurology 28, 940–944.PubMedGoogle Scholar
  77. Trauner D. A. and Adams H. (1981) Intracranial pressure elevations during octanoate infusion in rabbits: An experimental model of Reye’s Syndrome. Pediatr. Res. 15, 1097–1099.PubMedGoogle Scholar
  78. Trauner D. A. (1982) Pathologic changes in a rabbit model of Reye’s Syndrome. Pediatr. Res 16, 950–953.PubMedCrossRefGoogle Scholar
  79. Trauner D. A., Horvath E., and Davis L. E. (1988) Inhibition of fatty acid beta oxidation by influenza B virus and salicylic acid in mice: Implications for Reye’s syndrome. Neurology 38, 239–241.PubMedGoogle Scholar
  80. Venes J. L., Shaywitz B. A., and Spencer D. D. (1978) Management of severe cerebral edema in the metabolic encephalopathy of Reye Johnson syndrome. J. Neurosurg. 48, 903–915.PubMedCrossRefGoogle Scholar
  81. Yoder M. C., Egler J. M., Yudkoff M., Chatten J., Douglas S. D., and Polin R. A. (1985) Metabolic and mitochondrial changes that mimic Reye Syndrome after endotoxin administration to rats. Infect. Immun. 47, 329–331.PubMedGoogle Scholar

Copyright information

© The Humana Press Inc 1992

Authors and Affiliations

  • M. G. Murphy
    • 1
  • S. C. Digout
    • 2
  • J. F. S. Crocker
    • 2
  1. 1.Department of Physiology and BiophysicsDalhousie UniversityHalifaxCanada
  2. 2.Department ofPediatricsDalhousie UniversityHalifaxCanada

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