Ferrets are uniquely susceptible to human influenza infections and when they are exposed to an arginine-free diet, hyperammonemia and encephalopathy develops. We developed an animal model for Reye's syndrome (RS) in young, male ferrets by infecting them with influenza B virus, treating with aspirin and feeding a small amount of arginine-free diet. We plan to continue our study of the ferret model to extend the knowledge of the pathogenesis of Reye's syndrome and to improve the diagnosis, treatment and prevention of this disorder. Our study is also designed to gain new information on the dietary, metabolic and ultrastructural features of young, adult ferrets. We plan to (1) study the role of ammonia in RS. We plan to induce hyperammonemia in young ferrets by different means and study the interactions of influenza virus with aspirin and increased serum ammonia in producing RS-like disorder in ferrets; (2) investigate vomiting as a precipitating factor in the developmet of RS; (3) identify a possible causal relationsiip between aspirin ingestion and the development of RS-like features in ferrets. We also plan to test whether influenza virus or ammonia or both either blocks or alters the metabolism and pharmacokinetics of salicylates; (4) study the nature and cause of mitochondrial injury in RS; (5) We propose that all mitochondrial enzymes that are known to decrease in the liver of RS patients may appear in blood. To test this hypothesis we plan to assay several mitochondrial enzymes in the serum or plasma of RS patients during the course of illness and study the correlation of enzyme activities with serum ammonia levels and also with the stages of disorder (severity of sickness). We also plan to test other hypotheses to explain the decrease in liver motochondrial enzymes in RS; (6) test possible alterations of polyamine metabolism in RS. We plan to measure polyamines in the serum and urine of RS patients and test whether such determinations would be useful as an additional diagnostic criteria for RS; (7) test the role of L-carnitine as a therapeutic agent in RS; (8) study virologic and immunologic features of the ferret model; (9) measure additional parameters in the ferret model to provide a complete comparison of the model with RS and to further characterize the disorder in animals; (10) test compounds that may decrease blood ammonia levels and intracranial pressure; (11) use the ferret model to guide studies designed to improve the diagnosis, treatment and prevention of RS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI020236-04
Application #
3129750
Study Section
Neurology C Study Section (NEUC)
Project Start
1983-07-01
Project End
1989-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Marescau, B; Deshmukh, D R; Kockx, M et al. (1992) Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals. Metabolism 41:526-32
Deshmukh, D R; Meert, K; Sarnaik, A P et al. (1991) Guanidino compound metabolism in arginine-free diet induced hyperammonemia. Enzyme 45:128-36
Deshmukh, D R; Singh, K R; Meert, K et al. (1990) Failure of L-carnitine to protect mice against hyperammonemia induced by ammonium acetate or urease injection. Pediatr Res 28:256-60
Deshmukh, D R; Rusk, C D (1989) Effects of arginine-free diet on urea cycle enzymes in young and adult ferrets. Enzyme 41:168-74
Deshmukh, D R; Mungre, S M (1989) Purification and properties of 2-aminoadipate: 2-oxoglutarate aminotransferase from bovine kidney. Biochem J 261:761-8
Deshmukh, D R; Shope, T C; Sarnaik, A P (1987) Serum isocitrate dehydrogenase activity in Reye's syndrome. Biochem Med Metab Biol 37:255-7
Thomas, P E; Deshmukh, D R (1986) Effect of arginine-free diet on ammonia metabolism in young and adult ferrets. J Nutr 116:545-51
Deshmukh, D R; Thomas, P E; McArthur, B et al. (1985) Serum glutamate dehydrogenase and ornithine carbamyl transferase in Reye's syndrome. Enzyme 33:171-4
Deshmukh, D R; Thomas, P E (1985) Arginine deficiency, hyperammonemia and Reye's syndrome in ferrets. Lab Anim Sci 35:242-5
Deshmukh, D R (1985) Animal models of Reye's syndrome. Rev Infect Dis 7:31-40