Naturally occurring scrapie is associated with a lower CBG binding capacity in ewes

Naturally scrapie-affected ewes present a syndrome of hypercortisolism as e valuated by measuring total plasma cortisol concentrations. The objective o f this study was to investigate the plasma protein binding of cortisol and to evaluate the concentration of the biologically active free fraction of c ortisol in scrapie-affected ewes. Corticosteroid binding globulin (CBG) bin ding parameters were evaluated by equilibrium dialysis in 13 naturally scra pie-affected ewes and nine healthy ewes, during two periods of the clinical evolution of the disease. The hypercortisolism of the scrapie-affected ewe s was confirmed by a significant increase of the plasma 20 beta-dihydrocort isol and cortisone concentrations, while total cortisol concentrations, obt ained from an isolated sample, did not differ between scrapie-affected and control ewes. The scrapie diagnosis was confirmed by histopathology. The CB G maximal capacity (B-max) was two times lower in scrapie-affected ewes tha n in healthy ewes (37 +/- 32 nM and 73 +/- 28 nM respectively). The dissoci ation constant K-d (8.8 +/- 3.7 nM and 9.8 +/- 3.0 nM respectively) and the non-specific constant value of binding to albumin (1.13 +/- 0.18 and 1.14 +/- 0.23 respectively) did not differ significantly between diseased and co ntrol ewes. The significant increased concentrations of CBG-free cortisol ( i.e. both albumin-bound and free cortisol fractions) in scrapie-affected ew es indicates that total plasma cortisol concentration is not an appropriate index of pituitary-adrenocortical hyperactivity. In conclusion, ewes with naturally occurring scrapie display a syndrome of hypercortisolism associated with a lower CBG binding capacity which leads t o an overexposure of glucocorticoid-sensitive targets to CBG-free cortisol. The physiopathological consequences of this overexposure on the developmen t of the neurodegenerative process in prion disease are discussed.