Naturally
scrapie-affected ewes present a syndrome of
hypercortisolism as evaluated by measuring total plasma
cortisol concentrations. The objective of this study was to investigate the
plasma protein binding of
cortisol and to evaluate the concentration of the biologically active free fraction of
cortisol in
scrapie-affected ewes.
Corticosteroid binding globulin (
CBG) binding parameters were evaluated by equilibrium dialysis in 13 naturally
scrapie-affected ewes and nine healthy ewes, during two periods of the clinical evolution of the disease. The
hypercortisolism of the
scrapie-affected ewes was confirmed by a significant increase of the plasma
20 beta-dihydrocortisol and
cortisone concentrations, while total
cortisol concentrations, obtained from an isolated sample, did not differ between
scrapie-affected and control ewes. The
scrapie diagnosis was confirmed by histopathology. The
CBG maximal capacity (B(max)) was two times lower in
scrapie-affected ewes than in healthy ewes (37+/-32 nM and 73+/-28 nM respectively). The dissociation 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 control ewes. The significant increased concentrations of
CBG-free
cortisol (i.e. both
albumin-bound and free
cortisol fractions) in
scrapie-affected ewes 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 to an overexposure of
glucocorticoid-sensitive targets to
CBG-free
cortisol. The physiopathological consequences of this overexposure on the development of the neurodegenerative process in
prion disease are discussed.