In both humans and animals reduced early growth is a risk factor for cardiovascular disease, stroke, hypertension and type 2 diabetes. These associations involve changes in the hypothalamic-pituitary-adrenal axis (HPAA) activity, and regulated in part by glucocorticoids feedback to brain. One determinant of glucocorticoid activity in brain is the transfer of hormone across the blood-brain barrier. The aim of this study was to determine normal corticosterone delivery from blood to brain.
Brain penetration of [3H] corticosterone was investigated using a bilateral in situ brain perfusion technique with [14C] mannitol as the vascular marker, followed by capillary depletion analysis (Preston et al. 1995). Adult female Wistar rats (200-250 g) were anaesthetised I.P. with hypnorm (0.4 ml kg-1) and hypnovel (0.4 ml kg-1) and heparinized (100 000 units kg-1 I.P.). Both carotid arteries were perfused with Ringer containing dextran (39 g l-1), [3H] corticosterone and [14C] mannitol for up to 30 min. A CSF sample was taken by puncture of the cisterna magna, the rat humanely killed by decapitation and the choroid plexuses and pituitary removed. Brain was homogenised at 4 °C and capillaries removed using dextran density centrifugation. Ringer and tissue samples including whole brain homogenate, capillary-free (supernatant) and capillary-rich (pellet) fractions were solubilized and counted (β-liquid scintillation counter).
A plot of d.p.m. in tissue/d.p.m. in Ringer per unit weight against time produces a straight line with slope Kin (the initial rate constant for unidirectional transfer) (Preston et al. 1995).
Penetration of [3H] corticosterone was linear up to 30 min in adult rats and Kin values are summarized in Table 1. Greatest uptake was in the pituitary and choroid plexuses which lack the characteristically tight blood-brain barrier. However, even in the capillary-free brain samples and CSF, corticosterone Kin was at least 17 times greater than mannitol. These data demonstrate that corticosterone rapidly enters brain and CSF, despite presence of the blood-brain and blood-CSF barriers.
The work is supported by the British Heart Foundation.