The development of a blood-brain barrier mechanism in foetal sheep.

1. The penetration of a metabolically inert, small molecular radius lipid insoluble substance ([(13)C] and [(4)H]sucrose), from blood into brain and c.s.f., has been studied in developing sheep from 50 days gestation (term, 150 days) through to the new-born stage. Around 50 days gestation sucrose accumulated rapidly into brain and c.s.f., and reached a steady-state level in brain of about 12% of the plasma level by 3 hr. By 60 days sucrose penetrated less freely into brain and c.s.f.; the brain steady-state level was 10% by 4(1/2) hr. A large decrease in sucrose penetration occurred by 70 days gestation, and by 123 days (just before the time when a foetal lamb becomes viable) both the rate of penetration and the brain steady-state level of sucrose were similar to those of the adult of other species.2. The rate of c.s.f. secretion at different ages has been estimated by dye dilution during ventriculo-cisternal perfusion. The turnover of c.s.f. in 60 day foetuses was high (1.36%/min.g wet weight brain). From 123 days gestation to the adult stage the turnover was much lower, 0.02%/min.g at 123 and 137 days gestation and 0.01%/min.g in the adult ewe.3. A simple new method for measuring c.s.f. volume is described. The volume at 51 days was estimated to be 0.14 ml., S.E. +/- 0.03, n = 4 (brain weight = 0.87 g +/- 0.11), at 59 days it was 0.45 ml., S.E. +/- 0.04, n = 6 (brain weight = 2.0 g +/- 0.1) and near term it was 7.28 ml S.E. +/- 1.29, n = 4 (brain weight 42.0 g +/- 0.5).4. The results are discussed in relation to possible changes in permeability of the cerebral capillary endothelium, the sink effect of c.s.f., and changes in extracellular space of the brain during its development. It is concluded that the high rate of penetration and raised brain steady-state level of sucrose in immature sheep foetuses is probably due to immaturity of a permeability barrier at the level of the cerebral capillary endothelium or its associated glial processes. Some clinical implications of these findings are considered briefly.