Barranger J A, Rapoport S I, Fredericks W R, Pentchev P G, MacDermot K D, Steusing J K, Brady R O
Proc Natl Acad Sci U S A. 1979 Jan;76(1):481-5. doi: 10.1073/pnas.76.1.481.
The blood-brain barrier of rats was opened reversibly by infusing a hyperosmotic solution of arabinose into the external carotid artery. Permeability was increased maximally in the first 15 min and remained slightly elevated at 1 hr. Osmotic barrier opening significantly increased brain uptake of intravenously injected alpha-mannosidase (alpha-D-mannoside mannohydrolase, EC 3.2.1.2.4) (derived from human placenta) and horseradish peroxidase (donor:hydrogen-peroxide oxidoreductase, EC 1.11.1.7). By injection of 4 X 10(5) units of alpha-mannosidase into an animal, brain activity rose to about twice the normal control activity of the enzyme. After 30 min, activity of administered enzyme in the extracellular space of the brain was calculated to be 30% of the serum concentration. Biochemical and histological studies with horseradish peroxidase showed that exogenously administered enzyme entered the brain extracellular space immediately after barrier opening and was incorporated within neuronal lysosomal packets during the next 24 hr. Measurable peroxidase activity was found in brain as much as 72 hr after osmotic treatment. The results demonstrate that the blood-brain barrier can be reversibly opened to enzymes, that a glycoprotein enzyme is incorporated into neuronal lysosomes, and that the brain may now be considered a potential target for enzyme replacement therapy in heritable metabolic disorders.
通过向大鼠颈外动脉输注高渗阿拉伯糖溶液，可使大鼠的血脑屏障可逆性开放。在最初的15分钟内通透性最大程度增加，并在1小时时仍略有升高。渗透性屏障开放显著增加了静脉注射的α-甘露糖苷酶（α-D-甘露糖苷甘露水解酶，EC 3.2.1.2.4）（源自人胎盘）和辣根过氧化物酶（供体：过氧化氢氧化还原酶，EC 1.11.1.7）的脑摄取量。通过向动物注射4×10⁵单位的α-甘露糖苷酶，脑内该酶的活性升至正常对照活性的约两倍。30分钟后，计算得出脑细胞外间隙中所注入酶的活性为血清浓度的30%。用辣根过氧化物酶进行的生化和组织学研究表明，外源注入的酶在屏障开放后立即进入脑细胞外间隙，并在接下来的24小时内被纳入神经元溶酶体包中。在渗透处理后长达72小时的脑内均可检测到过氧化物酶活性。结果表明，血脑屏障可对酶进行可逆性开放，一种糖蛋白酶可被纳入神经元溶酶体，并且脑现在可被视为遗传性代谢疾病中酶替代疗法的潜在靶点。
