In mammals the blood-brain barrier (BBB) prevents many blood-borne, non-fat soluble substances from gaining access to brain parenchyma. Ascertaining a non-injurious approach to reversibly opening the BBB would have important clinical implications in the polychemotherapeutic treatment of individuals harboring primary and metastatic brain tumors as well as the delivery of psychotherapeutic drugs, antibiotics, and antidotes. We have recently come upon an agent which, when administered intravenously in mice, appears to temporarily open the BBB. The agent is dimethyl sulfoxide (DMSO), a membrane solvent. When DMSO together with the enzymatic tracer horseradish peroxidase (HRP) are injected intravenously into the mouse, HRP fills the brain. In the absence of DMSO, HRP fails to enter brain parenchyma. The normal BBB prohibits entry of blood-borne protein into the brain due to tight junctions between adjacent endothelial cells and the absence of vesicular transport through thess cells. Our preliminary data suggest that the normal BBB is not absolute, for pericytes lying on the surfaces of cerebral microvasculature become labels with HRP. Ultrastructurally, capillaries and arterioles pinocytose HRP into vesicles which appear to be directed mainly to lysosomes, as identified by acid hydrolase cytochemistry. Whether or not vesicular transport occurs in our preparations requires further investigation. Involvement of the BBB with vesicular transport remains highly controversial. Specifically, this project shall focus on: the potential use of DMSO as an agent for reversibly opening the BBB in vivo; ultrastructural determination of how the BBB is altered by DMSO; further characterization of the BBB with to lysosomal activity in microvasculature and phagocytic cells like pericytes; and the possibility of vesicular transport across the BBB Blood-borne tracers of differing molecular weight, ionic charge, and hydrated diameter will be employed to investigate BBB permeability under normal and DMSO-exposed conditions. Enzyme cytochemical methodologies for acid hydrolase activity shall be utilized to study the Lysosomal system in cerebral microvasculature and pericytes. The search for a safe and effective means of reversibly opening the BBB may depend on an increased understanding of the mechanisms of barrier function as demonstrated in normal and DMSO-treated animals.
Showing the most recent 10 out of 18 publications
