The dynamics of blood-brain barrier breakdown in an experimental model of glial cell degeneration

This study was undertaken to investigate the dynamics of blood-brain barrier breakdown in an in vivo rat model of selective CNS vulnerability. 1,3-Dinitrobenzene was used to induce rapid glial degeneration in highly defined areas of the brainstem. Leakage of fluorescent dextran was used to demonstrate the breakdown of the blood-brain barrier, and antibodies to glial and neuronal specific proteins to assess the accompanying cell changes. Beginning 18 h after a toxic dose of dinitrobenzene and before loss of glial ensheathment, a sub-population of blood vessels became permeable to fluorescent dextrans below 500,000 mol. wt in size. By 24h most macroglial cells had been lost from within susceptible areas and vascular leakage had reached peak levels. Macrophage invasion was detected three days following dinitrobenzene. Vessels continued to leak up to four days after the lesion was formed, but by six days blood-brain barrier integrity was largely re-established. Multiple tracer injections over time demonstrated that a single sub-population of vessels was leaking during the experimental period. From these findings we conclude that blood-brain barrier breakdown in this model system is highly selective, graded in extent and molecular weight specificity and not a direct consequence of astrocyte degeneration or microglial activation. This system could be useful in modeling human CNS pathological processes with a vascular component and for understanding in vivo glial blood-brain barrier interactions.