Permeability of the Blood–Brain Barrier to Protein and [3H]GABA in Intraparenchymal Fetal CNS Tissue Grafts

Abstract

In the present study solid grafts of rat fetal neocortex or substantia nigra were transplanted into young adult rat cortex or striatum. To study the permeability to protein and potential changes in the blood–brain barrier (BBB), HRP was administered intravascularly or, to examine endogenous protein exudation, noninjected animals were evaluated after immunocytochemical stain for rat serum albumin. In addition, [3H]GABA, a neurotransmitter that does not cross the BBB, was systemically administered to cortical graft-bearing hosts in order to determine if a barrier to small potentially bioactive compounds was present. Postoperative periods ranged between 1 week and 15 months for the cortical grafts and between 1 week and 8 months for nigral grafts; the experiments were repeated several times at the same time point in order to determine the potential for variability in the model systems. The results show that a high percentage (80%) of both neocortical and nigral grafts lack a complete BBB to protein up to 2–3 weeks postoperative. After this time the majority of neocortical grafts were impermeable to protein yet 20–30% of longer-term specimens showed variable degrees of permeability to protein; permeability to [3H]GABA, which manifested in the transmitter being sequestered by graft neurons, was observed only up to 4 weeks postoperative. Nigral grafts after 4 weeks postoperative showed negligible permeability to serum protein. Although in all early CNS grafts protein permeation is extensive in both graft and adjacent host, the mature host brain resolved the exudation far more efficiently so that the reaction appeared exclusively in the graft or interface and not in the host by 2–3 weeks, suggesting that the graft tissue may lack appropriate mechanisms for clearance of extracellular materials. It is unclear why this phenomenon occurred consistently but in a minority percentage of cortical specimens. It is suggested that either frank pathology or immunopathology provides a subtle and incomplete rejection process that allows the interface vessel to be permeable over the life of the graft. Since nigral grafts appeared to have significantly less BBB dysfunction variation it is possible that the maturation levels or the ontogeny between different graft sources may play a role in differing responses to injury or vascular problems after transplant surgery.