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Fig. 6. NO and tPA contribute to BBB breakdown. (A) Wild-type and tPA–/– mice infused or not with tPA (1 µg/µl) were injected with 2% Evans Blue intraperitoneally immediately after intrahippocampal KA injection. At day 1, the mice were sacrificed, their hippocampi dissected, weighed and homogenized. The amount of BBB breakdown was assessed as the amount of Evans Blue that leaked into the brain parenchyma quantified at 620 nm minus the background and divided by the wet weight of each hemisphere. Each experimental group is represented by the percentage of the total signal for each individual experiment. *Indicates a significant difference as compared with the respective uninjected side (P<0.05) by a two-tailed t test; # indicates a significant difference (P<0.05) between the 400 µM NMMA ipsilateral side as compared with wild-type, PBS-infused, ipsilateral side. n=7. (B) Infusion of NMMA and 300 µM PTIO, but not 2 µM FeTMPyP or 10 µM FeTPPS, prior to KA injection partially attenuates vascular permeability, indicating a role for NO in BBB breakdown. (C) Injection of 1 mM NOC-18 alone does not mediated BBB breakdown in wild-type or tPA–/– mice. However, co-injection of NOC-18 and KA in tPA–/– mice restores the ability of KA to disrupt the BBB. (D) The specificity of BBB breakdown was assessed by immunofluorescent staining of the tight junction protein occludin. Only the KA-injected side of wild-type mice and wild-type mice treated with FeTMPyP showed diminished staining with the anti-occludin antibody, indicating a breakdown in the BBB. n=7.
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