Effects of a PDGFR-a Antagonist Imatinib on Blood-Brain Barrier Disruption in Focal Cerebral Ischemia in Younger and Older Rats

摘要

Background: One of the pathways involving blood-brain barrier (BBB) disruption in focal ischemia can act through the platelet derived growth factor a receptor (PDGFR-a) system including PDGF-CC and tissue plasminogen activator (tPA). This study was performed to compare the effects of imatinib, a PDGFR-a antagonist, on blood-brain barrier (BBB) permeability in younger and older rats in focal cerebral ischemia and to determine whether the protein levels of PDGFR-a vary with age.?Methods: Three month old (Younger) and 24 month old (Older) male Fischer 344 rats were used. One hour before middle cerebral artery (MCA) occlusion, rats were treated by gavage with normal saline (control) or imatinib mesylate 200 mg/kg. At one and a half hours after MCA occlusion, BBB permeability was determined by measuring the transfer coefficient (Ki) of 14C-a-aminoisobutyric acid and volume of dextran distribution. Western blot analysis of PDGFR-a was performed on additional rats.?Results: With MCA occlusion, the Ki of the ischemic cortex (IC) significantly increased in both age groups. The Ki of the IC of the older control rats was significantly lower (-57%) than that of the younger control rats. In the younger rats, imatinib significantly decreased the Ki of the IC (-48%). In the older rats, however, imatinib failed to decrease the Ki. The difference in volume of dextran distribution between the IC and the contralateral cortex was significant only in the younger control rats and became insignificant with imatinib. Imatinib did not affect the volume of dextran distribution in the older rats. Neither aging nor imatinib affected BBB permeability in non-ischemic brain regions. The ratio of density of PDGFR-a normalized for tubulin level was similar between the younger and older rats (younger: 0.85 ± 0.48 vs older: 0.93 ± 0.58).?Conclusion: Imatinib decreased BBB disruption caused by focal cerebral ischemia in the younger rats but failed to decrease it in the older rats in spite of similar protein level of PDGFR-a.doi: http://dx.doi.org/10.4021/jnr118w