|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1995 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1994 : ¥1,600,000 (Direct Cost : ¥1,600,000)
This project was planned to clarify the physiological roles and expression mechanis of the blood brain barrier (BBB) specific membrane proteins, and further to implicate them for the treatment of pathological conditions of BBB.Using rat brain tumor model, human brain tumor samples, and rat brain infarct model, the expression of gamma-glutamyl transpeptidase (gamma-GTP), P-glycoprotein, and several angiogenic factors was investigated immunohistochemically and biochemically. BBB related proteins were expressed in the normal capillary endothelial cells and blood tumor barrier in gliomas. Tumor vessels in non-glial tumor did not express BBB related proteins. These results explained difficulty of the chemotherapy of gliomas.
To overcome these condition, several vasoactive agents, such as calcium antagonists and bradykinin, were useful to selectively increase regional blood flow and capillary permeability in gliomas, respectiverly, when administered through the carotid artery.
We also investig
ated angiogenic factors, especially vascular endothelial growth factor (VEGF) , which had been involved in tumor angiogenesis. In glioma and meningioma, the expression of VEGF was statistically corelated with vascularity. Chronological investigation of rat brain infarct revealed that BBB-related proteins were disappear wihtin 3 days after infarct and reappeared in endothelial cells with their maturation in conjunction with reactive gliosis. Macrophages, glial cells, and interestingly neurons could be the sourse of VEGF secretion. These results suggested that newly formed capillaries were immature and permeable in pathological condition. The healing process of infarct cleary showed the importance of glial cells for the expression of BBB related proteins. The maturation of BBB requires the contact between endothelial cells and glial cells, and further requres the expression of BBB related proteins.
The modulation of these expression might be useful to control brain edema formation and tumor growth. Less