2000 Fiscal Year Final Research Report Summary
Regulation of drugs on abnormal neovascularization of choroidal capillaries in diabetic rats
| Project/Area Number |
10672069
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Hokuriku University |
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Principal Investigator |
KOBAYASHI Shinjiro Hokuriku University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (10186744)
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| Project Period (FY) |
1998 – 2000
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| Keywords | diabetic retinopathy / cultured choroidal capillary / cultured retinal capillary / neovascularization / anti CML antibody(6D12) / advanced glycation end product / vascular endothelial growth factor / derivatives of tetrandrine |
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| Research Abstract |
We investigated roles of choroidal dysfunction with angiogenesis for induction of pathogenesis in diabetic retinopathy. (1) We developed in vitro culture system to study condition of choroidal capillaries in early and advanced stages of streptozotocin (STZ)-diabetic rats. The mumber of microvessels budded from explants was evaluated as index of in vitro neovascularization. (2) Choroidal capillaries in the early stage of diabetes facilitated neovascularization both with and without fetal bovine serum (FBS) to a greater extent than capillaries in age-matched normal young rats. (3) N(epsilon)-(carboxymthyl)lysine (CML)-modified proteins, one of advanced glycation end products facilitated choroidal neovascularization.
6D12, a monoclonal antibody against CML, Suppressed the diabetic stale-facilitation of choroidal neovascularization but not neovascularization in normal capillaries. (4) Cultured choroidal capillaries in early stage-diabetes released higher concentration of vascular endothelia
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l growth factor (VEGF) and tended to increase tumor necrosis factor (TNT)-alpha and platelet-derived growth factor (PDGF)-BB, relative to tle Control. (5) Tetrandrine, a principal bis-benzylisoquinoline alkaloid isolated from."Stephania letrandrae S.Moore (root)" and its related synthetic compound (KS-1-4) selectively inhibited choroidal neovascularization ill early stage-diabetes and VEGF- and PDGF-BB-facilitaled choroidal neovascularization. (6) The early stagediabetes did not affect neovascularization of retinal capillaries but newly formed choroidal capillaries suppressed retinal neovascularization in co-culture. 6D12 restored choroidal capillary-induced suppression of the retinal neovascularization. (7) Choroidal capillaries facililaled neovascularizalion in normal older rat but did not change it in advanced stage-diabetes. 6D12 suppressed age-induced choroidal neovascularization. Retinal capillaries in advanced stage-diabetes facilitated neovascularization and were potentiated neovascularization by co-cultured choroidal capillaries. In conclusion, CML-modified proteins accumulated in choroidal capillary release VEGF, probably TNF and PDGF.and suppress the retinal neovascularization in early stage-diabetes. However, CML-modified proteins potentiated retinal neovascularization through the angiogenic activity of choroidal capillaries in the advanced stage-diabetes to induce pathogenesis of diabetic retinopathy. Less
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