Inhibitory effects of tetrandrine and related synthetic compounds on angiogenesis in streptozotocin-diabetic rodents.

Structure-activity relationships of tetrandrine, isolated from a Kampo medicine, Stephania tetrandrae S. MOORE (root), and related synthetic compounds, were investigated in in vitro fetal bovine serum (FBS)-stimulated angiogenesis of cultured choroids in streptozotocin-diabetic Wistar rats, and air-pouch granuloma angiogenesis in vivo in diabetic mice. Tetrandrine, KS-1-1 (6,7-dimethoxy-1-[[4-[5-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroiso quinolinyl)methyl-2-methoxy]phenoxy]benzyl]-2-methyl-1,2,3,4-tetrahyd roisoquinoline), and KS-1-4 (6,7-dimethoxy-1-[[4-[4-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroiso quinolinyl)methyl]phenoxy]benzyl]-2-methyl-1,2,3,4-tetrahydroisoquino line), potently inhibited choroidal angiogenesis and air-pouch granuloma angiogenesis in the diabetic state. Their inhibitory effects on diabetic choroids were greater than those on normal choroids. Among these compounds, KS-1-4 inhibited only diabetic angiogenesis. These compounds significantly inhibited FBS-stimulated tube formation in vascular endothelial cells from normal rats. Tetrandrine and KS-1-4, but not KS-1-1, inhibited vascular endothelial growth factor- and platelet-derived growth factor-BB-stimulated angiogenesis in normal choroids. The bis[tetrahydroisoquinoline] moiety, connected by oxy-bis[phenylenemethylene] and 2,2'-dimethyl groups in tetrandrine, contributes to the inhibition of diabetic choroidal angiogenesis. KS-1-4 may be a candidate for anti-choroidopathy and retinopathy drugs in the diabetic state.

Inhibitory effects of tetrandrine on angiogenesis in adjuvant-induced chronic inflammation and tube formation of vascular endothelial cells.

The inhibitory effects of tetrandrine (an alkaloid isolated from the Chinese medicine Stephania tetrandrae S. Moore) were investigated in terms of the angiogenesis in an adjuvant-induced chronic inflammation model of mouse and tube formation of rat vascular endothelial cells (EC). Tetrandrine (7.5-30 mg/kg) reduced the carmine content, granuloma weight, inflammatory cell count and pouch fluid weight in the inflammation model in a dose-dependent manner. The inhibitory pattern of tetrandrine on these parameters was similar to that of hydrocortisone. The inhibitory effect of tetrandrine on carmine content was 0.56-fold smaller than that of hydrocortisone. Tetrandrine (0.1-10 microM) also inhibited 2% fetal bovine serum (FBS)-stimulated tube formation of vascular EC. The inhibitory effect of tetrandrine on tube formation was more than 100-fold greater than that of hydrocortisone. Tetrandrine (10-30 nM) inhibited the tube formation stimulated by interleukin (IL)-1alpha and platelet-derived growth factor (PDGF)-BB to a greater extent than FBS-stimulated tube formation. The inhibitory effects of tetrandrine on the action of IL-1alpha and PDGF-BB were non-competitive. These results demonstrate that tetrandrine may reduce the tube formation of EC in the angiogenic process through inhibition on the post-receptor pathway of IL-1alpha and PDGF-BB in chronic inflammation.

Inhibitory effects of traditional Chinese medicine Shimotsu-to and its included crude fractions on adjuvant-induced chronic inflammation of mice.

Effects of a traditional Chinese medicine, Shimotsu-to (a combined prescription of cnidium rhizome, peony root, angelica root and rehmannia root), and its included crude fractions were investigated on an adjuvant-induced chronic inflammation model of mice. The aqueous extract (30, 100 and 300 mg/kg, i.p.) of Shimotsu-to reduced the carmine content, granuloma weight, inflammation cell count and pouch fluid weight in the inflammation model, respectively. The extract of Shimotsu-to without cnidium at the same doses did not produce significant changes in these four inflammatory parameters. The same doses of extracts of Shimotsu-to without peony, and without angelica, weakly reduced these parameters, except for pouch fluid weight. The extract (30, 100 and 300 mg/kg) of cnidium significantly reduced these four parameters. The same doses of peony extract reduced carmine content, granuloma weight and pouch fluid weight, but less than those of the cnidium extract. The extract of cnidium and peony at the same doses reduced in an additive manner these inflammatory parameters in their combination. These results demonstrated that the Shimotsu-to extract reduced angiogenesis, granuloma formation, inflammatory cell migration and pouch fluid exudation in the adjuvant-induced chronic inflammation model. Cnidium represented the main ingredient for producing the anti-chronic inflammatory effects of Shimotsu-to extract. Cnidium and peony exhibited additive anti-inflammatory effects in combination.