Acteoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent (2): Effect of acteoside on leukocyte accumulation in the glomeruli of nephritic rats.

We investigated the effect of acteoside in comparison with that of cyclosporin A on leukocyte accumulation in the glomeruli of rats with crescentic-type anti-glomerular basement membrane (GBM) nephritis. Acteoside given p.o. at a dose of 30 mg/kg once a day for 15 consecutive days after treatment with anti-GBM serum markedly suppressed the urinary protein as well as glomerular histological changes. Acteoside given p.o. for 5 or 15 consecutive days markedly suppressed the accumulation of total leukocytes, ED-1-positive cells (monocytes/macrophages), CD4-positive cells, CD8-positive cells, interleukin-2-receptor-positive cells (activated T cells) and Ia-positive cells in the glomeruli. These effects of cyclosporin A (20 mg/kg/day, p.o.) were also as potent as those of acteoside (30 mg/kg/day, p.o.). Cyclosporin A also strongly suppressed the elevation of plasma antibody level against rabbit gamma-globulin. However, in this dose, acteoside did not significantly suppress the antibody formation. It can be concluded from these results that acetoside may exert its antinephritic action by suppressing the accumulation of leukocytes in the glomeruli.

Acetoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent: effect of acteoside on crescentic-type anti-GBM nephritis in rats.

Effects of acetoside (ACT) on crescentic-type anti-GBM nephritis in rats were investigated. When rats were treated with ACT from the 1st day after i.v. injection of anti-GBM serum, ACT inhibited the elevation of protein excretion into urine. In the ACT-treated rats, cholesterol and creatinine contents and antibody production against rabbit gamma-globulin in the plasmas were lower than those of the nephritic control rats. Histological observation demonstrated that this agent suppressed hypercellularity and the incidence of crescent formation, adhesion of capillary wall to Bowman's capsule and fibrinoid necrosis in the glomeruli. Furthermore, rat-IgG and C3 deposits on the GBM were significantly less in the ACT-treated group than in the control nephritic group. When the treatment was started from the 20th day after i.v. injection of anti-GBM serum, by which the disease had been established, ACT resulted in a similar effect on the nephritic rats as stated above. These results suggest that ACT may be a useful medicine against rapidly progressive glomerulonephritis, which is characterized by severe glomerular lesions with diffuse crescents.

Studies on the antinephritic effect of plant components (4): Reduction of protein excretion by berberine and coptisine in rats with original-type anti-GBM nephritis.

The present study was conducted to investigate the antinephritic effects of berberine and coptisine, which are contained in Coptidis rhizoma, on original-type anti-GBM nephritis in rats. Berberine and coptisine at the doses of 0.5, 1.0 and 5.0 mg/kg/day, i.p. were effective in inhibiting urinary protein excretion, elevation of serum cholesterol and creatinine contents as well as glomerular histopathological changes. In addition, berberine at 20 mg/kg/day, p.o. also inhibited urinary protein excretion throughout the experimental periods. Berberine and coptisine inhibited platelet aggregation in both in vitro and in vivo assays, and berberine inhibited the decline of renal blood flow. Although berberine inhibited an increase in thromboxane B2 formation, it increased the formation of 6-keto-prostaglandin F1 alpha in platelets and isolated glomeruli. These results indicate that the antinephritic effects of berberine and coptisine may be partly due to antiplatelet action and improved renal hemodynamics via changing prostanoid synthesis.

[Studies on anti-nephritic effects of plant components (5). Effects of pherodendrin on original and crescentic-type anti-GBM nephritis in rats].

Effects of pherodendrin (OB-5) on anti-GBM nephritis were investigated. OB-5 (50 mg/kg/day, i.p.) prevented the urinary protein excretion in original and crescentic-type anti-GBM nephritis in rats. In addition, OB-5 also inhibited the elevation of serum creatinine, urea nitrogen and cholesterol contents in both models of nephritis. Histopathological observations indicated that OB-5 prevented the hypercellularity, crescent formation, adhesion and fibrinoid necrosis in the glomeruli of nephritic rats. OB-5 and cyclosporine A, a positive control drug, prevented the increase in the number of OX-1, CD8 and ED-1 positive cells in the glomeruli. These results indicated that OB-5 may be effective in human glomerulonephritis, and anti-nephritic mechanisms of OB-5 may be due to its inhibition of the activation of macrophages or cytotoxic T cells.

Studies on antinephritic effect of TJ-8014, a new Japanese herbal medicine (3): Effects on crescentic-type anti-GBM nephritis in rats.

We investigated the antinephritic effects of TJ-8014, in comparison to dipyridamole, on crescentic-type anti-GBM nephritis in rats. When administration of test drugs was started from the heterologous phase (from the day after the anti-GBM serum injection), TJ-8014 at 2.0 g/kg/day, p.o., markedly inhibited the urinary protein excretion and elevations of plasma cholesterol and urea nitrogen levels as well as glomerular histopathological changes (i.e., crescent formation, adhesion and fibrinoid necrosis) throughout the 40-day observation period. TJ-8014 at 0.1 and 0.5 g/kg/day, p.o., and dipyridamole at 0.4 g/day, p.o., inhibited only the histopathological changes. When treatment was started from the autologous phase (from the 22nd day after the anti-GBM serum injection) after the disease had been established, only the high dose of 5.0 g/kg/day of TJ-8014, p.o., was effective in improving the histopathological changes of the established nephritis, as assessed on the 53rd day. The low doses of TJ-8014 and dipyridamole were ineffective. These results suggest that TJ-8014 may be a useful Japanese herbal medicine against rapidly progressive glomerulonephritis, which is characterized by severe glomerular lesions with the extensive formation of crescents. Furthermore, the mechanisms of action of this medicine will be discussed.

Studies on antinephritic effect of TJ-8014, a new Japanese herbal medicine, and its mechanisms (2): Effect on the release of corticosterone from adrenal glands.

In order to elucidate the mechanisms of the antinephritic action of TJ-8014, the effect of this drug on corticosterone release from the adrenal cortex was investigated by using normal rats and rats with original-type anti-GBM nephritis. When the serum corticosterone level was determined 5 hr after test drugs were given p.o. to normal rats, TJ-8014 at 0.5 and 2.0 g/kg significantly elevated the hormone level by 48% and 74%, respectively. Of the crude drugs that constitute TJ-8014, Bupleuri radix (SAIKO) and Glycyrrhizae radix (KANZOU) at 1.0 g/kg also significantly elevated the serum level. When TJ-8014 was given p.o. daily from the next day of anti-GBM serum injection to the 15th day, 2.0 g/kg/day of the drug inhibited the urinary protein excretion. In addition, TJ-8014 (2.0 g/kg/day) inhibited the decrease in the serum and adrenal corticosterone levels induced by nephritis. When corticosterone at 10 mg/kg was given s.c. daily from the next day of the anti-serum injection to the 10th day, it not only reduced proteinuria, but also inhibited glomerular histopathological changes. In contrast, metyrapone, a corticosterone synthetase inhibitor, at 100 mg/kg x 2/day, p.o., aggravated the nephritis. These results suggest that the antinephritic action of TJ-8014 may be partly due to the enhancement of the synthesis or release of corticosterone from the adrenal cortex.

Studies on antinephritic effect of TJ-8014, a new Japanese herbal medicine, and its mechanisms (1): Effects on original-type anti-GBM nephritis in rats and platelet aggregation.

In this study, we investigated the antinephritic effects of TJ-8014 and crude drugs in TJ-8014, in comparison to dipyridamole, on original-type anti-GBM nephritis in rats. TJ-8014 (2.0 and 3.0 g/kg/day, p.o., for 12 days) markedly inhibited the urinary protein excretion and the elevation of the plasma urea nitrogen (UN). In addition, TJ-8014 was effective in inhibiting the histopathological changes of hypercellularity and adhesion in glomeruli. Although dipyridamole (0.4 g/kg/day, p.o., for 12 days) had no effect on the plasma UN level, it was as effective as TJ-8014 on the other parameters. When each crude drug which constitutes TJ-8014 was given p.o., daily at 0.2 g/kg, only. Holen was effective in inhibiting the urinary protein excretion as well as histopathological changes. Ginseng radix reduced both the hypercellularity and the adhesion, while Bupleuri radix. Glycyrrhizae radix and Zizyphi fructus reduced only the hypercellularity. TJ-8014 and dipyridamole inhibited the platelet aggregation in normal and nephritic rats. These results indicate that TJ-8014, like dipyridamole, has a beneficial effect on original-type anti-GBM nephritis in rats and the antinephritic action of TJ-8014 may be partly due to the antiplatelet action of this agent.

Pharmacological studies on experimental nephritic rats (2). Antinephritic effect of various drugs on Masugi's nephritis.

Masugi's nephritis was induced in rats by a single i.v. injection of antikidney serum from rabbits immunized with the homogenate of rat whole kidneys. The antinephritic effect of drugs was evaluated through determination of biochemical parameters such as contents of protein and enzymes excreted into the urine and serum cholesterol content by the preadministration and intermittent administration tests. In the preadministration test, of test drugs, betamethasone (0.2 mg/kg +/- 3 p.o.) and azathioprine (25 mg/kg +/- 3 p.o.) showed an antinephritic effect. Betamethasone in particular resulted in normalization of urine and serum parameters. In the intermittent test, all drugs tested were effective. Significant recovery effects were observed with betamethasone (0.1 mg/kg +/- 6 p.o.),, prednisolone (5 mg/kg +/- 6 p.o.), azathioprine (30 mg/kg +/- 6 p.o.), tranexamic acid (200 mg/kg +/- 6 i.p.) and cetraxate (100 mg/kg 6 i.p.) on urinary protein excretion and with all test drugs including indomethacin (5 mg/kg +/- 6 p.o.) and cyclophosphamide (2.5 mg/kg +/- 6 p.o.) on urinary exzyme excretions. Serum cholesterol levels reverted to normal levels after administration of betamethasone. Using this nephritic model, the antinephritic effect of drugs could be tentatively evaluated.