The genus Stephania - Dr. DS Kothari Postdoctoral Fellowship ...

378 D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383
the plant were shown to be as active as verapamil (standard)
in reversing doxorubicin resistance in human breast cancer cells
(MCF-7 cells). Isotrilobine has MDR-reversing activity comparable
to verapamil at concentrations less than the ED 20 of isotrilobine
on MCF-7/ADR cells. Trilobine has low activity with a slope of 28
as compared with slopes of 211 and 232 for isotrilobine and verapamil,
respectively. The greater efficacy of isotrilobine to trilobine
appears to be a result of the methyl group at N-2 ′ . This is the only
structural difference between the two compounds and suggests
that a tertiary amine is preferred at this position to a secondary
amine. The slightly increased lipophilicity induced by the addition
of another methyl group may also contribute to the increased
activity (Hall and Chang, 1997).
4.9. Anti-inflammatory and analgesic activity
To investigate the anti-inflammatory effects of S. tetrandra
S. Moore in vitro and in vivo, its effects on the production of
IL-6 and inflammatory mediators were analyzed. When human
monocytes/macrophages (stimulated with silica) were treated
with 0.1–10 g/mL the plant, the production of IL-6 was inhibited
up to 50%. It also suppressed the production of IL-6 by
alveolar macrophages. In addition, it inhibited the release of
superoxide anion and hydrogen peroxide from human monocytes/macrophages.
To assess the anti-fibrosis effects of S. tetrandra,
its effects on in vivo experimental inflammatory models were evaluated.
In the experimental silicosis model, IL-6 activities in the
sera and in the culture supernatants of pulmonary fibroblasts were
also inhibited by it. In vitro and in vivo treatment with S. tetrandra
reduced collagen production by rat lung fibroblasts and lung
tissue. It also reduced the levels of serum GOT and GPT in the
rat cirrhosis model induced by CCl 4 , and was effective in reducing
hepatic fibrosis and nodular formation (Kang et al., 1996). The antiinflammatory
constituents, tetrandrine (18) and fangchinoline (50)
from S. tetrandra have been shown to decrease IL-1beta, IL-6, IL-8
and TNF-alpha as well as decrease leukotriene and prostaglandin
generation. Furthermore, tetrandrine has been shown to inhibit the
production of TNF-alpha and IL-6 by microglial cells (Teh et al.,
1990; Xue et al., 2008). The combined analgesic effect of aconitum
(Ac) and S. tetrandra (St) was found superior to that of Ac and St
when used alone. The combined Ac-St showed remarkable analgesic
activity within 3 h (p < 0.01) in rabbits and mice models (Li et
al., 2000).
4.10. Immunomodulating activity
S. tetrandra S. Moore has been used to treat autoimmune
diseases such as rheumatoid arthritis and systemic lupus erythe
matosus. Tetrandrine (18) has potential immunomodulating
and anti-inflammatory effects. T-lymphocytes play a critical
role as autoactive and pathogenic population in autoimmune
and inflammatory diseases. Some experimental data showed
that, through down-regulating the protein kinase C (PKC) signaling,
interleukin-2 secretion and the expression of the T
cell activation antigen (CD71), tetrandrine inhibited phorbol
12-myristate 13-acetate (PMA)+ionomycin-induced T cell proliferation
dependent on interleukin-2 receptor chain and CD69,
such an action was unrelated to Ca 2+ channel blockade (Ho
et al., 1999). Tetrandrine (0.1–10 ML −1 ) significantly inhibited
neutrophil-monocyte chemotactic factor-1 upregulation and
adhesion to fibrinogen induced by N-formyl-methionyl-leucylphenylalanine
and PMA. Tetrandrine at 0.1–100 ML −1 caused
dose and time-dependent loss of cell viability of mouse peritoneal
macrophages, guinea-pig alveolar macrophages and mouse
macrophage-like J774 cells, reduced production of oxygen free
radical, down-regulated synthesis and release of some proinflammatory
cytokines (Pang and Hoult, 1997; Shen et al.,
1999).
4.11. Antifibrotic effect
Antifibrotic effect of a methanol extract from S. tetrandra S.
Moore on experimental liver fibrosis has been investigated. Liver
fibrosis was induced by bile duct ligation and scission (BDL/S) in
rats. In BDL/S rats, activity levels of aspirate transaminase, alanine
transaminase, alkaline phosphatase, concentration of total
bilirubin in serum, and 100 mg/kg/day or 200 mg/kg/day, (p.o. for
4 weeks) in BDL/S rats reduced the serum aspirate transaminase,
alanine transaminase, alkaline phosphatase activity levels significantly
(p < 0.01) (Nan et al., 2000).
4.12. Anti-hyperglycemic effect
The ethanolic extract of the tubers of S. glabra (Roxb.) Miers
was evaluated for its hyperglycemic effects against alloxan-induced
diabetic and significantly decreased the blood sugar level in experimental
animals (Semwal et al., 2010a). A palmatine derivative,
11-hydroxypalmatine (44) isolated from this plant was also evaluated
for its anti-hyperglycemic activity. The test compound was
administered at doses of 25, 50, and 100 mg/kg, p.o., 36 h after
alloxan injection (60 mg/kg, i.v.). The alloxan-induced diabetic mice
showed significant reduction in blood glucose after treatment with
the test compound by 52% as compared to the positive control
glibenclamide (54%) and the diabetic control (27%) (Semwal et al.,
2010b). S. tetrandra S. Moore roots increases the blood insulin level
and reduces the blood glucose level in streptozotocin diabetic mice.
Actions of bisbenzylisoquinoline alkaloids isolated from the plant
were investigated in the hyperglycemia of diabetic mice. A main
bisbenzylisoquinoline alkaloid fangchinolin (0.3–3 mg/kg) significantly
reduced blood glucose level of the diabetic mice. The effect
of fangchinoline was 3.9 fold greater than that of water extract
(Tsutsumi et al., 2003). S. tetrandra has a direct effect on the retinal
capillary of posterior ocular region and suppressed neovascularization
of retinal capillary in streptozotocin diabetic rats through
the activation of tetrandrine (Liang et al., 2002). The oral administration
of ethanol and aqueous extract (400 mg/kg body weight) of
powdered corm of S. hernandifolia significantly (p < 0.05) decreased
the blood glucose of normal and Streptozotocin-induced diabetic
rats up to 12 h. Glibenclamide was used as a standard drug at a dose
of 0.25 mg/kg (Sharma et al., 2010).
4.13. Ca 2+ channel blocking activity
Abnormal Ca 2+ signaling and elevated concentration of intracellular
free Ca 2+ are the basic pathophysiological events involved
in various diseases. As a Ca 2+ antagonist, tetrandrine (S. tetrandra)
can inhibit extracellular Ca 2+ entry, int ervene in the distribution
of intracellular Ca 2+ , maintain intracellular Ca 2+ homeostasis, and
then disrupt the pathological processes. As shown in whole cell
patch-clamp recordings, tetrandrine blocked bovine chromaffin
cells voltage-operated Ca 2+ channel current in a time and concentration
dependently manner. In rat phaeochromocytoma PC 12
cells, 100 mol L −1 tetrandrine abolished high K + (30 mmol L −1 )
-induced sustained increase in cytoplasmic Ca 2+ concentration,
inhibited bombesin-induced inositol triphosphate accumulation in
NIH/3T3 fibroblast and abolished Ca 2+ entry (Takemura et al., 1996).
Tetrandrine can affect cardiovascular electrophysiologic properties
by inhibit the contractility, ±dt/dp max , and automaticity of
myocardium, prolong the FRP, and exert concentration-dependent
negative inotropic and chronotropic effects without altering cardiac
excitability. Tetrandrine directly blocks both T-type and L-type
calcium current in ventricular cells and vascular smooth muscle