Tanshinones as Possible Therapeutic Agents for Cardiovascular, Cerebral, Hepatic, and Bone Diseases

Abstract

The root of Salvia miltiorrhiza (Tan shen) has been used as a traditional drug for circulatory disorders including ischemic diseases such as angina pectoris. Effective components protecting the myocardium against ischemia-induced metabolic disturbances; tanshinone IIA, tanshinone I, tanshinone V, tanshinone VI, and dihydrotanshinone were isolated. Among them, we found tanshinone VI as the most effective and possible agent with cardioprotection against ischemia/reperfusion injury in Langendorff manner by using rat isolated hearts. We have shown that the possible mechanisms underlying an enhancement of post-hypoxic contractile recovery of perfused hearts may be exerted via an enhancement of energy restoration and an attenuation of Ca2+ overload in the reoxygenated myocardium. We also found another beneficial effect of tanshinone VI on cardiac remodeling in primary cultured cardiomyocytes and cardiac fibroblasts. It is generally accepted that cardiac remodeling such as cardiac hypertrophy and fibrosis enhances the development and progression of heart failure following various cardiac diseases including acute myocardial infarction. Treatment of cardiomyocytes and cardiac fibroblasts with tanshinone VI attenuated humoral factor-induced cellular hypertrophy and fibrosis under in vitro experimental conditions. Thus, tanshinone VI may be a possible agent for attenuating the development of cardiac remodeling such as cardiac hypertrophy and fibrosis, which may lead to cardiac contractile dysfunction. Furthermore, inhibition of tanshinone VI to bone resorption through the prevention of osteoclast differentiation by inhibiting receptor activator of NFκB ligand (RANKL) expression and NFκB induction, was exhibited. Pharmacological suppression of NFκB and RANKL induced by tanshinone VI in vivo may be an effective approach to improve bone loss suppressing osteoclastic bone resorption in rheumatoid arthritis. Anti-inflammatory effect of tanshinone I, having a similar abietane structure to tanshinone VI, is shown on neuroprotection against cerebral ischemia-reperfusion injury in the gerbil hippocampus, and apoptosis in activated hepatic satellite cells (HSCs). Neuroprotection of tanshinone IIA against cerebral ischemia/reperfusion injury through inhibition of macrophage migration inhibitory factor and tanshinone IIA-mediated HSC-T6 apoptosis through Akt inhibition and ERK-Bax-caspase-3/9 signaling pathways are presented. Tanshinone IIA decreased the lipopolysaccharide-induced activation of rat hepatic satellite cells. Possible therapeutic effects of tanshinones VI, I, and IIA on cardiac contractile failure, cerebral infarction, born resorption, and apoptosis of hepatic satellite cells are discussed.