ABSTRACT
Danshen or Chinese red sage (Salvia miltiorrhiza, Bunge) is used by traditional Chinese medicine (TCM) practitioners to treat neurological, cardiovascular, and cerebrovascular disorders and is included in some TCM formulations to control epileptic seizures. In this study, acetonic crude extracts of danshen inhibited pentylenetetrazol (PTZ)-induced seizure activity in zebrafish larvae. Subsequent zebrafish bioassay-guided fractionation of the extract resulted in the isolation of four major tanshinones, which suppressed PTZ-induced activity to varying degrees. One of the active tanshinones, tanshinone IIA, also reduced c-fos expression in the brains of PTZ-exposed zebrafish larvae. In rodent seizure models, tanshinone IIA showed anticonvulsive activity in the mouse 6-Hz psychomotor seizure test in a biphasic manner and modified seizure thresholds in a complex manner for the mouse i.v. PTZ seizure assay. Interestingly, tanshinone IIA is used as a prescription drug in China to address cerebral ischemia in patients. Here, we provide the first in vivo evidence demonstrating that tanshinone IIA has anticonvulsant properties as well.
Subject(s)
Abietanes/administration & dosage , Anticonvulsants/administration & dosage , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional/methods , Pentylenetetrazole/antagonists & inhibitors , Seizures/drug therapy , Abietanes/physiology , Abietanes/therapeutic use , Alzheimer Disease/drug therapy , Animals , Anticonvulsants/therapeutic use , Brain Ischemia/drug therapy , Disease Models, Animal , Disease Progression , Fertilization in Vitro/drug effects , Injections, Intraventricular , Larva/drug effects , Male , Mice , Microinjections , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/therapeutic use , Pentylenetetrazole/administration & dosage , Pentylenetetrazole/toxicity , Plant Extracts/administration & dosage , Plant Extracts/therapeutic use , Plant Roots/chemistry , Proto-Oncogene Proteins c-fos/antagonists & inhibitors , Proto-Oncogene Proteins c-fos/biosynthesis , Salvia miltiorrhiza/chemistry , Seizures/diagnosis , Seizures/mortality , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/therapeutic use , Zebrafish/embryologyABSTRACT
Pathological cardiac hypertrophy induced by adrenergic overactivation can subsequently develop to heart failure which remains as a leading cause of mortality worldwide. Tanshinone IIA is a lipid-soluble pharmacologically active compound extracted from the rhizome of the Chinese herb Salvia miltiorrhiza, a well-known traditional Chinese medicine used for the treatment of cardiovascular disorders. However, little is know about the effect of Tanshinone IIA on cardiac hypertrophy. The present study was aimed to investigate whether Tanshinone IIA prevents cardiac hypertrophy induced by isoproterenol (ISO) and to clarify its possible mechanisms. Cardiomyocytes hypertrophy was induced by ISO 10 µM for 48 h with or without Tanshinone IIA 10, 30, 100 µM pretreatment, and evaluated by determining the cell size and the expression of ANP, BNP, ß-MHC, Calcineurin, and NFATc3 by real-time PCR and western blot. We found that Tanshinone IIA pretreatment attenuated the enlargement of cell surface area induced by ISO in cultured cardiomyocytes. The mRNA level of ANP, BNP and ß-MHC was obviously elevated in ISO-treated cardiac cells, which was effectively inhibited by Tanshinone IIA. Moreover, we found that Tanshinone IIA pretreatment could prevent the augment of intracellular calcium transient in ISO-treated cardiomyocytes. The further study revealed that Calcineurin, NFATc3, ANP, BNP and ß-MHC proteins were upregulated by ISO in ventricular myocytes, and Tanshinone IIA pretreatment significantly attenuate the increased expression of Calcineurin, NFATc3, ANP, BNP and ß-MHC proteins. In summary, Tanshinone IIA attenuated cardiomyocyte hypertrophy induced by ISO through inhibiting Calcineurin/NFATc3 pathway, which provides new insights into the pharmacological role and therapeutic mechanism of Tanshinone IIA in heart diseases.
