Abstract 3296: Phenolic Compounds Present In Danshen Extract Protect Against Doxorubicin-induced Cardiotoxicity
The acute clinical effects of doxorubicin (DOX) administration include EKG changes, tachycardia, and hypertension. DOX-induced superoxide generation in heart mitochondria has been shown to play a pivotal role in these injurious effects; as such, it is feasible that free radical scavengers could help protect against DOX-induced cardiac injury. Salvia miltiorrhiza (Danshen) is a rich source of phenolic compounds that have potent antioxidant activity. In our experiments, we tested the hypothesis that the active components in Danshen extract protect against DOX-induced cardiotoxicity. Mice were treated with DOX (22.5 mg/kg, i.p.). After 5 days, left ventricular performance was analyzed in mice anesthetized with 2% isoflurane using an ARIA pressure-volume conductance system (Millar Instruments). Our studies demonstrated that cardiac function was significantly depressed in DOX treated mice, as evidenced by a significant decrease in heart rate (40%), stroke volume index (41%), cardiac output index (65%), ejection fraction (44%) and preload recruitable stroke work (55%). Systolic function (control vs. DOX-treated mice) (P<0.05) was 90 ± 2 vs. 68 ± 1.7 mmHg for end-systolic pressure, 5.7 ± 0.2 vs. 9.1 ± 0.25 μl for end-systolic volume, and 11,370 ± 618 vs. 5,714 ± 837 mmHg/s for +dP/dt. Diastolic function (control vs. DOX-treated mice) (P<0.05), was 3.2 ± 0.3 vs. 6.1 ± 0.9 mmHg for end-diastolic pressure, 17.7 ± 0.38 vs. 14.6 ± 0.41 μl for end-diastolic volume, 9,092 ± 859 vs. 3,846 ± 412 mmHg/s for -dP/dt, and 6.3 ± 0.6 vs. 13.5 ± 1.5 ms for tau (time constant of isovolumic relaxation). Daily administration of the injectable Danshen extract (0.1 ml/mouse, i.p.) completely restored the cardiac function of DOX-treated mice and improved their survival rate from 60% to 100%. Daily injection of 5 mg/kg of either denshensu or protocatechualdehyde, two of the active components of the Danshen extract, conferred more than 80% protection against all of the aforementioned changes. Of note, neither compound interfered with the anti-tumor potency of DOX. These results demonstrate that phenolic compounds present in Danshen extract may have a clinical use as protective agents against DOX-induced cardiotoxicity.