Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage, oxidative stress and inflammation through inhibition of MAPK/p53 signaling.
Doxorubicin (Dox) is a highly effective antineoplastic drug. However, Dox-induced apoptosis in cardiomyocytes leads to irreversible degenerative cardiomyopathy, which limits Dox clinical application. Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents. In current study, we investigated possible protective effects of Sch B against Dox-induced cardiomyopathy in mice. Mice received a single injection of Dox (20 mg/kg IP). Five days after Dox administration, left ventricular (LV) performance was significantly depressed and was improved by Sch B treatment. Sch B prevented the Dox-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart. In addition, the increased expression of phospho-p38 MAPK and phospho-MAPK activated mitogen kinase 2 levels by Dox were significantly suppressed by Sch B treatment. Sch B also attenuated Dox-induced higher expression of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3 positive cells and phopho-p53 levels in mice. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species were significantly less in Sch B treatment mice after Dox injection. These findings suggest that Sch B attenuates Dox-induced cardiotoxicity via antioxidative and anti-inflammatory effects.
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), Higashijima, Akiha Ku, Niigata, Japan; Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, Texas, United States of America.
Rajarajan A
RA
Thandavarayan
J.K.K. Nattraja College of Pharmacy, Komarapalayam, Tamil Nadu, India.
Vijayasree V
VV
Giridharan
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), Higashijima, Akiha Ku, Niigata, Japan.
Somasundaram
S
Arumugam
Department of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Kenji
K
Suzuki
Section of Biochemistry and Cell Biology, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
Kam Ming
KM
Ko
Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, Texas, United States of America.
Prasanna
P
Krishnamurthy
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), Higashijima, Akiha Ku, Niigata, Japan.
Kenichi
K
Watanabe
Basic studies on second generation functional foods, NUPALS, NUPALS Liaison R/D promotion devision, Higashi-jima 265-1, Akiha-ku, Niigata, Japan, and Changchun University of Chinese Medicine, Bosuo Road #1035 Jingyue Economic Development District, Changchun, RP China.
Tetsuya
T
Konishi
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D034242:Cyclooctanes / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D017705:Lignans / Q000008:administration & dosage* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011083:Polycyclic Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D034242:Cyclooctanes; D017705:Lignans; D011083:Polycyclic Compounds; C015499:schizandrin B; C002744:3-nitrotyrosine; D014443:Tyrosine; D004317:Doxorubicin