Abstract
Huang-Lian-Jie-Du-Decoction (HLJDD, Oren-gedoku-to in Japanese) is commonly used in traditional Chinese medicine (TCM) to treat ischemic stroke. This study investigated the efficacy of various combinations of the major components of HLJDD, berberine (A), baicalin (B), and jasminoidin (C), on the treatment of ischemic stroke modeled by middle cerebral artery occlusion (MCAO) in rats. The effects of A, B and C individually and their combinations were investigated using proton nuclear magnetic resonance (1H NMR)-based metabolomics complemented with neurologic deficit scoring, infarct volume measurement, biochemistry, histopathology and immunohistochemistry, as well as quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Ischemic stroke produces severe oxidative stress, which induces further damage. Our results show that the ABC combination treatment increased levels of cellular antioxidants that scavenged reactive oxygen species during ischemia-reperfusion via the nuclear erythroid 2-related factor 2 (Nrf2) signaling cascade. These protective effects were not observed with the other treatments. These results suggest that a combination of component herbs in HLJDD exhibit stronger effects than the individual herbs alone. Our integrated metabolomics approach also provides a tractable, powerful tool for understanding the science behind TCM formulations.
Highlights
Stroke is one of the leading causes of mortality [1], accounting for approximately 87% of all stroke cases [2]
This study investigated the efficacy of various combinations of the major components of HLJDD, berberine (A), baicalin (B), and jasminoidin (C), on the treatment of ischemic stroke modeled by middle cerebral artery occlusion (MCAO) in rats
A 1H NMR-based metabolomics approach was adopted and complemented with current biochemical techniques to investigate the synergistic effects of the major active components of HLJDD and explore their underlying mechanisms
Summary
Stroke is one of the leading causes of mortality [1], accounting for approximately 87% of all stroke cases [2]. Despite of the use of aspirin and thrombolytics, there are few effective treatments for ischemic stroke due to its extremely narrow therapeutic time window [3]. Combination therapies have been advocated by prescriptions called formulae in traditional Chinese medicine (TCM) for more than 2,500 years [7]. The combinatorial rules of herbal formulae have been difficult to clarify using traditional methods due to the complexity of their components. This has hampered the use of TCM formulae, as well as the development of drugs or therapies based on these formulae. We sought to apply metabolomics to explore the effects of drug combinations and the underlying mechanisms of TCM formulae
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