Effects of Salvia miltiorrhiza on CNS Neuronal Injury and Degeneration: A Plausible Complementary Role of Tanshinones and Depsides.

Salvia miltiorrhiza is a very important herbal drug of traditional Chinese medicine. Bioactive constituents are represented by two main groups of secondary metabolites, the lipophilic diterpenic quinones known as tanshinones and the hydrophilic depsides known as salvianolic acids. S. miltiorrhiza extracts and single constituents have been shown to have positive effects in central nervous system neuronal injury and degeneration in several animal models by various biological mechanisms. Both tanshinones and depsides protect against β-amyloid-induced toxicity, but their mechanisms are complementary due to their different structure, the lipophilic tanshinones and the hydrophilic depsides. A number of anti-inflammatory mechanisms is also reported for both tanshinones and depsides. Common mechanisms are the effects on cytokines, inducible nitric oxide synthase, and glial fibrillary acidic protein. In addition, depsides are inhibitors of nitric oxide and cyclooxygenase-2, while tanshinones inhibit hypoxia-inducible factor-1α and nuclear factor kappa β. Both constituents can also modulate the protection of the central nervous system from oxidative stress with different but complementary mechanisms: tanshinones can enhance the activities of superoxide dismutase and glutathione peroxidase, while depsides can decrease reactive oxygen species.Furthermore, neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. Both classes of constituents can enhance the antiapoptotic B-cell leukemia protein-2 family members and decrease the translocation of cytochrome c, and, in addition, depsides decrease caspase-3 and intracellular Ca(2+). Again, both classes of constituents have an activity on vascular endothelial growth factor but it is opposite, whereas tanshinones are inhibitors of acetylcholinesterase.Besides the extensive studies reporting on the biological mechanisms of depsides and tanshinones, pharmacokinetics studies are still very limited and not conclusive, especially for brain distribution. Further research is warranted to address the mechanisms of the multitarget actions of S. miltiorrhiza constituents and to translate this knowledge into clinical practice.