HPLC-Based Activity Profiling of Salvia miltiorrhiza for MAO A and iNOS Inhibitory Activities

Abstract

In the course of a screening of plant extracts for potential CNS and anti-inflammatory activities, a dichloromethane extract of Salvia miltiorrhiza showed a pronounced inhibitory effect on recombinant monoamine oxidase A (MAO A) and on inducible NO synthase (iNOS) induction in Raw 267.4 cells. With the aid of HPLC-based profiling techniques, activities could be linked, to a significant extent, to peaks of tanshinone-type diterpenoids, four of which were subsequently isolated. The IC₅₀ of the most active compound, 15,16-dihydrotanshinone I, on human recombinant MAO A was at 23 μM, and 2.4 μM on lipopolysaccharide-mediated iNOS induction in Raw 267.4 cells.

Salvia miltiorrhiza - Lamiaceae - diterpenoids - tanshinones - HPLC-DAD-MS - MAO A inhibition - inhibition of iNOS induction - Raw 267.4 cells

References

• 1 Schmidt K, Li Z, Schubert B, Huang B, Stoyanova S, Hamburger M. Screening of entomopathogenic deuteromycetes for activities on targets involved in degenerative diseases of the central nervous system.  J Ethnopharmacol. 2003;  89 251-60
• 2 Hamburger M. Isatis tinctoria - from the rediscovery of an ancient medicinal plant towards a novel anti-inflammatory phytopharmaceutical.  Phytochemistry Rev. 2002;  1 333-44
• 3 Schmidt K, Günther W, Stoyanova S, Schubert B, Li Z, Hamburger M. Militarinone A, a neurotrophic pyridone alkaloid from Paecilomyces militaris .  Org Lett. 2002;  4 197-9
• 4 Tang W, Eisenbrand G. Chinese drugs of plant origin. Heidelberg; Springer-Verlag 1992: pp 891-902
• 5 Kuang P, Wu W, Zhu K. Evidence for ameliorating cellular damage in ischemic rat brain by radix Salviae miltiorrhizae treatment - immunocytochemistry and histopathology studies.  J Tradit Chin Med. 1993;  13 38-4
• 6 Kuang P, Tao Y, Tian Y. Effect of radix Salviae miltiorrhizae on nitric oxide in cerebral ischemic reperfusion injury.  J Tradit Chin Med. 1996;  16 224-7
• 7 Dittmann K. Neue Bioaktivitäten von Salvia miltiorrhiza Bunge (Lamiaceae) - Aktivitätsprofiling, Methodenentwicklung und Charakterisierung isolierter Verbindungen. PhD Thesis University of Jena; 2004
• 8 Keung W M. Monoamine oxidase inhibitors.  Expert Opin Ther Patents. 2002;  12 1813-29
• 9 Hooper D C, Bagasra O, Marini J C, Zborek A, Ohnishi S T, Kean R, Champion J M, Sarker A B, Bobroski L, Farber J L, Akaike T, Maeda H, Koprowski H. Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis.  Proc Natl Acad Sci USA. 1997;  94 2328-33
• 10 Simonian N A, Coyle J T. Oxidative stress in neurodegenerative diseases.  Annu Rev Pharmacol Toxicol. 1996;  36 83-106
• 11 Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews R T, Beal M F. Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons.  Nat Med. 1996;  2 1017-21
• 12 Ikeshiro Y, Hashimoto I, Iwamoto Y, Mase I, Tomita Y. Diterpenoids from Salvia miltiorrhiza .  Phytochemistry. 1991;  30 2791-2
• 13 Yang M H, Blunden G, Xu Y X, Nagy G, Mathe I. Diterpenoids from Salvia species.  Pharmaceutical Sciences. 1996;  2 69-71
• 14 Ryu S Y, No Z, Kim S H, Ahn J W. Two novel abietane diterpenes from Salvia miltiorrhiza .  Planta Med. 1997;  63 44-6
• 15 Nagy G, Yang M H, Günther G, Blunden G, Crabb T, Mathe I. Tanshinone-type diterpenes from the roots of Salvia glutinosa .  Pharm Pharmacol Lett. 1998;  8 37-8
• 16 Sairafianpour M, Christensen J, Staerck D, Budnik BA, Kharazmi A, Bagherzadeh K, Jaroszewski J W. Leishmanicidal, antiplasmodial and cytotoxic activity of novel diterpenoid 1,2-quinones from Perovskia abrotanoides: new sources of tanshinones.  J Nat Prod. 2001;  64 1398-1402
• 17 Dittmann K, Riese U, Hamburger M. HPLC-based bioactivity profiling of plant extracts: an assay for the identification of monoamine oxidase A inhibitors using human recombinant monoamine oxidase A. Phytochemistry in press
• 18 Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhäuser C. Nuclear factor κB is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms.  J Biol Chem. 2001;  276 32 008-15
• 19 Ding A H, Nathan C F, Stuehr D J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production.  J Immunol. 1988;  141 2407-12
• 20 Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren J T, Bokesch H, Kenney S, Boyd M R. New colorimetric cytotoxicity assay for anticancer-drug screening.  J Natl Cancer Inst. 1990;  82 1107-12
• 21 Jang S I, Jeong S I, Kim K J, Kim H J, Yu H H, Park R, Kim H M, You Y O. Tanshinone IIA from Salvia miltiorrhiza inhibits inducible nitric oxide synthase expression and production of TNF-α, IL-1b and IL-6 in activated RAW 264.7 cells.  Planta Med. 2003;  69 1057-9
• 22 Gerhäuser C, Klimo K, Hiess E, Neumann I, Gamal-Eldeen A, Knauft J, Liu G Y, Sitthimonchai S, Frank N. Mechanism-based in vitro screening of potential cancer chemopreventive agents.  Mutation Res. 2003;  523 - 524 163-72