Pharmacological and molecular docking assessment of cryptotanshinone as natural-derived analgesic compound

• Published in: Biomedicine & pharmacotherapy 2020-06, Vol.126, p.110042-110042, Article 110042
• Main Authors: De Caro, Carmen, Raucci, Federica, Saviano, Anella, Cristiano, Claudia, Casillo, Gian Marco, Di Lorenzo, Ritamaria, Sacchi, Antonia, Laneri, Sonia, Dini, Irene, De Vita, Simona, Chini, Maria Giovanna, Bifulco, Giuseppe, Calignano, Antonio, Maione, Francesco, Mascolo, Nicola
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics - chemistry; Analgesics - metabolism; Analgesics - pharmacology; Animals; Cryptotanshinone; Docking; Humans; Male; Mice; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Opiods; Pain Measurement; Phenanthrenes - chemistry; Phenanthrenes - metabolism; Phenanthrenes - pharmacology; Protein Conformation; Receptors, Opioid - chemistry; Receptors, Opioid - metabolism
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110042

[Display omitted] •Cryptotanshinone relieves central and peripheral pain.•Cryptotanshinone effect is free from tolerance when chronically administrated.•Cryptotanshinones reduction of intestinal transit is revered by naloxone.•Cryptotanshinone displays selective, in silico, μ- and k-opioid activity. Medicinal plants from traditional chinese medicine are used increasingly worldwide for their benefits to health and quality of life for the relevant clinical symptoms related to pain. Among them, Salvia miltiorrhiza Bunge is traditionally used in asian countries as antioxidant, anticancer, anti-inflammatory and analgesic agent. In this context, several evidences support the hypothesis that some tanshinones, in particular cryptotanshinone (CRY), extracted from the roots (Danshen) of this plant exhibit analgesic actions. However, it is surprisingly noted that no pharmacological studies have been carried out to explore the possible analgesic action of this compound in terms of modulation of peripheral and/or central pain. Therefore, in the present study, by using peripheral and central pain models of nociception, such as tail flick and hot plate test, the analgesic effect of CRY in mice was evaluated. Successively, by the aim of a computational approach, we have evaluated the interaction mode of this diterpenoid on opioid and cannabinoid system. Finally, CRY was dosed in mice serum by an HPLC method validated according to European Medicines Agency guidelines validation rules. Here, we report that CRY displayed anti-nociceptive activity on both hot plate and tail flick test, with a prominent long-lasting peripheral analgesic effect. These evidences were indirectly confirmed after the daily administration of the tanshinone for 7 and 14 days. In addition, the analgesic effect of CRY was reverted by naloxone and cannabinoid antagonists and amplified by arginine administration. These findings were finally supported by HPLC and docking studies, that revealed a noteworthy presence of CRY on mice serum 1 h after its intraperitoneal administration and a possible interaction of tested compound on μ and k receptors. Taken together, these results provide a new line of evidences showing that CRY can produce analgesia against various phenotypes of nociception with a mechanism that seems to be related to an agonistic activity on opioid system.