Monoamine Oxidase Inhibition by Major Tanshinones From Salvia Miltiorrhiza and Selective Muscarinic Acetylcholine M4 Receptor Antagonism by Tanshinone I
Abstract Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson's disease (PD). Lipophilic tanshinones are major phytoconstituents in dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective anti-Parkinson effects against dopaminergic neurotoxins and the inhibition of human monoamine oxidase (hMAO)-A. Since MAO-B inhibition is also considered an important therapeutic approach for PD, we accessed the potential of three abundant tanshinone congeners in hMAO-A and hMAO-B inhibition in vitro. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone with IC50 values less than 10 μM. They also suppressed hMAO-B activity with IC50 values lower than 25 μM. Although the hMAO-A inhibitory activity of tanshinones has been reported, the mechanism of enzyme inhibition and binding sites are yet to be studied. Thus, we conducted enzyme kinetics and molecular docking studies to evaluate the mode of enzyme inhibition and interactions. Proteochemometric modeling further predicted mAChRs as potential targets of 1 and an in vitro functional G-protein coupled receptor assay confirmed the selective M4 antagonist nature of 1. These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD.