Analysis of hyperforin (St. John’s wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs

Abstract

St. John’s wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.

Selective Activation of a TRPC6 Ion Channel Over TRPC3 by Metalated Type-B Polycyclic Polyprenylated Acylphloroglucinols

“…This structural feature aligns with preceding data that showcased α-helical attributes in the CD spectra of isolated TRPC6 peptides harboring the 777 LLKL 780 motif in both the presence and absence of hyperforin. This alignment between the predicted model and experimental data further supports the credibility of the projected structure …”

“…To further elaborate on the similarity of binding sites between hyperforin and PPAP53 at hTRPC6, a recently described mutant of TRPC6 was used. 21 Hyperforin is known to bind at the motif 777 LLKL 780 in the C-terminal region of hTRPC6, which was not resolved in recent cryoEM structures. This motif differs from the closely related hTRPC3 and hTRPC7 channels by the corresponding amino acids 708 IMRI 711 of hTRPC3 and 722 IMRI 725 of hTRPC7.…”

“…The ascending titration of hyperforin (1−50 μM) showed a stronger fluorescence intensity in a native TRPC6 peptide compared to a mutant TRPC6 peptide with the sequence IMRI instead of 777 LLKL 780 . 21 The results of our docking simulations are consistent with experimental data and provide insight into the binding situation of PPAP53 and hyperforin with RT-TRPC6.…”

Cytotoxic and Antioxidant Activity of Hypericum perforatum L. Extracts against Human Melanoma Cells from Different Stages of Cancer Progression, Cultured under Normoxia and Hypoxia

“…The raw material of Hypericum perforatum ( Hyperici herba ) is rich in variable chemicals, including, among others, phenolics and flavonoids, which are typical of compounds of the genus Hypericum , with hyperforin and its derivatives. Hyperforin, widely known as an antidepressant agent [ 32 , 33 ], has also confirmed an anticancer effect [ 26 , 34 ]. Considering the wide range of its occurrence in central Europe and Asia, and its commonness, H. perforatum is potentially cheap to obtain and easily available for research in phytochemistry studies, despite its chemical content being dependent on environmental conditions [ 20 , 21 , 35 ].…”

Current Knowledge of the Antidepressant Activity of Chemical Compounds from Crocus sativus L.

“…It is reasonable to draw attention to the potential of the application of drugs based on phytochemicals with lower toxicity and effective action [ 70 , 71 , 72 ]. Currently, phytotherapy supporting the treatment of depression and alleviating its symptoms is based on various active chemical compounds obtained from many plant taxa from different families of monocotyledons: Cyperaceae [ 73 ], Iridaceae [ 71 , 74 , 75 ], Xanthorrhoeaceae [ 74 , 76 ] as well as dicotyledons, e.g., Apiaceae [ 77 ], Aquifoliaceae [ 78 , 79 ], Asteraceae [ 80 ], Capparaceae [ 81 , 82 ], Caprifoliaceae [ 83 , 84 ], Fabaceae [ 85 ], Hypericaceae [ 86 , 87 , 88 , 89 , 90 , 91 ], Lamiaceae [ 92 , 93 , 94 ], Lauraceae [ 95 ], Passifloraceae [ 96 , 97 , 98 ], Polygalaceae [ 99 ], Rutaceae [ 100 , 101 ], Thymelaeaceae [ 73 ], and Solanaceae [ 102 ] ( Table 1 ).…”