Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.
Yamina El HamdaouiFang ZhengNikolas FritzLian YeMai Anh TranKevin SchwickertTanja SchirmeisterAlbert BraeuningDajana LichtensteinUte A HellmichDorothee WeikertMarkus HeinrichGiulia TreccaniMichael K E SchäferGabriel NowakBernd NürnbergChristian AlzheimerChristian P MüllerKristina FriedlandPublished in: Molecular psychiatry (2022)
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.
Keyphrases
- major depressive disorder
- vascular smooth muscle cells
- bipolar disorder
- depressive symptoms
- sleep quality
- drug induced
- crispr cas
- metabolic syndrome
- high fat diet induced
- emergency department
- physical activity
- signaling pathway
- oxidative stress
- binding protein
- transcription factor
- cell proliferation
- spinal cord injury
- blood brain barrier
- transcranial direct current stimulation
- insulin resistance
- cell death
- drug delivery
- adipose tissue
- replacement therapy
- subarachnoid hemorrhage
- smoking cessation