The International Journal of Neuropsychopharmacology

Research Article

The antidepressant hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner

Julien Gibona1a2a3, Jean-Christophe Deloulmea2a3a4, Tiphaine Chevalliera5a6 *, Elodie Ladevèzea5a6 *, Djoher Nora Abrousa5a6 and Alexandre Bourona1a2a3 c1

a1 UMR CNRS 5249, Grenoble, France

a2 CEA, DSV, IRTSV, Grenoble, France

a3 Université Joseph Fourier, Grenoble, France

a4 Inserm U 836, Grenoble Institut des Neurosciences, Grenoble, France

a5 Université Bordeaux 2, Bordeaux, France

a6 Inserm U 862, Neurocentre Magendie, Bordeaux, France

Abstract

Hyperforin is one of the main bioactive compounds that underlie the antidepressant actions of the medicinal plant Hypericum perforatum (St. John's wort). However, the effects of a chronic hyperforin treatment on brain cells remains to be fully addressed. The following study was undertaken to further advance our understanding of the biological effects of this plant extract on neurons. Special attention was given to its impact on the brain-derived neurotrophic factor (BDNF) receptor TrkB and on adult hippocampal neurogenesis since they appear central to the mechanisms of action of antidepressants. The consequences of a chronic hyperforin treatment were investigated on cortical neurons in culture and on the brain of adult mice treated for 4 wk with a daily injection (i.p.) of hyperforin (4 mg/kg). Its effects on the expression of the cyclic adenosine monophosphate response element-binding protein (CREB), phospho-CREB (p-CREB), TrkB and phospho-TrkB (p-TrkB) were analysed by Western blot experiments and its impact on adult hippocampal neurogenesis was also investigated. Hyperforin stimulated the expression of TRPC6 channels and TrkB via SKF-96365-sensitive channels controlling a downstream signalling cascade involving Ca2+, protein kinase A, CREB and p-CREB. In vivo, hyperforin augmented the expression of TrkB in the cortex but not in the hippocampus where hippocampal neurogenesis remained unchanged. In conclusion, this plant extract acts on the cortical BDNF/TrkB pathway leaving adult hippocampal neurogenesis unaffected. This study provides new insights on the neuronal responses controlled by hyperforin. We propose that the cortex is an important brain structure targeted by hyperforin.

(Received August 07 2011)

(Reviewed September 10 2011)

(Revised November 23 2011)

(Accepted November 26 2011)

(Online publication January 09 2012)

Key words

  • Antidepressants;
  • CREB;
  • neurogenesis;
  • PKA;
  • TrkB;
  • TRPC6

Correspondence:

c1 Address for correspondence: Mr A. Bouron, Laboratoire de Chimie et Biologie des Métaux, UMR CNRS 5249, CEA, 17 rue des Martyrs, 38054 Grenoble, France. Tel.: 00 33 4 38 78 44 23 Fax: 00 33 4 38 78 54 87 Email: alexandre.bouron@cea.fr

Footnotes

*  These authors contributed equally to this work.

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