Highlight | Pharmacology
Researchers at the Chemistry and Biology of Metals Laboratory are working on hyperforin, a bioactive molecule isolated from a plant and exhibiting antidepressant effects. The other pharmacological interests of hyperforin reside in the fact that it is a potent inhibitor of angiogenesis and it displays anti-inflammatory properties.
The plant St John's wort (SJW) (Hypericum perforatum) is one of the most frequently prescribed medicinal plants in the world. It has antidepressant actions and is prescribed to alleviate symptoms of mild to moderate depression. Results of clinical trials showed that SJW is safe, well tolerated, and is as effective as standard antidepressants. Furthermore, extracts of SJW produce fewer side effects than these standard antidepressant.
Researchers of the
Biology of Metals
team at the Chemistry and Biology of Metals Laboratory are currently defining the biological properties of hyperforin. So far, nearly 2 dozens of bioactive compounds have been isolated from SJW such as the phoroglucinols hyperforin and adhyperforin. Hyperforin is regarded as the main antidepressant molecule present in the total extracts of SJW. Like many synthetic antidepressant molecules, it inhibits the uptake of many neurotransmitters (dopamine, serotonin, noradrenalin, glutamate, GABA).
In vivo studies showed that it increases the extracellular levels of catecholamines, serotonin and glutamate and enhances the release of acetylcholine. In addition, it displays 2 interesting properties: it is a selective activator of the cationic channel TRPC6, a plasma membrane protein involved in the transport of Ca, Na and Zn ions. In addition, hyperforin depolarizes the mitochondrial membrane potential which is associated with the release of Ca and Zn ions. The chronic treatment of cultured neurons and intra-peritoneal injections of hyperforin in adult mice for 4 weeks induce an intracellular redistribution of Zn, enhance the levels of metallothioneins and TRPC6. This treatment also causes an augmentation of the cellular levels of TrkB, the receptor of the brain-derived neurotrophic factor (BDNF)
[1-5]. Of interest, hyperforin influences the metabolism of the amyloid precursor protein (APP). For instance, it favors the production of sAPP which prevents the formation of the amyloid peptides Aß40 and Aß42. Since it is a potent inhibitor of enzymes like 5-lipoxygenase or cyclo-oxygenase-1, several laboratories started to synthesize hyperforin analogues. Another field of research concerns the anti-tumoral properties of hyperforin. This molecule causes the death of tumor cells and inhibits the development of the vascular bed surrounding tumors.
In vitro and
in vivo experiments revealed that hyperforin is a promising anti-angiogenic agent.
Hyperforin is a molecule of natural origin possessing promising interesting pharmacological properties. One major challenge is to develop more stable and specific hyperforin derivatives.
At the cellular level, the hyperforin depolarizes the mitochondrial membrane potential, releasing zinc (and calcium) from these organelle. Moreover, it is a potent activator of TRPC6, cation channels in the plasma membrane. During a chronic treatment, hyperforin controls the expression of both TRPC6 channels and TrkB, the receptor of the BDNF growth factor. This control is made via an intracellular signaling cascade involving the protein kinase A (PKA) and the CREB transcription factor.
 Gibon J, Deloulme JC, Chevallier T, Ladevèze E, Abrous DN and Bouron A
The antidepressant hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner.
International Journal of Neuropsychopharmacoly, 2012
 Gibon J, Richaud P and Bouron A
Hyperforin changes the zinc-storage capacities of brain cells.
 Gibon J, Tu P and Bouron A
Store-depletion and hyperforin activate distinct types of Ca2+-conducting channels in cortical neurons.
Cell Calcium, 2010
 Tu P, Gibon J and Bouron A
The TRPC6 channel activator hyperforin induces the release of zinc and calcium from mitochondria.
Journal of Neurochemistry, 2010
 Tu P, Kunert-Keil C, Lucke S, Brinkmeier H and Bouron A
Diacylglycerol analogues activate second messenger-operated calcium channels exhibiting TRPC-like properties in cortical neurons.
Journal of Neurochemistry, 2009
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