NEURON 2013 - Appel à Projets Transnational dans le cadre de l'ERA-NET NEURON II sur les Maladies Mentales - Volet international de l’AAP SAMENTA 2013

HYPerforin analogues, ZInc and TRPC6 channels – a new antidepressant concept? – HYPZITRP

Submission summary

Depression is a widespread illness characterized by decreased mood, pleasure, motivation
and reward. The World Health Organization showed in the global burden of disease study that
depression is the fourth leading cause of disease burden world wide accounting for 12 % of all total
years lived with disability1. The treatment of major depressive disorder is confounded by high rates of
treatment resistance coupled with low probabilities of achieving lasting remission. Such clinical
realities, paired with high economic burden, have motivated the consortium of HYPZITRP to identify
and develop new alternative therapeutic approaches and to better understand the pathophysiology of
depression. Although the monoamine hypothesis of depression has dominated pharmacological
treatment strategies, recent work suggests that the neuropathology of depression is stratified across
the reduction of synaptic plasticity ranging from reduced synapse number to impaired dendrititc
lengths and arborization to altered hippocampal neurogenesis. Beside other mechanisms, recent
evidence suggests that the non-selective ion channels, the canonical transient receptor potential
channel 6 (TRPC6), regulates synaptic plasticity probably via the influx of calcium and zinc ions.
Furthermore, TRPC6 channels are the molecular target of hyperforin, the antidepressant active
constituent of St. John’s wort extracts. St. John’s wort extracts are used since Paracelsus to treat mild
to moderate depression. Beside hyperforin’s high chemical instability it shows only a modest potency
at TRPC6 channels limiting its use as a lead compound for a new class of antidepressants. Therefore,
the HYPZITRP consortium decided to first focus on the synthesis and detailed pharmacological and
behavioural characterization of new hyperforin derivatives and second to better understand the
importance and interplay of Zn and TRPC6 channels in the pathophysiology of depression.

Project coordination

Kristina Leuner ()

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS laboratoire de chimie et biologie des métaux

Help of the ANR 111,840 euros
Beginning and duration of the scientific project: April 2014 - 36 Months

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