HYPZITRP

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.