BDNF/TrkB pathway promising alternative for new antidepressants

A potential novel mechanism of action for treating depression involves enhancing the signalling of the brain-derived neurotrophic factor (BDNF) through its receptor TrkB. The BDNF/TrkB pathway appears promising, as new data characterised positive allosteric modulators of TrkB for the treatment of depression [1].

BDNF plays a key role in neuronal plasticity events in the brain such as long-term potentiation and memory formation. Accumulating evidence suggests BDNF plays a role in depression. All existing antidepressants bind directly to the TrkB receptor, through which they mediate part of their effect. Targeting the TrkB receptor directly with a positive allosteric modulator (PAM) could offer an even more selective way of enhancing the BDNF signalling, avoiding side effects of classical antidepressants.

Researchers screened compound libraries and identified multiple compounds as positive modulators of nerve growth factor (NGF) and BDNF signalling. These compounds, for example ACD856, enhanced BDNF/TrkB signalling, some with both modulatory as well as agonistic properties. ACD855 potentiated BDNF signalling and enhanced ERK 1/2 phosphorylation in an activity-dependent manner in a mouse model. Subcutaneous administration of ACD856 in rats significantly increased their levels of serotonin compared with vehicle; it also increased noradrenalin and dopamine. In a forced swim test, ACD856 significantly reduced immobility time in mice. This effect was comparable to that of 20 mg/kg fluoxetine. ACD856 also had a positive effect on cognitive function. It significantly and dose-dependently reversed scopolamine-induced memory impairment in mice in the passive avoidance model. The attenuating effect of ACD856 could be blocked by a selective TrkB antagonist, suggesting that the effects were indeed mediated by TrkB. ACD856 is currently in clinical development.

1. Sandin J, et al. Characterization of positive allosteric modulators of TrkB for the treatment of depression. P.0229, ECNP 2021 Congress, 2–5 October.

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Posted on 26 November 202117 May 2024