TrkB partial agonists: potential treatment strategy for major depression

Brain-derived neurotrophic factor (BDNF) regulates a wide variety of processes in the nervous system, including neural development, function and survival, through activation of the tyrosine kinase B receptor (TrkB). Evidence suggests that low central BDNF activity, especially in the hippocampus, may play a pivotal role in the pathophysiology of major depression, and that agents that can increase BDNF-TrkB pathway signaling may be therapeutic for this disease. However, recent studies showed that increased BDNF activity in the mesolimbic region may cause a depressed state. A partial agonist is an agent that elicits a maximum response that is less than that of an agonist and acts as an antagonist in the presence of excess full agonist. Recently some small peptides have been synthesized that act as TrkB partial agonists. Since BDNF might be pro-depressive in the mesolimbic system and anti-depressive in the hippocampus region, it is proposed that these peptides or other partial TrkB agonists may provide a novel strategy for the treatment of major depression, which may be associated with BDNF-TrkB hypofunction in hippocampus and/or hyperfunction in the mesolimbic system. Furthermore, given the potential imbalance of BDNF in specific brain regions in major depression, selection of agents with maximal hippocampus/mesolimbic BDNF activation ratio could be of importance in the development of novel antidepressants.