TrkB partial agonists: potential treatment strategy for epilepsy, mania, and autism

Brain-derived neurotrophic factor (BDNF) is a member of a family of neurotrophins that, by activating a tyrosine kinase B receptor (TrkB), regulates a wide variety of processes in the nervous system, including neural development, function and survival. Evidence suggests that excess BDNF is involved in the pathogenesis of epilepsy, mania and autism. Thus, agents that can decrease BDNF-TrkB pathway signaling may be therapeutic for these diseases. However, blocking BDNF-TrkB pathways with TrkB antagonists may be harmful, as BDNF-TrkB deficiency has been related to major depression and Alzheimer's disease. A partial agonist is an agent that elicits a maximum response that is less than that of an agonist (e.g., the physiological ligand), so, in the presence of excess full agonist, a partial agonist would act as an antagonist. Interestingly, a dopaminergic partial agonist, aripiprazole, has been successfully developed for the treatment of psychotic disorders. Recently specific TrkB partial agonists have been synthesized by O'Leary and Hughes; it is proposed that these partial TrkB agonists may provide a novel strategy for the treatment of epilepsy, mania or autism, which may be associated with BDNF-TrkB hyperfunction.