Small Molecules Targeting TrkB/BDNF for Neurodegenerative Disease Therapeutic Discovery

Abstract Neurodegenerative diseases comprise a collection of disorders that systematically bring about the death of a variety of cell types within the brain, resulting in cognitive and/or motor impairments that gradually decrease the quality of life until eventual death. While each disease possesses its own unique phenotype, many neurodegenerative diseases share the same pathologic etiology. However, an understudied aspect of neurodegenerative diseases is depleted neurotrophic signaling. Under healthy conditions, neurotrophins promote cell survival through the activation of neurite formation, neurogenesis, cytoskeletal rearrangement, and long-term potentiation. Given the multitude of cellular benefits of neurotrophins, targeting their signaling pathways may facilitate neurodegenerative disease therapy development. In this Review, we examine various neurodegenerative diseases and how they may benefit from tropomyosin receptor kinase B/brain-derived neurotrophic factor (TrkB/BDNF)-targeted therapies. The molecular mechanisms of neurotrophin signaling that contribute to neuronal survival are discussed, and a comprehensive overview of experimentally validated small molecules that exhibit neuroprotective effects by modulating the TrkB/BDNF signaling pathway in neurodegenerative diseases is provided.