Molecular neurobiological insights on integrative role of Trk neurotrophic receptors and their small-molecule agonists in neurodegenerative conditions

Neurodegenerative conditions signify an irreversible, progressive loss of neurons eventually resulting in a wide array of symptoms including cognitive decline, gradual loss of memory, compromised motor functions. Conventional therapies available principally attempt to either restore neurotransmitter levels, or activate its subordinate receptors; while underlying disease pathology of neurodegeneration being overlooked. This narrowed therapeutic approach ultimately results in irreversible, augmented neurodegeneration, leading to hastened disease progression, resulting in long-term complications, and impaired quality of life. This poses an imperative need for newer treatments to curb the progression of the disease. Neurotrophins; NGF and BDNF are proteins that are classically acknowledged during the development of vertebrate nervous system. Proneurotrophins and Mature neurotrophins activate their specific p75NTR and Trk receptors, which initiate intracellular neuronal survival signaling cascades that play an imperative role in maintaining survival of neurons, apoptosis, and synaptic plasticity. Such neuroprotective effects, native neurotrophins could mainly be a potent strategy in the treatment of neurodegenerative disorders. Due to their deprived drugability, neurotrophins failed to pass on further. Hence, small molecule neurotrophin mimetics that corresponds to its receptor domains might show promising results by increasing receptor-induced neuronal survival, differentiation, and initiation of downstream signalling pathways. Prospects that these small molecule mimetics possesses influential neurotrophic effects might as well lead to the application of such compounds that might be crucial to treat the underlying pathology of neurodegeneration that extends beyond the standard symptomatic treatments of neurodegenerative disorders.