Pathophysiological mechanisms for actions of the neurotrophins

Neurotrophins provide trophic and tropic support for different neuronal subpopulations in the developing and adult nervous systems. Expression of the neurotrophins and their receptors can be altered in several different disease or injury states that impact upon the functions in the central and peripheral nervous systems. The intracellular signals used by the neurotrophins are triggered by ligand binding to the cell surface Trk and p75(NTR) receptors. In general, signals emanating from Trk receptors support survival, growth and synaptic strengthening, while those emanating from p75(NTR) induce apoptosis, attenuate growth and weaken synaptic signaling. Mature neurotrophins are the preferred ligand for Trk proteins while p75(NTR) binds preferentially to the proneurotrophins and serves as a signaling component of the receptor complex for growth inhibitory molecules of central nervous system myelin [ie, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgP) and Nogo]. The functional antagonism between Trk and p75(NTR) signaling may significantly impact the pathogenesis of human neurodevelopmental and neurodegenerative diseases and further complicate therapeutic uses of exogenous neurotrophins. The potential for each is discussed in this review.