Neurotrophin-based strategies for neuroprotection

Abstract

Neurotrophins activate a number of signaling pathways relevant to neuroprotection; however, their poor pharmacological properties and their pleiotropic effects resulting from interaction with the p75^NTR-Trk-sortilin three-receptor signaling system limit therapeutic application. While local application of neurotrophin proteins addresses some of the pharmacological challenges, selective targeting of neurotrophin receptors might allow for more selective application of neurotrophin receptor signaling modulation. Recent studies have supported the feasibility of developing non-peptidyl small molecules that mimic specific domains of neurotrophins and modulate signaling of specific neurotrophin receptors. The expression of p75^NTR by populations of neurons most vulnerable in Alzheimer's disease and the linkage of p75^NTR signaling to aberrant signaling mechanisms occurring in this disorder, point to potential applications for p75^NTR-based small molecule strategies. Small molecules targeted to p75^NTR in the settings of neurodegenerative disease and other forms of neural injury might serve to inhibit death signaling, block proNGF-mediated degenerative signaling and minimize deleterious effects promoted by pharmacologically upregulated Trk signaling.