Affiliations: [a] Department of Neurology, University of North Carolina, Chapel Hill, USA | [b] Department of Neurology, University of California, San Francisco and the San Francisco VA Medical Center, USA
Correspondence:
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Corresponding author: Frank M. Longo, Department of Neurology, UNC, Chapel Hill School of Medicine CB7025, Chapel Hill, NC 27599, USA. Tel.: +1 919 966 8178; Fax: +1 919 966 2922; E-mail: longof@glial.med.unc.edu.
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 p75NTR-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 p75NTR by populations of neurons most vulnerable in Alzheimer's disease and the linkage of p75NTR signaling to aberrant signaling mechanisms occurring in this disorder, point to potential applications for p75NTR-based small molecule strategies. Small molecules targeted to p75NTR 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.
