The receptor logic

Neurotrophins bind two receptor classes with opposite effects. Trk receptors (TrkA, TrkB, TrkC) promote survival and growth through PI3K/Akt and MAPK signaling. p75NTR—the "death receptor"—triggers apoptosis when unbound, but enhances Trk signaling when co-expressed.

This dual receptor system creates context-dependent outcomes. After nerve crush, Schwann cells upregulate both NGF and p75NTR. The initial p75NTR-mediated apoptosis clears damaged cells. Then TrkA activation on regrowing axons drives elongation. The sequence matters.

Schwann cell reprogramming

Denervated Schwann cells transform from myelinating cells to repair-competent "Bands of Büngner" that guide axons. This transition requires BDNF-TrkB signaling. In TrkB knockout mice, Schwann cells fail to dedifferentiate and axon regeneration stalls.

NT-3 plays a distinct role—it maintains the progenitor pool. Without NT-3/TrkC signaling, Schwann cell precursors deplete and remyelination fails. The three neurotrophins have non-redundant functions: NGF for axon elongation, BDNF for Schwann cell plasticity, NT-3 for precursor maintenance.

Clinical translation problems

Systemic NGF administration causes hyperalgesia—patients develop severe pain. Direct BDNF injection into nerve gaps improves recovery in rodents but requires precise dosing. Too much BDNF causes aberrant sprouting and neuroma formation.

Current approaches focus on localized delivery. Fibrin conduits releasing NGF show promise in primate models. Gene therapy using inducible promoters may allow spatial and temporal control. But no neurotrophin-based therapy has reached Phase 3 trials for peripheral nerve injury.

The timing problem

Neurotrophin expression follows a precise schedule after injury. NGF peaks at day 3-7 post-injury, then declines. BDNF rises more slowly, peaking at 2-3 weeks. Exogenous administration that doesn't match this natural rhythm may disrupt rather than help.

Early NGF promotes axon growth. Late NGF may cause nociceptor sensitization. Early BDNF has minimal effect—Schwann cells aren't yet competent to respond. Late BDNF enhances remyelination. The therapeutic window is narrow and neurotrophin-specific.

Testable predictions

1. Matching exogenous neurotrophin delivery to the endogenous expression profile will improve functional recovery compared to continuous administration
2. Combined TrkA/TrkB activation will outperform single-neurotrophin therapy for mixed motor/sensory nerves
3. p75NTR antagonists during the first 48 hours post-injury will reduce neuronal death without impairing subsequent regeneration

Research synthesis via domain knowledge