Modulation of p75NTR-dependent motor neuron death by a small non-peptidyl mimetic of the neurotrophin loop 1 domain

The p75 neurotrophin receptor (p75(NTR)) is expressed by degenerating spinal motor neurons in amyotrophic lateral sclerosis (ALS). The mature and pro-form of nerve growth factor (NGF) activate p75(NTR) to trigger motor neuron apoptosis. However, attempts to modulate p75(NTR)-mediated neuronal death in ALS models by downregulating or antagonizing p75(NTR) with synthetic peptides have led to only modest results. Recently, a novel ligand of p75(NTR), compound LM11A-24, has been identified. It is a non-peptidyl mimetic of the neurotrophin loop 1 domain that promotes hippocampal neuron survival through p75(NTR) and exerts protection against p75(NTR)-mediated apoptosis of oligodendrocytes induced by proNGF. Thus, LM11A-24 appears to activate p75(NTR)-linked survival but not death mechanisms, and may interfere with the ability of neurotrophins to induce apoptosis. Given these findings, we hypothesized that LM11A-24 might be a particularly potent inhibitor of motor neuron degeneration. We examined the effects of LM11A-24 on apoptosis of cultured rat embryonic motor neurons. Interestingly, in contrast to the effects observed in hippocampal cultures, LM11A-24 was unable to prevent motor neuron apoptosis induced by trophic factor deprivation. However, picomolar concentrations of LM11A-24 prevented p75(NTR)-dependent motor neuron death induced by either exogenous addition of NGF or spinal cord extracts from symptomatic superoxide dismutase-1(G93A) mice, in the presence of low steady-state concentrations of nitric oxide. LM11A-24 also inhibited motor neuron death induced by NGF-producing reactive astrocytes in co-culture conditions. These studies suggest that modulation of p75(NTR) by small molecule ligands targeting this receptor might constitute a novel strategy for preventing motor neuron degeneration.