| First Author | Pehar M | Year | 2006 |
| Journal | Eur J Neurosci | Volume | 24 |
| Issue | 6 | Pages | 1575-80 |
| PubMed ID | 17004921 | Mgi Jnum | J:112914 |
| Mgi Id | MGI:3663983 | Doi | 10.1111/j.1460-9568.2006.05040.x |
| Citation | Pehar M, et al. (2006) Modulation of p75-dependent motor neuron death by a small non-peptidyl mimetic of the neurotrophin loop 1 domain. Eur J Neurosci 24(6):1575-80 |
| abstractText | 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. |
