Modulation of P75-dependent Motor Neuron Death by a Small Non-peptidyl Mimetic of the Neurotrophin Loop 1 Domain.
From: Departamento de Neurobiología Celulary Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay.
The European journal of neuroscience
- Publish Date: Sep 2006
- ISSN: 0953-816X
- Volume: 24
- Issue: 6
- Pages: 1575-80
- Medium: Print
- Language: English
- Citation (JAMA): Pehar Mariana, Cassina Patricia, Vargas Marcelo R, et al. Modulation of P75-dependent Motor Neuron Death by a Small Non-peptidyl Mimetic of the Neurotrophin Loop 1 Domain.. Eur. J. Neurosci. Sep 2006;24:1575-80
Abstract
The p75 neurotrophin receptor (p75NTR) is expressed by degenerating spinal motor neurons in amyotrophic lateral sclerosis (ALS). The mature and pro-form of nerve growth factor (NGF) activate p75NTR to trigger motor neuron apoptosis. However, attempts to modulate p75NTR-mediated neuronal death in ALS models by downregulating or antagonizing p75NTR with synthetic peptides have led to only modest results. Recently, a novel ligand of p75NTR, compound LM11A-24, has been identified. It is a non-peptidyl mimetic of the neurotrophin loop 1 domain that promotes hippocampal neuron survival through p75NTR and exerts protection against p75NTR-mediated apoptosis of oligodendrocytes induced by proNGF. Thus, LM11A-24 appears to activate p75NTR-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 p75NTR-dependent motor neuron death induced by either exogenous addition of NGF or spinal cord extracts from symptomatic superoxide dismutase-1G93A 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 p75NTR by small molecule ligands targeting this receptor might constitute a novel strategy for preventing motor neuron degeneration.
Mesh Headings (Keywords): Analysis of Variance, Animals, Animals, Newborn, Astrocytes, Caffeine, Cell Count, Cell Death, Cells, Cultured, Dose-Response Relationship, Drug, Drug Interactions, Embryo, Mammalian, Glial Cell Line-Derived Neurotrophic Factor, Lipopolysaccharides, Motor Neurons, Nerve Growth Factor, Nerve Growth Factors, Protein Structure, Tertiary, Rats, Receptor, Nerve Growth Factor, Reverse Transcriptase Polymerase Chain Reaction, Spinal Cord
Check for Full Text / PubMed Unique Identifier (PMID): 17004921
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