Modulation of p75-dependent motor neuron death by a small non-peptidyl mimetic of the neurotrophin loop 1 domain.
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.
Pehar
Mariana
M
Departamento de Neurobiología Celulary Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay.
Cassina
Patricia
P
Vargas
Marcelo R
MR
Xie
Youmei
Y
Beckman
Joseph S
JS
Massa
Stephen M
SM
Longo
Frank M
FM
Barbeito
Luis
L
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000166:cytology
D051100:Glial Cell Line-Derived Neurotrophic Factor; C515869:LM11A-24; D008070:Lipopolysaccharides; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D002110:Caffeine; D020932:Nerve Growth Factor