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Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice.
- Source :
-
Journal of neuroscience research [J Neurosci Res] 2004 Oct 15; Vol. 78 (2), pp. 193-9. - Publication Year :
- 2004
-
Abstract
- Neurotrophin level imbalances and altered p75 neurotrophin receptor (p75(NTR)) expression are implicated in spinal motor neuron degeneration in human and mouse models of amyotrophic lateral sclerosis (ALS). Recently, elevated reactive astrocyte-derived nerve growth factor (NGF) was linked to p75(NTR)-expressing motor neuron death in adult transgenic ALS mice. To test the role of NGF-dependent p75(NTR)-mediated signalling in ALS, we examined the effects of a cyclic decapeptide antagonist of p75(NTR) ligand binding by using neurotrophin-stimulated cell death assays and transgenic ALS mice. Murine motor neuron-like (NSC-34) cell cultures expressed full-length and truncated p75(NTR), tyrosine receptor kinase B (TrkB), and the novel neurotrophin receptor homolog-2 (NHR2) but were TrkA deficient. Accordingly, treatment of cells with NGF induced dose-dependent cell death, which was significantly blocked by the cyclic decapeptide p75(NTR) antagonist. Application of brain-derived neurotrophic factor, neurotrophin-3, or neurotrophin-4 to cultures increased cell proliferation, and such trophic effects were abolished by pretreatment with the tyrosine kinase inhibitor K-252a. Systemic administration of a modified cyclic decapeptide p75(NTR) antagonist conjugated to the TAT4 cell permeabilization sequence to presymptomatic transgenic SOD1(G93A) mice affected neither disease onset nor disease progression, as determined by hindlimb locomotor, grip strength, and survival analyses. These studies suggest that disrupting NGF-p75(NTR) interactions by using this approach is insufficient to alter the disease course in transgenic ALS mice. Thus, alternate ligand-independent pathways of p75(NTR) activation or additional NGF receptor targets may contribute to motor neuron degeneration in ALS mice.<br /> (Copyright 2004 Wiley-Liss, Inc.)
- Subjects :
- Amino Acid Sequence
Animals
Blood-Brain Barrier drug effects
Carbazoles pharmacology
Cell Line
Cell Survival drug effects
Cell Survival physiology
Disease Progression
Indole Alkaloids
Mice
Mice, Transgenic
Molecular Sequence Data
Nerve Growth Factors antagonists & inhibitors
Nerve Growth Factors physiology
Neuropeptides pharmacology
Oligopeptides pharmacology
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Receptor Protein-Tyrosine Kinases physiology
Receptor, Nerve Growth Factor
Amyotrophic Lateral Sclerosis physiopathology
Receptors, Nerve Growth Factor antagonists & inhibitors
Receptors, Nerve Growth Factor physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0360-4012
- Volume :
- 78
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of neuroscience research
- Publication Type :
- Academic Journal
- Accession number :
- 15378612
- Full Text :
- https://doi.org/10.1002/jnr.20256