Abstract
Previously, we developed a proteolytically stable small molecule peptidomimetic termed D3 as a selective ligand of the extracellular domain of the TrkA receptor for the NGF. Ex vivo D3 was defined as a selective, partial TrkA agonist. Here, the in vivo efficacy of D3 as a potential therapeutic for cholinergic neurons was tested in cognitively impaired aged rats, and we compared the consequence of partial TrkA activation (D3) versus full TrkA/p75 activation (NGF). We show that in vivo D3 binds to TrkA receptors and affords a significant and long-lived phenotypic rescue of the cholinergic phenotype both in the cortex and in the nucleus basalis. The cholinergic rescue was selective and correlates with a significant improvement of memory/learning in cognitively impaired aged rats. The effects of the synthetic ligand D3 and the natural ligand NGF were comparable. Small, proteolytically stable ligands with selective agonistic activity at a growth factor receptor may have therapeutic potential for neurodegenerative disorders.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcholine / physiology
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Aging / psychology*
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Animals
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Basal Nucleus of Meynert / chemistry
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Basal Nucleus of Meynert / drug effects*
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Basal Nucleus of Meynert / physiopathology
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Biotinylation
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Cerebral Cortex / chemistry
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Cerebral Cortex / drug effects*
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Cerebral Cortex / physiopathology
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Choline O-Acetyltransferase / metabolism
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Cholinergic Fibers / drug effects
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Cholinergic Fibers / physiology
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Cognition Disorders / drug therapy*
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Cognition Disorders / etiology
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Cognition Disorders / physiopathology
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Drug Evaluation
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Injections, Intraventricular
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Male
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Maze Learning
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Memory Disorders / drug therapy
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Memory Disorders / etiology
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Memory Disorders / physiopathology
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Microscopy, Confocal
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Nerve Growth Factor / pharmacology
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Nerve Growth Factor / therapeutic use
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Nerve Tissue Proteins / metabolism
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Nootropic Agents / administration & dosage
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Nootropic Agents / pharmacokinetics
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Nootropic Agents / pharmacology
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Nootropic Agents / therapeutic use*
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Peptides, Cyclic / administration & dosage
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Peptides, Cyclic / pharmacokinetics
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Peptides, Cyclic / pharmacology
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Peptides, Cyclic / therapeutic use*
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Phenotype
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Phosphorylation / drug effects
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Phosphotyrosine / metabolism
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Protein Processing, Post-Translational / drug effects
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Rats
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Rats, Inbred F344
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Receptor, trkA / agonists*
Substances
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D3 compound
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Nerve Tissue Proteins
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Nootropic Agents
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Peptides, Cyclic
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Phosphotyrosine
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Nerve Growth Factor
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Choline O-Acetyltransferase
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Receptor, trkA
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Acetylcholine