Long-lasting rescue of age-associated deficits in cognition and the CNS cholinergic phenotype by a partial agonist peptidomimetic ligand of TrkA.
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.
Bruno
Martin A
MA
Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec, H3T 1E2 Canada.
Clarke
Paul B S
PB
Seltzer
Alicia
A
Quirion
Rémi
R
Burgess
Kevin
K
Cuello
A Claudio
AC
Saragovi
H Uri
HU
D000109:Acetylcholine / Q000502:physiology; D000375:Aging / Q000523:psychology*; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000737:chemistry / Q000187:drug effects* / Q000503:physiopathology; D019921:Biotinylation; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects* / Q000503:physiopathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004341:Drug Evaluation; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D018613:Microscopy, Confocal; D020932:Nerve Growth Factor / Q000494:pharmacology / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D020917:Receptor, trkA / Q000819:agonists*
C404517:D3 compound; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D010456:Peptides, Cyclic; D019000:Phosphotyrosine; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D020917:Receptor, trkA; D000109:Acetylcholine