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The Journal of Neuroscience, September 15, 2004, 24(37):8009-8018; doi:10.1523/JNEUROSCI.1508-04.2004

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Behavioral/Systems/Cognitive
Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

Martin A. Bruno,¹ Paul B. S. Clarke,¹ Alicia Seltzer,⁶ Rémi Quirion,^1,2 Kevin Burgess,⁷ A. Claudio Cuello,^1,3 * and H. Uri Saragovi^1,4,5 *

Departments of ¹Pharmacology and Therapeutics, ²Psychiatry/Douglas Hospital Research Center, ³Anatomy and Cell Biology, and ⁴Oncology/Cancer Center, and ⁵Lady Davis Research Institute, McGill University, Montréal, Quebec, H3T 1E2 Canada, ⁶Facultad de Medicina, Universidad de Cuyo, Mendoza 5500, Argentina, and ⁷Department of Chemistry, Texas A&M University, College Station, Texas 77842

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.

Key words: peptidomimetic; age; cognition; memory; TrkA; NGF; agonist; cholinergic; CNS

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Received June 25, 2003; revised July 29, 2004; accepted August 3, 2004.

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