title: Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm.
abstract: Neurodegenerative disorders are prevalent, complex and devastating conditions, with very limited treatment options currently available. While they manifest in many forms, there are commonalities that link them together. In this review, we will focus on neurotrophins - a family of related factors involved in neuronal development and maintenance. Neurodegenerative diseases often present with a neurotrophin imbalance, in which there may be decreases in trophic signaling through Trk receptors for example, and/or increases in pro-apoptotic activity through p75. Clinical trials with neurotrophins have continuously failed due to their poor pharmacological properties as well as the unavoidable activation of p75. Thus, there is a need for drugs without such setbacks. Small molecule neurotrophin mimetics are favorable options since they can selectively activate Trks or inactivate p75. In this review, we will initially present a brief outline of how these molecules are synthesized and their mechanisms of action; followed by an update in the current state of neurotrophins and small molecules in major neurodegenerative diseases. Although there has been significant progress in the development of potential therapeutics, more studies are needed to establish clear mechanisms of action and target specificity in order to transition from animal models to the assessment of safety and use in humans.
authors.affiliation: Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Josephy-Hernandez
authors.affiliation: Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Sean
authors.initials: S
authors.lastname: Jmaeff
authors.affiliation: Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Iulia
authors.initials: I
authors.lastname: Pirvulescu
authors.affiliation: Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Tahar
authors.initials: T
authors.lastname: Aboulkassim
authors.affiliation: Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada. Electronic address: uri.saragovi@mcgill.ca.
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
mesh_terms: D000818:Animals; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017475:Receptors, Nerve Growth Factor / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D017475:Receptors, Nerve Growth Factor
keywords: Mimetic; Neurodegeneration; Neurotrophin; Receptor; Small molecule; Therapy