NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome

Neuromolecular Med. 2015 Mar;17(1):71-82. doi: 10.1007/s12017-015-8341-2. Epub 2015 Jan 23.

Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / drug therapy
  • Brain / metabolism
  • Brain / physiopathology
  • Conditioning, Classical / drug effects
  • Dendrites / drug effects
  • Dendrites / ultrastructure
  • Drug Evaluation, Preclinical
  • Exploratory Behavior / drug effects
  • Fear / drug effects
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / genetics
  • Insulin-Like Growth Factor I / physiology*
  • Interpersonal Relations
  • MAP Kinase Signaling System / drug effects
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism
  • Nesting Behavior / drug effects
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Testis / abnormalities

Substances

  • Fmr1 protein, mouse
  • NNZ 2566
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Oligopeptides
  • Fragile X Mental Retardation Protein
  • Insulin-Like Growth Factor I
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt