NeuroMolecular Medicine

, Volume 17, Issue 1, pp 71–82 | Cite as

NNZ-2566, a Novel Analog of (1–3) IGF-1, as a Potential Therapeutic Agent for Fragile X Syndrome

  • Robert M. J. Deacon
  • Larry Glass
  • Mike Snape
  • Michael J. Hurley
  • Francisco J. Altimiras
  • Rodolfo R. Biekofsky
  • Patricia Cogram
Original Paper

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.

Keywords

Fragile X syndrome Insulin growth factor 1 NNZ-2566 Behavior Biomarkers 

References

  1. Baker, A. M., Batchelor, D. C., Thomas, G. B., Wen, J. Y., Rafiee, M., Lin, H., & Guan, J. (2005). Central penetration and stability of N-terminal tripeptide of insulin-like growth factor-I, glycine-proline-glutamate in adult rat. Neuropeptides, 39, 81–87.CrossRefPubMedGoogle Scholar
  2. Bickerdike, M. J., Thomas, G. B., Batchelor, D. C., Sirimanne, E. S., Leong, W., Lin, H., et al. (2009). NNZ-2566: A Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke. Journal of the Neurological Sciences, 278, 85–90.CrossRefPubMedGoogle Scholar
  3. Corvin, A. P., Molinos, I., Little, G., Donohoe, G., Gill, M., Morris, D. W., & Tropea, D. (2012). Insulin-like growth factor 1 (IGF1) and its active peptide (1–3) IGF1 enhance the expression of synaptic markers in neuronal circuits through different cellular mechanisms. Neuroscience Letters, 520, 51–56.CrossRefPubMedGoogle Scholar
  4. Deacon, R. M. J. (2006a). Assessing nest building in mice. Nature Protocols, 1, 1117–1119.CrossRefPubMedGoogle Scholar
  5. Deacon, R. M. J. (2006b). Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nature Protocols, 1, 122–124.CrossRefPubMedGoogle Scholar
  6. Deacon, R. M. J. (2013). The successive alleys test of anxiety in mice and rats. Journal of Visualized Experiments, 76, e2705.Google Scholar
  7. Deacon, R. M. J., Brook, R. C., Meyer, D., Haeckel, O., Ashcroft, F. M., Miki, T., et al. (2006). Behavioral phenotyping of mice lacking the KATP channel subunit Kir6.2. Physiology & Behavior, 87, 723–733.CrossRefGoogle Scholar
  8. Deacon, R. M. J., & Rawlins, J. N. P. (2005). Hippocampal lesions, species-typical behaviours and anxiety in mice. Behavioural Brain Research, 156, 241–249.CrossRefPubMedGoogle Scholar
  9. D’Ercole, A. J., & Ye, P. (2008). Minireview: Expanding the mind: Insulin-like growth factor I and brain development. Endocrinology, 149, 5958–5962.CrossRefGoogle Scholar
  10. Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B., Guyenet, P. G., & Kipnis, J. (2012). Wild type microglia arrest pathology in a mouse model of Rett syndrome. Nature, 484, 105–109.CrossRefPubMedCentralPubMedGoogle Scholar
  11. Ethell, I. M., Irie, F., Kalo, M. S., Couchman, J. R., Pasquale, E. B., & Yamaguchi, Y. (2001). EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron, 31, 1001–1013.CrossRefPubMedGoogle Scholar
  12. Ethell, I. M., & Yamaguchi, Y. (1999). Cell surface heparan sulfate proteoglycan syndecan-2 induces the maturation of dendritic spines in rat hippocampal neurons. Journal of Cell Biology, 144, 575–586.CrossRefPubMedCentralPubMedGoogle Scholar
  13. Guan, J., & Gluckman, P. D. (2009). IGF-1 derived small neuropeptides and analogues: A novel strategy for the development of pharmaceuticals for neurological conditions. British Journal of Pharmacology, 157, 881–891.CrossRefPubMedCentralPubMedGoogle Scholar
  14. Hagerman, R. J. (1997). Fragile X syndrome. Molecular and clinical insights and treatment issues. Western Journal of Medicine, 166, 129–137.PubMedCentralPubMedGoogle Scholar
  15. Henderson, C., Wijetunge, L., Kinoshita, M. N., Shumway, M., Hammond, R. S., Postma, F. R., et al. (2012). Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABA(B) receptors with arbaclofen. Science Translational Medicine, 4, 128.CrossRefGoogle Scholar
  16. Henkemeyer, M., Itkis, O. S., Ngo, M., Hickmott, P. W., & Ethell, I. M. (2003). Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. Journal of Cell Biology, 163, 1313–1326.CrossRefPubMedCentralPubMedGoogle Scholar
  17. Hoeffer, C. A., Sanchez, E., Hagerman, R. J., Mu, Y., Nguyen, D. V., Wong, H., et al. (2012). Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes, Brain, and Behavior, 11, 332–341.CrossRefPubMedCentralPubMedGoogle Scholar
  18. Irwin, S. A., Galvez, R., & Greenough, W. T. (2000). Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cerebral Cortex, 10, 1038–1044.CrossRefPubMedGoogle Scholar
  19. Jacobs, S., & Doering, L. C. (2010). Astrocytes prevent abnormal neuronal development in the fragile X mouse. Journal of Neuroscience, 30, 4508–4514.CrossRefPubMedGoogle Scholar
  20. Kumar, V., Zhang, M. X., Swank, M. W., Kunz, J., & Wu, G. Y. (2005). Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. Journal of Neuroscience, 25, 11288–11299.CrossRefPubMedGoogle Scholar
  21. Levenga, J., Hayashi, S., de Vrij, F. M., Koekkoek, S. K., van der Linde, H. C., Nieuwenhuizen, I., et al. (2011). AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. Neurobiology of Diseases, 42, 311–317.CrossRefGoogle Scholar
  22. Lister, R. G. (1987). The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl), 92, 180–185.Google Scholar
  23. Lopez Verrilli, M. A., Pirola, C. J., Pascual, M. M., Dominici, F. P., Turyn, D., & Gironacci, M. M. (2009). Angiotensin-(1–7) through AT receptors mediates tyrosine hydroxylase degradation via the ubiquitin-proteasome pathway. Journal of Neurochemistry, 109, 326–335.CrossRefPubMedGoogle Scholar
  24. Maezawa, I., & Jin, L. W. (2010). Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. Journal of Neuroscience, 30, 5346–5356.CrossRefPubMedGoogle Scholar
  25. Michalon, A., Sidorov, M., Ballard, T. M., Ozmen, L., Spooren, W., Wettstein, J. G., et al. (2012). Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron, 74, 49–56.CrossRefPubMedGoogle Scholar
  26. Nimchinsky, E. A., Oberlander, A. M., & Svoboda, K. (2001). Abnormal development of dendritic spines in FMR1 knockout mice. Journal of Neuroscience, 21, 5139–5146.PubMedGoogle Scholar
  27. Oostra, B. A., & Willemsen, R. (2003). A fragile balance: FMR1 expression levels. Human Molecular Genetics, 12, R249–R257.CrossRefPubMedGoogle Scholar
  28. Rodgers, R. J., & Johnson, N. J. (1995). Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacology, Biochemistry and Behavior, 52, 297–303.CrossRefPubMedGoogle Scholar
  29. Sara, V. R., Carlsson-Skwirut, C., Bergman, T., Jornvall, H., Roberts, P. J., Crawford, M., et al. (1989). Identification of Gly-Pro-Glu (GPE), the aminoterminal tripeptide of insulin-like growth factor 1 which is truncated in brain, as a novel neuroactive peptide. Biochemical and Biophysical Research Communications, 165, 766–771.CrossRefPubMedGoogle Scholar
  30. Sharma, A., Hoeffer, C. A., Takayasu, Y., Miyawaki, T., McBride, S. M., Klann, E., & Zukin, R. S. (2010). Dysregulation of mTOR signaling in fragile X syndrome. Journal of Neuroscience, 30, 694–702.CrossRefPubMedCentralPubMedGoogle Scholar
  31. Svedin, P., Guan, J., Mathai, S., Zhang, R., Wang, X., Gustavsson, M., et al. (2007). Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat. Developmental Neuroscience, 29, 393–402.CrossRefPubMedGoogle Scholar
  32. The Dutch-Belgian Fragile X Consortium, Bakker, C. E., Verheij, C., Willemsen, R., van der Helm, R., Oerlemans, F., et al. (1994). Fmr1 knockout mice: a model to study fragile X mental retardation. Cell, 78, 23–33.Google Scholar
  33. Tropea, D., Giacometti, E., Wilson, N. R., Beard, C., McCurry, C., Fu, D. D., et al. (2009). Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. PNAS, 106, 2029–2034.CrossRefPubMedCentralPubMedGoogle Scholar
  34. Wei, H. H., Lu, X. C., Shear, D. A., Waghray, A., Yao, C., Tortella, F. C., & Dave, J. R. (2009). NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats. Journal of Neuroinflammation, 6, 19–29.CrossRefPubMedCentralPubMedGoogle Scholar
  35. Yan, Q. J., Rammal, M., Tranfaglia, M., & Bauchwitz, R. P. (2005). Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology, 49, 1053–1066.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Robert M. J. Deacon
    • 1
  • Larry Glass
    • 2
  • Mike Snape
    • 3
  • Michael J. Hurley
    • 4
  • Francisco J. Altimiras
    • 5
  • Rodolfo R. Biekofsky
    • 1
  • Patricia Cogram
    • 1
    • 6
  1. 1.Neuro-DVI LLPLondonUK
  2. 2.Neuren Pharmaceuticals LtdCamberwellAustralia
  3. 3.Autism Therapeutics LtdLondonUK
  4. 4.Division of Brain Sciences, Centre for Neuroinflammation and NeurodegenerationImperial CollegeLondonUK
  5. 5.University of ChileSantiagoChile
  6. 6.Biomedicine Division, Centre for Systems BiotechnologyFraunhofer Chile Research FoundationSantiagoChile

Personalised recommendations