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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
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.
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.
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.
Deacon, R. M. J. (2006a). Assessing nest building in mice. Nature Protocols, 1, 1117–1119.
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.
Deacon, R. M. J. (2013). The successive alleys test of anxiety in mice and rats. Journal of Visualized Experiments, 76, e2705.
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.
Deacon, R. M. J., & Rawlins, J. N. P. (2005). Hippocampal lesions, species-typical behaviours and anxiety in mice. Behavioural Brain Research, 156, 241–249.
D’Ercole, A. J., & Ye, P. (2008). Minireview: Expanding the mind: Insulin-like growth factor I and brain development. Endocrinology, 149, 5958–5962.
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.
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.
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.
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.
Hagerman, R. J. (1997). Fragile X syndrome. Molecular and clinical insights and treatment issues. Western Journal of Medicine, 166, 129–137.
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.
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.
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.
Irwin, S. A., Galvez, R., & Greenough, W. T. (2000). Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cerebral Cortex, 10, 1038–1044.
Jacobs, S., & Doering, L. C. (2010). Astrocytes prevent abnormal neuronal development in the fragile X mouse. Journal of Neuroscience, 30, 4508–4514.
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.
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.
Lister, R. G. (1987). The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl), 92, 180–185.
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.
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.
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.
Nimchinsky, E. A., Oberlander, A. M., & Svoboda, K. (2001). Abnormal development of dendritic spines in FMR1 knockout mice. Journal of Neuroscience, 21, 5139–5146.
Oostra, B. A., & Willemsen, R. (2003). A fragile balance: FMR1 expression levels. Human Molecular Genetics, 12, R249–R257.
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.
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.
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.
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.
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.
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.
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.
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.
Acknowledgments
We are much indebted to FRAXA Research Foundation, USA, and Professor David Nelson, Baylor College of Medicine, USA, for sending us the two fmr1 knockout mice used in this study. We thank the FRAXA Research Foundation and Neuren Pharmaceuticals Ltd for supporting this work. We would like to thank Dr. Mike Bickerdike, for helpful advice and critical reading of the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Robert M. J. Deacon and Larry Glass have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Deacon, R.M.J., Glass, L., Snape, M. et al. NNZ-2566, a Novel Analog of (1–3) IGF-1, as a Potential Therapeutic Agent for Fragile X Syndrome. Neuromol Med 17, 71–82 (2015). https://doi.org/10.1007/s12017-015-8341-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-015-8341-2