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The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders.

ABSTRACT: Central nervous system (CNS) development is a finely tuned process that relies on multiple factors and intricate pathways to ensure proper neuronal differentiation, maturation, and connectivity. Disruption of this process can cause significant impairments in CNS functioning and lead to debilitating disorders that impact motor and language skills, behavior, and cognitive functioning. Recent studies focused on understanding the underlying cellular mechanisms of neurodevelopmental disorders have identified a crucial role for insulin-like growth factor-1 (IGF-1) in normal CNS development. Work in model systems has demonstrated rescue of pathophysiological and behavioral abnormalities when IGF-1 is administered, and several clinical studies have shown promise of efficacy in disorders of the CNS, including autism spectrum disorder (ASD). In this review, we explore the molecular pathways and downstream effects of IGF-1 and summarize the results of completed and ongoing pre-clinical and clinical trials using IGF-1 as a pharmacologic intervention in various CNS disorders. This aim of this review is to provide evidence for the potential of IGF-1 as a treatment for neurodevelopmental disorders and ASD.

SUBMITTER: Costales J

PROVIDER: S-EPMC4790729 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders.

Costales Jesse J Kolevzon Alexander A

Neuroscience and biobehavioral reviews 20160115

Central nervous system (CNS) development is a finely tuned process that relies on multiple factors and intricate pathways to ensure proper neuronal differentiation, maturation, and connectivity. Disruption of this process can cause significant impairments in CNS functioning and lead to debilitating disorders that impact motor and language skills, behavior, and cognitive functioning. Recent studies focused on understanding the underlying cellular mechanisms of neurodevelopmental disorders have id ...[more]

PMID: 26780584

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Project description:Axonal regeneration is an essential condition to re-establish functional neuronal connections in the injured adult central nervous system (CNS), but efficient regrowth of severed axons has proven to be very difficult to achieve. Although significant progress has been made in identifying the intrinsic and extrinsic mechanisms involved, many aspects remain unresolved. Axonal development in embryonic CNS (hippocampus) requires the obligate activation of the insulin-like growth factor 1 receptor (IGF-1R). Based on known similarities between axonal growth in fetal compared to mature CNS, we decided to examine the expression of the IGF-1R, using an antibody to the βgc subunit or a polyclonal anti-peptide antibody directed to the IGF-R (C20), in an in vitro model of adult CNS axonal regeneration, namely retinal ganglion cells (RGC) derived from adult rat retinas. Expression of both βgc and the β subunit recognized by C20 antibody were low in freshly isolated adult RGC, but increased significantly after 4 days in vitro. As in embryonic axons, βgc was localised to distal regions and leading growth cones in RGC. IGF-1R-βgc co-localised with activated p85 involved in the phosphatidylinositol-3 kinase (PI3K) signaling pathway, upon stimulation with IGF-1. Blocking experiments using either an antibody which neutralises IGF-1R activation, shRNA designed against the IGF-1R sequence, or the PI3K pathway inhibitor LY294002, all significantly reduced axon regeneration from adult RGC in vitro (∼40% RGC possessed axons in controls vs 2-8% in the different blocking studies). Finally, co-transfection of RGC with shRNA to silence IGF-1R together with a vector containing a constitutively active form of downstream PI3K (p110), fully restored axonal outgrowth in vitro. Hence these data demonstrate that axonal regeneration in adult CNS neurons requires re-expression and activation of IGF-1R, and targeting this system may offer new therapeutic approaches to enhancing axonal regeneration following trauma.

Project description:Previous work suggests the existence of different isoforms of the insulin-like-growth-factor-1 (IGF-1) receptor in various tissues. In the present study we provide support for the concept that heterogeneous IGF-1 receptors exist in the brain and that part of the heterogeneity is derived from IGF-1 receptor hybrids formed from different beta-subunits. IGF-1 receptors were extracted from adult-rat forebrain synaptosomes and partially purified by wheat-germ agglutinin (WGA) chromatography. Hormone-binding studies in this preparation demonstrate the presence of receptors for IGF-1 and insulin. An antibody, a-RIR, specific for the rat insulin receptor was used to remove insulin receptors from the WGA extract. Studies with the immunodepleted material demonstrated two proteins of 92 and 99 kDa that are phosphorylated on tyrosine during incubation with low concentrations of IGF-1. Both proteins bound with high affinity and specificity to IGF-1 immobilized on agarose, and each underwent phosphorylation when the agarose beads were incubated with [gamma-32P]ATP and MnCl2. Two-dimensional phosphopeptide maps after exhaustive trypsin treatment of the two proteins showed significant differences in their structure as well as differences from the phosphopeptide map for the beta-subunit of the insulin receptor. The relationship of the two proteins to the IGF-1 receptor was further probed by an antibody (a-HF) raised against a specific sequence in the beta-subunit of the human IGF-1 receptor, and a polyclonal antibody raised against the liver insulin receptor (L1) which cross-reacts with the IGF-1 receptor. Both antibodies immunoprecipitated the two phosphorylated proteins. However, reduction of the receptors to form receptor dimers or monomers showed that a-HF precipitated only the 99 kDa protein, whereas L1 precipitated primarily the 92 kDa protein. In conclusion, the brain IGF-1 receptor apparently has two structurally different beta-subunits, one of 92 kDa and a second of 99 kDa. Interestingly, at least a portion of the IGF-1 receptor population has both isoforms in the same receptor.

Dataset Information

The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders.

Publications

The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders.

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