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.

Keywords: ASD; Autism spectrum disorder; CNS development; Central nervous system disorders; Fragile X syndrome; IGF-1; Insulin-like growth factor 1; Neurodevelopmental disorders; Neurotrophic factors; Phelan-McDermid syndrome; Rett syndrome.

Figure 1. IGF-1 downstream effects on transcription, protein synthesis and cell growth

IGF-1 acts on its receptor to initiate several pathways responsible for protein translation, which in turn aids in cell growth, migration and differentiation. Activation of the PI3K/Akt/mTOR pathway by IGF-1 leads to activation of S6 kinase proteins and phosphorylation of eIF4E, which in turn lead to increased mRNA translation (Hay & Sonenberg, 2004). IGF-1 also activates the MAPK pathway, which increases neuronal proliferation via ERK activation and increases gene transcription via ELK1 activation ((Fernandez & Torres-Aleman, 2012) Abbreviations: IGF-1, insulin-like growth factor 1; IRS-1, insulin receptor substrate 1, PI3K., phosphatidylinositol-3 kinase; PTEN, phosphate and tensin homolog; Akt, serine/threonine-specific protein kinase; mTOR, mammalian target of rapamycin; FMRP, Fragile X mental retardation protein; S6K, P70-S6 kinase 1; eIF4E, eukaryotic translation initiation factor 4E; Shc, Src-homology and collagen homology; SOS1, son of sevenless homolog 1; GRB2, growth factor receptor-bound protein 2; Raf1, Rapidly accelerating fibrosarcoma kinase protein 1; MEK, MAPK/ERK kinase or mitogen-activated protein kinases/extracellular signal-regulated kinases; ELK1, ETS-domain protein Elk-1

Figure 2. IGF-1 mechanisms of inhibiting apoptosis

IGF-1 receptor activation mediates cell survival via several pathways, including inhibition of apoptosis via three pathways shown below. Two converging pathways have the similar end result of blocking BAD induced cell death: 1) activation of PI3K/Akt pathway, which phosphotylates BAD to block apoptosis (Datta et al., 1997) and 2) activation of the MAP kinase pathways to phosphorylate BAD, thus blocking apoptosis (Bonni et al., 1999). The third pathway involves Akt inhibition of apoptosis signaling FOXO transcription factors (Stitt et al., 2004). Abbreviations: IGF-1, insulin-like growth factor 1; IRS, insulin receptor substrate, PI3K., phosphatidylinositol-3 kinase; SHC, Src-homology and collagen homology; SOS, son of sevenless homolog; GRB2, growth factor receptor-bound protein 2; Raf, Rapidly accelerating fibrosarcoma kinase protein; MEK, MAPK/ERK kinase or mitogen-activated protein kinases/extracellular signal-regulated kinases; PKB/Akt, protein kinase B/serine/threonine kinase; BAD, Bcl-2 associated death promoter; FOXO, forkhead box O

Figure 3. Pre- and post-synaptic markers influenced by IGF-1

IGF-1 is important for the development and maintenance of mature synapses via influence on various synaptic markers. The presence of IGF-1 is necessary for proper levels of synapsin-1, a pre-synaptic protein that regulates neurotransmitter release (Hilfiker et al., 1999), and PSD-95, a post-synaptic scaffolding protein that aids in maintaining synaptic structure, as well as AMPA and NMDA receptor binding (Corvin et al., 2012; Kim & Sheng, 2004). Abbreviations: CASK, calcium/calmodulin dependent serine protein kinase; NMDA, N-methyl-D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; PSD-95; PDZ (1–3), post-synaptic density protein 95 – drosophila disc large tumor suppressor and zonula occludens-1 protein; SH3, SRC Homology 3 Domain; GK, glycerol kinase; GKAP, guanylate kinase-associated protein; TARP, TCR gamma alternate reading frame protein