Institute of Biomedical and Biomolecular Science (IBBS)

Neuroprotective effect of the specific splice variant of IGF-1 in brain hypoxia-ischaemia

The ischaemic stroke is a common and devastating disease, it affects 1 in 250 persons and its frequency is on the increase in aging populations (Fig.1). Neonatal hypoxia-ischaemia occurs in approximately 1:4,000 - 1:10,000 newborns and causes neurological deficits in ~75% of those affected. Unfortunately, no treatment is available for these two diseases while the human and the economic costs are enormous.

The insulin-like growth factor 1 (IGF-1) is a multifunctional peptide with a widespread spatial and temporal expression in development and in adult tissues. IGF-1, amongst its many functions, also has a role in neuronal maintenance and can prevent neuronal damage. Alternative promoters and elaborate alternative splicing result in the production of distinct circulating (IGF-1Ea) and tissue-specific e.g. IGF-1Eb and IGF-1Ec (MGF) isoforms of IGF-1. Alternative splicing of the 3’-exons results in IGF-1s with specific C-terminal domains, which may function as independent biologically active peptides (Fig.2 and reviewed in Gorecki et al., 2007).

(Figure 2) - Schematic representation of IGF-1 gene and its isoforms resulting from the alternative splicing. The specific parts of exons contributing to the final translated transcript are shaded and those contributing to the mature peptide are underlined. For details see Gorecki et al., 2007.

Working in collaboration with Dr. B. Zablocka’s group we have demonstrated specific changes in the expression patterns of IGF-1 splice variants in adult and developing brains and in ischaemia. In contrast to the normal brain, the insult produced increased and prolonged expression of one specific isoform - IGF-1Ec (Dluzniewska et al., 2005 and Beresewicz et al., 2010). In the post-ichaemic brains the levels of both the IGF-1Ec transcript and peptide were increased selectively in regions resistant to the ischaemic insult (Dluzniewska et al., 2005). IGF-1Ec variant appears to play a role in the pathology of hypoxia-ischeamia. Therefore, this peptide has a potential to be developed into a therapeutic modality for the prevention of neuronal damage. Indeed, a single dose of synthetic, chemically stabilized C-terminal MGF peptide prevented neurodegeneration of vulnerable neurones in vitro and following brain ischaemia in vivo (Dluzniewska et al., 2005). Importantly, protection provided by this C-terminal MGF was not inhibited by the blockade of the canonical ligand-binding site on the IGF-1 receptor. Apparently, in addition to the functional complexity of the IGF-1 isoforms, which stems from alternative splicing of the primary transcript, the post-translational modifications may produce further peptide domain(s) with autonomous functions and a new, IGF-1 receptor-independent mode of action (Fig.3).

(Figure 3) - Schematic representation of IGF-1 splicing and neuroprotective effects in hypoxia-ischaemia.