Endocrine Abstracts (2009) 20 S5.4

IGF-I and neuroprotection

Ignacio Torres Aleman

Cajal Institute, Madrid, Spain.

Neuroprotection defines a set of homeostatic, self-repair mechanisms that probably evolved for the specially demanding conditions imposed by brain function. Among these, intercellular messengers such as the insulin-like growth factors (IGFs), that appeared very early during phylogeny, apparently play a prominent role despite their peripheral origin. In contrast to the heterogeneity seen in primitive organisms where at least 30 different IGF-like peptides are described, in mammals only 3 of them, insulin and IGF-I/II are so far known. All exert neuroprotective actions, probably playing also a crucial role in a wide diversity of brain diseases. Although originally ascribed exclusively to the IGF-I receptor, the neuroprotective actions of these peptides in all probability also includes the insulin and IGF-II receptors. Several aspects of these peptides in relation to their brain actions warrant further investigation: 1) altered glucose metabolism, not only in brain but also in the periphery, is unusually common in brain pathologies. An as yet not well understood interaction between insulin and IGF-I signalling probably contributes to it. 2) Hetero-dimerization of insulin and IGF-I hemi-receptors and the unusual chaperone-like properties of the IGF-II receptor undoubtedly adds to the complexity of IGFs actions in the brain, and elsewhere. Their ultimate significance remains undetermined. 3) Insulin/IGF-I resistance triggered by neuro-inflammation, oxidative stress, excess excitatory neurotransmission, or endoplasmic reticulum stress (the four major disruptions linked to brain pathology) is a common process in pathological pathways in brain diseases. Their molecular underpinnings constitute an area for potential druggable targets. 4) Many neuroprotective mechanisms include activity-dependent processes and our recent evidence indicates that serum IGF-I enters into the brain in an activity-dependent fashion. These initial observations suggest an important role of IGF-I in cognitive reserve buildup. Thus, the concerted brain actions of IGFs likely contribute to environmental influence on brain health, brain aging and cognition.

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