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IGF-I and -II are potent neuronal mitogens and survival factors. The actions of IGF-I and -II are mediated via the type I IGF receptor (IGF-IR) and IGF binding proteins regulate the bioavailability of the IGFs. Cell viability correlates with IGF-IR expression and intact IGF-I/IGF-IR signaling pathways, including activation of MAPK/phosphatidylinositol-3 kinase. The expression of IGF-I and -II, IGF-IR, and IGF binding proteins are developmentally regulated in the central and peripheral nervous system. IGF-I therapy demonstrates mixed therapeutic results in the treatment of peripheral nerve injury, neuropathy, and motor neuron diseases such as amyotrophic lateral sclerosis. In this review we discuss the role of IGFs during peripheral nervous system development and the IGF signaling system as the potential therapeutic target for the treatment of nerve injury and motor neuron diseases.

Diabetic neuropathy (DN) is a common complication of diabetes. Currently, there is no drug treatment to prevent or slow the development of DN. Rosiglitazone (Rosi) is a potent insulin sensitizer and may also slow the development of DN by a mechanism independent of its effect on hyperglycemia. A two by two design was used to test the effect of Rosi treatment on the development of DN. Streptozotocin-induced diabetic DBA/2J mice were treated with Rosi. DN and oxidative stress were quantified, and gene expression was profiled using the Affymetrix Mouse Genome 430 2.0 microarray platform. An informatics approach identified key regulatory elements activated by Rosi. Diabetic DBA/2J mice developed severe hyperglycemia, DN, and elevated oxidative stress. Rosi treatment did not affect hyperglycemia but did reduce oxidative stress and prevented the development of thermal hypoalgesia. Two novel transcription factor binding modules were identified that may control genes correlated to changes in DN after Rosi treatment: SP1F_ZBPF and EGRF_EGRF. These targets may be useful in designing drugs with the same efficacy as Rosi in treating DN but with fewer undesirable effects.

The receptor for advanced glycation end products (RAGE) may promote diabetic vascular and renal disease through the activation of intracellular signaling pathways that promote oxidative stress. Oxidative stress is a mediator of hyperglycemia-induced cell injury and a unifying theme for all mechanisms of diabetic complications, but there are few studies on the expression and potential contribution of RAGE in diabetic neuropathy. The current study demonstrates that dorsal root ganglia neurons express functional RAGE and respond to the RAGE ligand S100 with similar downstream signaling, oxidative stress, and cellular injury as other diabetic complication-prone tissues. RAGE-induced phosphatidylinositol-3 kinase activity is associated with formation of reactive oxygen species, caspase-3 activation, and nuclear DNA degradation. These events are prevented by treatment with the antioxidant alpha-lipoic acid. Our data indicate that therapies aimed at decreasing RAGE ligands, blocking RAGE signaling, or preventing oxidative stress could significantly decrease the development of neuropathy in diabetic patients.

The insulin-like growth factors (IGF-I and IGF-II) are peptide growth factors with both growth-promoting and insulin-like activities. In the nervous system, the expression of both IGF-I and IGF-II messenger RNAs (mRNAs) is developmentally regulated, with IGF-I expression highest during puberty, and IGF-II levels peaking during the perinatal period. The IGFs interact with and are modulated by a group of six binding proteins, the IGF-binding proteins (IGFBP-1 to IGFBP-6). IGFBP-2 mRNA is most prevalent in the nervous system, where, like IGF-II, its expression correlates with a period of brain growth. In the current study, cells containing IGF-II and IGFBP-2 were identified within the developing nervous system of the rat on embryonic day 12 (E12), E14, E18, and postnatal day 1 and in the adult. IGF-II immunoreactivity was detected within the mesenchymal core of the choroid plexus at all ages examined and was also observed in the developing leptomeninges. IGF-II appeared transiently in the central nervous system in presumptive glia of the hippocampus and medial basal hypothalamus and in a small population of neurons in the brain stem. IGFBP-2 was consistently observed in the epithelium of the choroid plexus as well as in the epithelia of the developing otic and olfactory placodes. While these results confirm the developmental expression of IGF-II and IGFBP-2 mRNA in the central nervous system, discrepancies exist between these data and those using molecular techniques. This may be due in part to differential sites of IGF-II and IGFBP-2 production compared to sites of action.