IGF-II promotes neuroprotection and neuroplasticity recovery in a long-lasting model of oxidative damage induced by glucocorticoids

Abstract

Insulin-like growth factor-II (IGF-II) is a naturally occurring hormone that exerts neurotrophic and neuroprotective properties in a wide range of neurodegenerative diseases and ageing. Accumulating evidence suggests that the effects of IGF-II in the brain may be explained by its binding to the specific transmembrane receptor, IGFII/M6P receptor (IGF-IIR). However, relatively little is known regarding the role of IGF-II through IGF-IIR in neuroprotection. Here, using adult cortical neuronal cultures, we investigated whether IGF-II exhibits long-term antioxidant effects and neuroprotection at the synaptic level after oxidative damage induced by high and transient levels of corticosterone (CORT). Furthermore, the involvement of the IGF-IIR was also studied to elucidate its role in the neuroprotective actions of IGF-II. We found that neurons treated with IGF-II after CORT incubation showed reduced oxidative stress damage and recovered antioxidant status (normalized total antioxidant status, lipid hydroperoxides and NAD(P) H:quinone oxidoreductase activity). Similar results were obtained when mitochondria function was analysed (cytochrome c oxidase activity, mitochondrial membrane potential and subcellular mitochondrial distribution). Furthermore, neuronal impairment and degeneration were also assessed (synaptophysin and PSD-95 expression, presynaptic function and FluoroJade B® stain). IGF-II was also able to recover the long-lasting neuronal cell damage. Finally, the effects of IGF-II were not blocked by an IGF-IR antagonist, suggesting the involvement of IGF-IIR. Altogether these results suggest that, in or model, IGF-II through IGF-IIR is able to revert the oxidative damage induced by CORT. In accordance with the neuroprotective role of the IGF-II/IGF-IIR reported in our study, pharmacotherapy approaches targeting this pathway may be useful for the treatment of diseases associated with cognitive deficits (i.e., neurodegenerative disorders, depression, etc.).

NF-κB p65 directs sex-specific neuroprotection in human neurons

“…Within a mouse model of Alzheimer’s disease, IGF2 administration rescued spine formation and synaptic transmission in the hippocampus 60 . In accordance to the present findings, IGF2 was reported to have an antioxidant and neuroprotective effect on oxidative damage and mitochondrial function in cultured adult rat cortical neurons 61 , 62 . In contrast to their female counterparts, male ITSC-derived neurons showed a significant increase in the expression level of PKAcatα after TNF-α/H 2 O 2 -treatment.…”

Sexual dimorphisms in adult human neural, mesoderm‐derived, and neural crest‐derived stem cells

“…SOD2 is well known for protecting cells against oxidative stress resulting in longevity [55]. IGF-2 is known to promote synapse formation and spine maturation [56], and it has antioxidant, neuroprotective effects against oxidative damage [57,58]. Taken together, we could show that NF-jB p65 is a key player in neuroprotection of human glutamatergic NC-derived neurons, although the protective gene expression program beneath is sexually dimorphic.…”

“…2 for overview). IGF-2 is known to promote synapse formation and spine maturation [56], and it has antioxidant, neuroprotective effects against oxidative damage [57,58]. While female neurons upregulated the NF-jB target genes SOD2 and IGF2 to induce neuroprotection, male neurons showed elevated expression of the neuroprotective NF-jB target gene PKA cat alpha [41].…”

Effects of running on adiponectin, insulin and cytokines in cerebrospinal fluid in healthy young individuals

“…In addition, we observed >10% decrease in CSF levels of IL-18Rβ and PDGF, involved in the regulation of feeding in mice 36 and in neuronal plasticity and embryonic development of the nervous system, respectively 37,38 . Other exercise-modulated cytokines in CSF are known to be involved in neuroprotection (IGF-II) 39 and lipid metabolism (TGFβ) 40 . However, CSF levels of neurotrophins BDNF, VEGF and IGF-1, involved in exercise-induced neurogenesis/brain plasticity 41,42 , did not change after a single bout of long-distance running.…”