Abstract
Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H2O2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H2O2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments. Moreover, studies using various glutamate receptor subtype antagonists displayed that N-methyl-D -aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) blocked the effects of H2O2, whereas other glutamate receptor subtype antagonists, such as non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), metabolic glutamate receptor antagonists LY341495 and CPCCOEt, had no effect. Further studies revealed that NR2B-containing NMDARs are responsible for these effects as its effects were blocked by pharmacological inhibitor Ro25-698 or specific siRNA for NR2B, but not NR2A. Finally, our data also showed that Ca2+ influx contributes to the effects of H2O2. Similar results were obtained in primary cultured cortical neurons. Taken together, the results from the present study suggested that H2O2 attenuated IGF-1R tyrosine phosphorylation and its survival signaling properties via NR2B containing NMDA receptors and Ca2+ influx in SH-SY5Y cells. Therefore, NMDAR antagonists, especially NR2B-selective ones, combined with IGF-1 may serve as an alternative therapeutic agent for oxidative stress related neurodegenerative disease.
Highlights
Progressive oxidative stress is a major event which leads to neuronal death in various neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s disease [1,2,3]
Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like protein kinase B (AKT) and ERK1/2 in these cells
As tyrosine phosphorylation of IGF-1R is the essential and initial step of IGF-1R signaling, we looked in to the tyrosine phosphorylation of IGF-1R and AKT/MAPK kinase, the key kinases in two major signaling pathways named the phosphatidylinositol 3-kinase (PI3K)/AKT and the MAPK pathways involved in IGF-1 survival signaling
Summary
Progressive oxidative stress is a major event which leads to neuronal death in various neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s disease [1,2,3]. Oxidative stress lacks any specific clinical symptom, yet it is observed that reactive oxygen species (ROS) or/and reactive nitrogen species (RNS) are its main causative agents [4, 5]. The biological activities of IGF-1 are mainly arbitrated by type I IGF receptors [13]. IGF1 confers neuroprotection via these signaling cascades against multiple abuses such as potassium deprivation, serum deprivation, SNP toxicity, cerebral ischemia, and glutamate excitotoxicity [15,16,17,18]. IGF-1 is gaining increasing attention as a potential therapeutic agent for the treatment of neurodegenerative disorders
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