Neuroprotective Effect of Insulin-like Growth Factor-II on 1- Methyl-4-Phenyl Pyridinium-Induced Oxidative Damage in Cortical Neuronal Cells

Abstract

Purpose: To evaluate the receptor-mediated neuroprotective effect of insulin-like growth factor-II (IGF-II) on 1-methyl-4-phenyl pyridinium (MPP)-induced oxidative damage in adult cortical neuronal cultures. Methods: Adult rats were randomly divided into 5 groups. Cortical neurons were prepared from rats. The cells were exposed to 10 μM of MPP (group 1, G1); MPP + 100 ng/mL of IGF-II (group 2, G2); MPP + IGF in the presence of 20 ng/μL IGF-I analogue (group 3; G3); 5 ng/μL anti-IGF-IIR (group 4; G4); or MPP + IGF II + IGF inhibitor (group 5; G5). The level of reactive oxygen species (ROS), levels of oxidative stress markers, antioxidant enzymes, mitochondrial functional markers were analyzed in the MPP-treated neuronal cells (with or without treatment with IGF-II). Results: The results demonstrate that IGF-II treatment protects MPP-induced toxicity by decreasing ROS production (58.33 %; p ˂ 0.001), AChE levels (50 %), and maintaining the innate antioxidants to near normal levels. The study on oxidative functional markers showed that IGF-II significantly decreased the MPP-induced elevated levels and mitochondrial markers (TBARS, 40 %, LOOH-39.28 %) to near normal levels. Further analysis using inhibitors of IGF-IR (IGF-I analogue) and IGF-IIR (anti-IGF-IIR) showed that involvement of IGF-IIR might have greatly contributed to the neuroprotective effect of IGF-II. Conclusion: IGF-II receptors play a significant role in the neuroprotective mechanism of IGF-II by acting as an antioxidant, thereby reducing the neuro-degeneration induced by oxidative insults. This indicates that IGF-II receptors are a potential target for the treatment of diseases related to imbalance in redox homeostasis.

Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons

“…Our results indicated that IGF-II protects the neurons against ROS production and the dramatic increase in the levels of the cell damage markers AOPP and LOOH; the reduction in TAS and GPX activity is also counteracted. These changes agree with previous results in cellular models of PD [ 24 , 27 ] and after administration of CORT in neuronal cultures [ 12 ], where IGF-II prevented oxidative balance and GPX expression.…”

“…Parkinson disease and conditions of emotional stress are strongly related to increases in oxidative distress and mitochondrial damage, contributing to enlarged neurodegeneration and/or death [ 18 , 39 , 51 , 52 , 53 ]. The protective effect of IGF-II found in the cellular oxidative stress model induced by the CORT [ 12 , 13 ] and the PD models [ 24 , 27 ], which is mediated through its specific IGF-IIR, suggests a potential decrease in the mitochondrial-oxidative damage observed in this combined PD experimental model after IGF-II administration, leading to protecting dopaminergic neurons from cell death. Accordingly, the co-incubation with IGF-II and both drugs prevented the release of LDH, whereas the incubation in the presence of an inhibitor of IGF-IR and RIns (BMS) used to define the receptor involved in the IGF-II effect, did not modify the effect of IGF-II.…”

“…Although the specific functions of IGF-II are still poorly understood in adults, new evidence is emerging on the role of IGF-II as a key neuroprotective factor in pathological conditions, the study of IGF-II in neurodegenerative diseases being of increasing interest [ 21 , 22 , 23 ]. To date, only a small number of studies relate the neuroprotective mechanisms of IGF-II to its antioxidant function [ 12 , 13 , 23 , 24 , 25 , 26 , 27 , 28 ]. Thus, IGF-II has been shown to exhibit neuroprotective actions in Alzheimer’s disease, PD and ageing conditions [ 24 , 25 , 28 ], glucocorticoid-mediated stress situations [ 12 , 13 ], and neuropsychiatric disorders such as schizophrenia and autism [ 29 , 30 , 31 ].…”

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

“…Our results suggest that the oxidative stress induced by CORT is maintained despite CORT removal, as shown by the results of the oxidative stress markers. We previously reported that IGF-II exerts antioxidant and neuroprotective effects in different experimental models related to oxidative damage [18] , [62] , [63] . Most of these effects are more likely mediated by interactions with its specific receptor IGF-IIR, although it cannot be completely excluded that the decrease in lipid damage was also partially (nearly 39% of the effect) mediated by the IGF-IR, as shown in the brain tissue of old rats treated with IGF-I [64] , [65] .…”