Astrocytic Insulin-Like Growth Factor-1 Protects Neurons Against Excitotoxicity.

Wei Chen,Jinsong Zeng,Bin He,Ping Zheng,Wusong Tong

doi:10.3389/fncel.2019.00298

Abstract

BackgroundExogenous insulin like growth factor-1 (IGF-1) is known to be neuroprotective in animal models with brain insults, while it can also cause hyperexcitability in rodents. In this regard, the role of endogenous IGF-1 in brain responses to brain insults like excitotoxicity, a common pathology in brain injuries, remains to be elucidated. Here, we investigated the potential role of cell-specific endogenous IGF-1 in the kainic acid (KA) -induced degeneration of the neurons.MethodsKainic acid was given to primary cultured cortical neurons and co-cultured astrocytes were added as a supportive system. We evaluated the cell proliferation rate, IGF-1 level in different groups and applied the PCR-Chip assay to explore the downstream of IGF-1. In addition, we applied the viral transfer of astrocytic IGF-1 to rodents treated with KA and assessed the associated molecular marker and behavioral outcomes in these rodents.ResultsWe found KA induced increased cell death and hyperphosphorylated tau in neurons; co-cultured astrocytes could prevent these pathologies, and this rescuing effect was abrogated with blockade of the astrocytic IGF-1 with AG1024 (IGF-1R inhibitor). PCR-Chip assay identified that astrocytic IGF-1 could decrease the p-GSK-3 at Tyr 216 in neurons treated with KA and this effect was abrogated with AG1024 as well. In addition, in vivo study showed that gene transfer of astrocytic IGF-1 decreased p-tau and cognitive dysfunction in KA mice.ConclusionOur results show astrocytic IGF-1 exhibits neuroprotective properties in neurodegenerative processes in the CNS.

Highlights

Excitotoxicity is involved in neurodegenerative diseases such as traumatic brain injury, stroke and epilepsy
It would be interesting to investigate the effect of cell-specific endogenous insulin growth factor-1 (IGF-1), and we report here that co-cultured astrocytes protect neurons against excitotoxicity and, very importantly, gene delivery of IGF-1 in astrocytes shows a neuroprotection in vivo following excitotoxicity
Viability of neurons was measured by thiazolyl blue tetrazolium bromide (MTT) at OD 490 1 and 2 days after kainic acid (KA) treatment in the presence or absence of wild type astrocytes (A,B, F2,24 = 78.35, ∗∗∗P < 0.0001 and F2,24 = 294.2, ∗∗∗P < 0.0001, neurons+KA vs. neurons+astrocytes+KA; #P < 0.0001 compared to neurons in KA0 group, n = 6 in each group)

Summary

Introduction

Excitotoxicity is involved in neurodegenerative diseases such as traumatic brain injury, stroke and epilepsy Following neurotoxic lesions such as ischemia (Aberg et al, 2006), or injury to the cortex (Pansiot et al, 2016) or the spinal cord (Sisti et al, 2019), insulin growth factor-1 (IGF-1), and its receptors are found to increase in associated brain lesions, implying a role of IGF-1 in the Abbreviations: GSK-3β, glycogen synthase kinase; IGF-1, insulin-like growth factor-1; KA, kainic acid; MLPT, modified limb preference test; MTT, thiazolyl blue tetrazolium bromide. Exogenous insulin like growth factor-1 (IGF-1) is known to be neuroprotective in animal models with brain insults, while it can cause hyperexcitability in rodents. In this regard, the role of endogenous IGF-1 in brain responses to brain insults like excitotoxicity, a common pathology in brain injuries, remains to be elucidated. We investigated the potential role of cell-specific endogenous IGF-1 in the kainic acid (KA) -induced degeneration of the neurons

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Discussion

Conclusion