Intracellular Neuroprotective Mechanisms in Neuron-Glial Networks Mediated by Glial Cell Line-Derived Neurotrophic Factor.

Еlena V Mitroshina,Alexey A Babaev,Maria M Loginova,Ekaterina A Epifanova,Tatiana A Mishchenko,Victor S Tarabykin,Maria V Vedunova,Tatiana A Astrakhanova,Olesya M Shirokova

doi:10.1155/2019/1036907

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has a pronounced neuroprotective effect in various nervous system pathologies, including ischaemic brain damage and neurodegenerative diseases. In this work, we studied the effect of GDNF on the ultrastructure and functional activity of neuron-glial networks during acute hypoxic exposure, a key damaging factor in numerous brain pathologies. We analysed the molecular mechanisms most likely involved in the positive effects of GDNF. Hypoxia modelling was performed on day 14 of culturing primary hippocampal cells obtained from mouse embryos (E18). GDNF (1 ng/ml) was added to the culture medium 20 min before oxygen deprivation. Acute hypoxia-induced irreversible changes in the ultrastructure of neurons and astrocytes led to the loss of functional Сa2+ activity and neural network disruption. Destructive changes in the mitochondrial apparatus and its functional activity characterized by an increase in the basal oxygen consumption rate and respiratory chain complex II activity during decreased stimulated respiration intensity were observed 24 hours after hypoxic injury. At a concentration of 1 ng/ml, GDNF maintained the functional metabolic network activity in primary hippocampal cultures and preserved the structure of the synaptic apparatus and number of mature chemical synapses, confirming its neuroprotective effect. GDNF maintained the normal structure of mitochondria in neuronal outgrowth but not in the soma. Analysis of the possible GDNF mechanism revealed that RET kinase, a component of the receptor complex, and the PI3K/Akt pathway are crucial for the neuroprotective effect of GDNF. The current study also revealed the role of GDNF in the regulation of HIF-1α transcription factor expression under hypoxic conditions.

Highlights

Glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in various pathologies, including Parkinson’s disease [1,2,3], Alzheimer’s disease [4, 5], and ischaemic damage [5,6,7,8], to the central and peripheral nervous systems
Analysis of the possible GDNF mechanism revealed that RET kinase, a component of the receptor complex, and the PI3K/Akt pathway are crucial for the neuroprotective effect of GDNF
We demonstrated a key role of the PI3K/Akt pathway in the implementation of GDNF neuroprotective effects as well as neurotrophic factor participation in the regulation of HIF-α expression in nervous cells

Summary

Introduction

Glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in various pathologies, including Parkinson’s disease [1,2,3], Alzheimer’s disease [4, 5], and ischaemic damage [5,6,7,8], to the central and peripheral nervous systems. The mechanisms activated by GDNF injection could be more complex and associated with modification of numerous subcellular cascades in both neurons and astrocytes [11, 12]. Activation of these molecular reactions unites the neuron-glial network into a single functional and metabolic system capable of a comprehensive adaptive response [12, 13]. The main action of GDNF is associated with activation of the GFRα-mediated RET kinase metabolic. Studies on key intracellular kinases involved in the neuroprotective effect of GDNF allow for elucidation of crucial points of GDNF action and the mechanisms underlying its reduced effectiveness in certain conditions

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Results

Conclusion