[en] 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 Сa(2+) 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.
Mitroshina, Еlena V ; Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny ; Privolzhskiy Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny
Mishchenko, Tatiana A; Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny ; Privolzhskiy Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny
Shirokova, Olesya M; Privolzhskiy Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny
Astrakhanova, Tatiana A; Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny
Loginova, Maria M; Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny
Epifanova, Ekaterina ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny
Babaev, Alexey A; Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny
Tarabykin, Victor S; Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny ; Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin,
Vedunova, Maria V ; Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny
Language :
English
Title :
Intracellular Neuroprotective Mechanisms in Neuron-Glial Networks Mediated by Glial Cell Line-Derived Neurotrophic Factor.
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