S G Gaidin1, M V Turovskaya1, M S Gavrish2, A A Babaev2, V N Mal'tseva1, E V Blinova3,4, E A Turovsky1. 1. Institute of Cell Biophysics, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", Russian Academy of Sciences, Pushchino, Russia. 2. Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia. 3. I.M. Sechenov First Moscow State Medical University, Moscow, Russia. 4. N. P. Ogarev Mordovia State University, Saransk, Russia.
Abstract
Objective: Cerebral ischemia is accompanied by damage and death of a significant number of neurons due to glutamate excitotoxicity with subsequent a global increase of cytosolic Ca2+ concentration ([Ca2+]i). This study aimed to investigate the neuroprotective action of BDNF overexpression in hippocampal neurons against injury under ischemia-like conditions (oxygen and glucose deprivation) and glutamate-induced excitotoxicity (GluTox). Methods: The overexpression of BDNF was reached by the transduction of cell cultures with the adeno-associated (AAV)-Syn-BDNF-EGFP virus construct. Neuroprotective effects were mediated by Ca2+-dependent BDNF release followed by activation of the neuroprotective signaling cascades and changes of the gene expression. Thus, BDNF overexpression modulates Ca2+ homeostasis in cells, preventing Ca2+ overload and initiation of apoptotic and necrotic processes. Results: Antiapoptotic effect of BDNF overexpression is mediated via activation of phosphoinositide-3-kinase (PI3K) pathway and changing the expression of PI3K, HIF-1, Src and an anti-inflammatory cytokine IL-10. On the contrary, the decrease of expression of proapoptotic proteins such as Jun, Mapk8, caspase-3 and an inflammatory cytokine IL-1β was observed. These changes of expression were accompanied by the decrease of quantity of IL-1β receptors and the level of TNFα in cells in control, as well as 24 h after OGD. Besides, BDNF overexpression changes the expression of GABA(B) receptors. Also, the expression of NMDA and AMPA receptor subunits was altered towards a change in the conductivity of the receptors for Ca2+. Conclusion: Thus, our results demonstrate that neuronal BDNF overexpression reveals complex neuroprotective effects on the neurons and astrocytes under OGD and GluTox via inhibition of Ca2+ responses and regulation of gene expression.
Objective: Cerebral ischemia is accompanied by damage and death of a significant number of neurons due to glutamate excitotoxicity with subsequent a global increase of cytosolic Ca2+ concentration ([Ca2+]i). This study aimed to investigate the neuroprotective action of BDNF overexpression in hippocampal neurons against injury under ischemia-like conditions (oxygen and glucose deprivation) and glutamate-induced excitotoxicity (GluTox). Methods: The overexpression of BDNF was reached by the transduction of cell cultures with the adeno-associated (AAV)-Syn-BDNF-EGFP virus construct. Neuroprotective effects were mediated by Ca2+-dependent BDNF release followed by activation of the neuroprotective signaling cascades and changes of the gene expression. Thus, BDNF overexpression modulates Ca2+ homeostasis in cells, preventing Ca2+ overload and initiation of apoptotic and necrotic processes. Results: Antiapoptotic effect of BDNF overexpression is mediated via activation of phosphoinositide-3-kinase (PI3K) pathway and changing the expression of PI3K, HIF-1, Src and an anti-inflammatory cytokine IL-10. On the contrary, the decrease of expression of proapoptotic proteins such as Jun, Mapk8, caspase-3 and an inflammatory cytokine IL-1β was observed. These changes of expression were accompanied by the decrease of quantity of IL-1β receptors and the level of TNFα in cells in control, as well as 24 h after OGD. Besides, BDNF overexpression changes the expression of GABA(B) receptors. Also, the expression of NMDA and AMPA receptor subunits was altered towards a change in the conductivity of the receptors for Ca2+. Conclusion: Thus, our results demonstrate that neuronal BDNF overexpression reveals complex neuroprotective effects on the neurons and astrocytes under OGD and GluTox via inhibition of Ca2+ responses and regulation of gene expression.
Authors: Egor A Turovsky; Maria V Turovskaya; Evgeniya I Fedotova; Alexey A Babaev; Viktor S Tarabykin; Elena G Varlamova Journal: Int J Mol Sci Date: 2021-05-31 Impact factor: 5.923