Российская академия наук


MECHANISMS OF APOPTOSIS AND ITS REGULATION DURING EXCITOTOXIC STRESS IN CORTICAL NEURONS



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MECHANISMS OF APOPTOSIS AND ITS REGULATION DURING EXCITOTOXIC STRESS IN CORTICAL NEURONS.

Antonov S.M., Nur M.M.

I.M. Sechenov institute of evolutionary physiology and biochemistry of the Russian academy of sciences, Saint-Petersburg, Russia, antonov452002@yahoo.com


Apoptosis or programmed cell death plays an important role in development, organ formation and in functioning of fast renewing tissues. In the neuronal tissue this process is distractive and involved in the pathogenesis of many neurodegenerative and psychiatric disorders. As a result of glutamate receptor (GluR) hyperactivation the excitotoxic state develops, that causes the death of neurons by necrosis and apoptosis. In our experiments the activation of NMDAR (GluR, which are activated by N-methyl-D-aspartate) caused apoptosis, developing by the Cas-3-independent cascade, by means of direct release of apoptosis inducing factor from mitochondria and its action on nuclei. The activation of AMPA/KAR (GluR, which are activated by kainate) was followed by apoptosis developing by the caspase-3-dependent mechanism. This receptor specificity of apoptosis pathways during excitotoxic stress, induced by selective GluR agonists – NMDA and kainate - may disclose a new

avenue in selective therapy. Apoptotic injury was completely prevented when the agonists were applied together with 0.1 or 1 nM ouabain, a specific ligand of the Na+,K+-ATPase cardiac glycoside binding site. In addition, subnanomolar concentrations of ouabain prevented the increase of spontaneous excitatory postsynaptic current’s frequency and the intracellular Ca2+ overload induced by excitotoxic insults. Loading neurons with BAPTA-AM or inhibition of the plasma membrane Na+,Ca2+-exchanger by its selective inhibitor, KB-R7943, eliminated ouabain’s effects on NMDA- or kainite-evoked enhancement of spontaneous synaptic activity. Our data suggest that during excitotoxic insults ouabain accelerates Ca2+ extrusion from neurons via the Na+,Ca2+-exchanger. Because intracellular Ca2+ accumulation caused by the activation of glutamate receptors and boosted synaptic activity represents a key factor in triggering neuronal apoptosis, up-regulation of Ca2+ extrusion abolishes its development. These antiapoptotic effects are independent of Na+,K+-ATPase ion transport function and are initiated by concentrations of ouabain that are within the range of an endogenous analog, suggesting a novel functional role for Na+,K+-ATPase in neuroprotection. This work was supported by RFBR grant # 11-04-00397.



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