Ouabain as an antiapoptotic drug in neurodegenerative diseases.

Abstract

The enzyme Na,K-ATPase (Sodium Potassium Adenosine Trisfosfatase) is an integral membrane protein, highly conserved in eukaryotes, which through hydrolysis of one ATP molecule establishes the electrochemical gradient across the plasma membrane, which is essential to maintain the osmotic balance of cells, the resting membrane potential and the excitatory property of nerve and muscle cells. Besides its role in ion homeostasis, several recent studies suggest that this pump may also act as a signal transducer and transcription activator involved in cell growth, differentiation and programmed cell death. Ouabain (OUA), the ligand of Na,K-ATPase, is a hormone that is produced by the adrenal cortex and hypothalamus. After OUA binding, the Na,K-ATPase signaling seems to activate pathways such as NFkappaB and causes Calcium oscillations.The overall goal of this project is to test the applicability of the Na,K-ATPase survival signal following neurotrauma and in neurodegenerative diseases. For this purpose, we propose to examine the anti-apoptotic effect of OUA/ Na,K-ATPase signaling in a primary hippocampal neuronal culture challenged with shiga toxin and oxidative stress; conditions that activate the intrinsic mitochondrial apoptotic pathway, and finally to examine the molecular mechanisms by which ouabain/ Na,K-ATPase signaling protects from apoptosis using microscopy technics.