NA,K-ATPASE SIGNALING AS A TARGET OF ALPHA-LIPOIC ACID IN BRAIN AGING

The Na,K-ATPase is a P-type ATPase that utilizes ATP to transport Na⁺ and K⁺ across the plasma membrane, thereby maintaining transmembrane ion gradients. A distinctive feature of the Na,K-ATPase, compared with other P-type ATPases, is its ability to bind cardiotonic steroids (CTS). CTS, such as ouabain, are not only specific inhibitors of the Na,K-ATPase but also act as hormone-like ligands that activate intracellular signaling pathways independently of the enzyme's classical ion-transport function. Activation of Na,K-ATPase-dependent signaling is associated with the generation of reactive oxygen species (ROS) and the development of oxidative stress.
Alpha-lipoic acid (ALA) is a potent endogenous antioxidant with demonstrated efficacy against oxidative stress-related disorders. ALA scavenges reactive oxygen and nitrogen species, reduces lipid peroxidation, and enhances antioxidant defense in discrete brain regions of aged animals.
In the present study, we investigated the modulatory effect of ALA on Na,K-ATPase signaling during aging, with particular focus on the hippocampus. We evaluated the effects of ALA on (1) components of the Na, K-ATPase signaling pathway and (2) Na,K-ATPase activity and α-subunit isoform expression. Our results demonstrate that ALA modulates Na,K-ATPase signaling and significantly enhances enzyme activity in aged animals.
These findings suggest that ALA may exert neuroprotective effects during aging by regulating Na,K-ATPase signaling and enzyme activity in the hippocampus.
This work was supported by the Shota Rustaveli National Science Foundation of Georgia (Project No FR-24-4786)