Decreased content of ascorbic acid (vitamin C) in the brain of knockout mouse models of Na+,K+-ATPase-related neurologic disorders

Abstract

Na+,K+-ATPase is a crucial protein responsible for maintaining the electrochemical gradients across the cell membrane. The Na+,K+-ATPase is comprised of catalytic α, β, and γ subunits. In adult brains, the α3 subunit, encoded by ATP1A3, is predominantly expressed in neurons, whereas the α2 subunit, encoded by ATP1A2, is expressed in glial cells. In foetal brains, the α2 is expressed in neurons as well. Mutations in α subunits cause a variety of neurologic disorders. Notably, the onset of symptoms in ATP1A2- and ATP1A3-related neurologic disorders is usually triggered by physiological or psychological stressors. To gain insight into the distinct roles of the α2 and α3 subunits in the developing foetal brain, whose developmental dysfunction may be a predisposing factor of neurologic disorders, we compared the phenotypes of mouse foetuses with double homozygous knockout of Atp1a2 and Atp1a3 (α2α3-dKO) to those with single knockout. The brain haemorrhage phenotype of α2α3-dKO was similar to that of homozygous knockout of the gene encoding ascorbic acid (ASC or vitamin C) transporter, SVCT2. The α2α3-dKO brain showed significantly decreased level of ASC compared with the wild-type (WT) and single knockout. We found that the ASC content in the basal ganglia and cerebellum was significantly lower in the adult Atp1a3 heterozygous knockout mouse (α3-HT) than in the WT. Interestingly, we observed a significant decrease in the ASC level in the basal ganglia and cerebellum of α3-HT in the peripartum period, during which mice are under physiological stress. These observations indicate that the α2 and α3 subunits independently contribute to the ASC level in the foetal brain and that the α3 subunit contributes to ASC transport in the adult basal ganglia and cerebellum. We propose that decreases in ASC levels may affect neural network development and are linked to the pathophysiology of ATP1A2- and ATP1A3-related neurologic disorders.

Oxidative Stress and Cognitive Decline: The Neuroprotective Role of Natural Antioxidants

“…The importance of vitamin C in preventing and combating neurological disorders has also been demonstrated in a recent work: in a murine model, decreased levels of AA levels influenced the neural network development, and this alteration correlated with the pathophysiology of neurological disorders (Ikeda et al, 2021). In an in vitro study, Lee et al (2021) investigated the protective effect of AA administration in preventing age-induced oxidative damage in hippocampal neurons, demonstrating that a regular AA treatment protected hippocampal neurons from free radical damages.…”

“…The importance of vitamin C in preventing and combating neurological disorders has also been demonstrated in a recent work: in a murine model, decreased levels of AA levels influenced the neural network development, and this alteration correlated with the pathophysiology of neurological disorders ( Ikeda et al, 2021 ).…”

Oxidative stress, dysfunctional energy metabolism, and destabilizing neurotransmitters altered the cerebral metabolic profile in a rat model of simulated heliox saturation diving to 4.0 MPa

“…In this study, compared with CON rats, a significantly higher concentration of FMA in the HSDX group and a decreased concentration of Suc may indicate an energy metabolism decline, which was further confirmed by an increased AMP and a decreased ATP produced mainly by glycolysis and the TCA cycle. Na-K-ATPase, a key enzyme for the maintenance of a proper electrochemical gradient of sodium ions across the cell membrane, requires approximately 50% of the energy available to the brain [38,39]. The malfunction of Na-K-ATPase has an essential role in the development of neurodegenerative diseases [40,41].…”

Oxidative stress, dysfunctional energy metabolism, and destabilizing neurotransmitters altered cerebral metabolic profile in a rat model of a simulated heliox saturation diving to 4.0 Mpa

“…In this study, compared with CON rats, a signi cantly higher concentration of FMA in the HSDX group and a decreased concentration of Suc may indicate an energy metabolism decline, which was further con rmed by an increased AMP and a decreased ATP produced mainly by glycolysis and the TCA cycle. Na-K-ATPase, a key enzyme for the maintenance of a proper electrochemical gradient of sodium ions across the cell membrane, requires approximately 50% of the energy available to the brain [39,40]. The malfunction of Na-K-ATPase has an essential role in the development of neurodegenerative diseases [41,42].…”