Is galactose a hormetic sugar? Evidence from rat hippocampal redox regulatory network

• Published in: bioRxiv
• Main Authors: Homolak, J, Babic, Perhoc A, Knezovic, A, Kodvanj, I, Virag, D, Osmanovic, Barilar J, Riederer, P, Salkovic-Petrisic, M
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 08.03.2021
• Subjects: Adenine; Aging; Alzheimer's disease; Animal models; Antioxidants; Cognitive ability; Detoxification; Galactokinase; Galactose; Hereditary diseases; Hippocampus; Monosaccharides; Neurodegenerative diseases; Oral administration; Oxidative stress; Pentose phosphate pathway
• DOI: 10.1101/2021.03.08.434370

Abstract Galactose is a ubiquitous simple monosaccharide with yet incompletely understood biochemical and physiological role. Most of what we currently know about galactose is based on induction from the research on inherited disorders of galactose metabolism and animal models that exploit galactose-induced oxidative stress to model aging in rodents, however, recent evidence also demonstrates unique properties of galactose to conserve cellular function during the periods of starvation, and prevent and alleviate cognitive deficits in a rat model of sporadic Alzheimer’s disease. Here, we try to understand the molecular background of both detrimental and beneficial effects of galactose by exploring the acute systemic and hippocampal biochemical changes upon oral administration of galactose solution focusing primarily on the components of the redox regulatory network (RRN). Although orogastric gavage of galactose solution (200 mg/kg) was insufficient to induce systemic RRN disbalance in the first two hours upon administration, analysis of hippocampal RRN revealed a mild pro-oxidative shift accompanied by a paradoxical increase in tissue reductive capacity, suggesting overcompensation of endogenous antioxidant systems in the response to the pro-oxidative stimulus. The more thorough analysis revealed that galactose-induced increment of reductive capacity was accompanied by inflation of the hippocampal pool of nicotinamide adenine dinucleotide phosphates indicating ROS detoxification through disinhibition of the oxidative pentose phosphate pathway flux, reduced neuronal activity, and upregulation of Leloir pathway gatekeeper enzyme galactokinase-1. Based on the observed findings, and in the context of previous work on galactose, we propose a hormetic hypothesis of galactose action suggesting that the protective effects of galactose might be inseparable from its pro-oxidative effects at the biochemical level. Competing Interest Statement The authors have declared no competing interest.