Is Galactose a Hormetic Sugar? An Exploratory Study of the Rat Hippocampal Redox Regulatory Network

Abstract

Scope: Galactose, a ubiquitous monosaccharide with incompletely understood physiology is often exploited for inducing oxidative-stress mediated aging in animals. Recent research demonstrates that galactose can conserve cellular function during periods of starvation and prevent/alleviate cognitive deficits in a rat model of sporadic Alzheimer's disease. The present aim is to examine the acute effects of oral galactose on the redox regulatory network (RRN). Methods and Results: Rat plasma and hippocampal RRNs are analyzed upon acute orogastric gavage of galactose (200 mg kg -1 ). No systemic RRN disbalance is observed; however, a mild pro-oxidative shift accompanied by a paradoxical increment in tissue reductive capacity suggesting overcompensation of endogenous antioxidant systems is observed in the hippocampus. Galactose-induced increment of reductive capacity is 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. Conclusion: Based on the observed findings, and in the context of previous work on galactose, a hormetic hypothesis of galactose is proposed suggesting that the protective effects may be inseparable from its pro-oxidative action at the biochemical level.

The effect of acute oral galactose administration on the redox system of the rat small intestine

“…Lipid peroxidation was assessed based on quantification of lipid peroxidation end products using the thiobarbituric acid reactive substances (TBARS) assay as described previously [5,23]. Supernatants of tissue homogenates (12 μL) were mixed with 120 μL of the TBA-TCA reagent (0.038% thiobarbituric acid (Kemika, Croatia) in 15% trichloroacetic acid (Merck, USA).…”

“…The concentration of low molecular weight thiols and protein sulfhydryl content Low molecular weight thiols (LMWT) and protein sulfhydryl content (SH) were measured by quantification of 5-thio-2-nitrobenzoic acid (TNB) in the reaction between reactive sulfhydryl groups present in the supernatant and protein precipitate of the tissue sample and 5,5′-dithio-bis(2-nitrobenzoic acid) (DTNB) [5,34,35]. 25 μL of each homogenate was incubated with the same volume of sulfosalicylic acid (4% w/v) for 1 h on ice.…”

“…Furthermore, together with glucose (in the form of disaccharide lactose) galactose is a cornerstone of animal milk that provides structural and metabolic support during the most sensitive developmental period [3]. Regardless of its importance as a nutrient and pertinent physiological role best reflected in biological consequences of inherited defects of its metabolism, the biochemistry of galactose and its implications in health and disease remain enigmatic [4][5][6].…”

“…important measures to reduce the risk of bias were reported only rarely) [10]; iii) the effects of dose/time-response, route of administration, region-dependent metabolic capacities, and the presence/absence of underlying pathophysiological processes are still insufficiently explored, and iv) the observed association of galactose administration and oxidative stress is seldom questioned with little concern for the lack of mechanistic explanations. The latter is well illustrated by the fact that the GO-catalyzed generation of H2O2 is often referred to as a probable mechanism of galactose-induced oxidative stress and senescence in rodents [7,8,13] regardless of the fact that this is a fungal enzyme that doesn't exist in rodents [5,14].…”

“…Furthermore, galactose can be utilized for energy storage and production, replenishment of antioxidants, and synthesis of nucleotides and nucleic acids depending on tissue demands as i) UDP-galactose can be converted to UDP-glucose (a precursor of glycogen synthesis) by UDP-glucose 4-epimerase (GALE; EC 5.1.3.2), and ii) UDPglucose can be metabolized to glucose-1-phosphate (G-1-P) and then to glucose-6-phosphate (G-6-P) to fuel either the pentose phosphate pathway (PPP) or glycolysis [3,5,6]. Interestingly, galactose-derived G-6-P seems to be primarily shuttled towards the PPP rather than the glycolytic pathway [18,19] favoring the replenishment of NADPH and nucleotides over energy metabolism possibly due to the same mechanisms responsible for galactoseinduced oxidative stress [5].…”