𝜷-hydroxybutyric acid attenuates oxidative stress and improves markers of mitochondrial function in the HT-22 hippocampal cell line

Abstract

Ketone bodies have been the topic of research for their possible therapeutic neurotropic effects in various neurological diseases such as Parkinson's disease, dementia, and seizures. However, continuing research on ketone bodies as a prophylactic agent for decreasing the risk for various neurodegenerative diseases is currently required. In this paper, hippocampal HT-22 cells were treated with βhydroxybutyric acid at different doses to elucidate the neurotropic effects. In addition, markers of oxidative stress, mitochondrial function, and apoptosis were investigated. As a result, the ketone body (β-hydroxybutyric acid) showed a significant increase in hippocampal neuronal viability at a moderate dose. Results show that β-hydroxybutyric acid exhibited antioxidant effect by decreasing prooxidant oxidative stress markers such as reactive oxygen species, nitrite content, and increasing glutathione content leading to decreased lipid peroxidation. Results show that β-hydroxybutyric acid improved mitochondrial functions by increasing Complex-I and Complex-IV activities and showing that β-hydroxybutyric acid significantly reduces caspase-1 and caspase-3 activities. Finally, using computational pharmacokinetics and molecular modeling software, we validated the pharmacokinetic effects and pharmacodynamic (N-Methyl-D-aspartic acid and acetylcholinesterase) interactions of βhydroxybutyric acid. The computational studies demonstrate that β-hydroxybutyric acid can interact with N-Methyl-D-aspartic acid receptor and cholinesterase enzyme (the prime pharmacodynamic targets for cognitive impairment) and further validates its oral absorption, distribution into the central nervous system. Therefore, this work highlights the neuroprotective potential of ketone bodies in cognitive-related neurodegenerative diseases.

Association between Edinburgh Postnatal Depression Scale and Serum Levels of Ketone Bodies and Vitamin D, Thyroid Function, and Iron Metabolism

“…In this study, we assumed that the higher the level of serum 3-hydroxybutyrate, which is said to have a protective effect on brain cells, the lower the EPDS score and thus the less likely the occurrence of postpartum depression [ 27 ]. This is because 3-hydroxybutyrate has been shown to have antioxidant effects that protect brain cells, and 3-hydroxybutyrate has been shown to have an advantage against diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and epilepsy [ 14 , 15 , 16 , 28 ].…”

Metabolic Regulation Effect and Potential Metabolic Biomarkers of Pre-Treated Delphinidin on Oxidative Damage Induced by Paraquat in A549 Cells

“…Moreover, PQ also decreased the level of 3-hydroxybutyric acid, a normal metabolite of fatty acid oxidation, which can be used as an energy resource in the case of hypoglycemia [ 35 ]. Studies have shown that 3-hydroxybutyric acid can reduce the level of ROS, nitrite, and lipid peroxidation, increase the levels of glutathione, and improve mitochondrial function in hippocampal HT-22 cells [ 36 ]. The significant upregulation of 3-hydroxybutyric acid may be related to the antioxidant activity of Del.…”

Chlorogenic Acid Ameliorates High-Fat and High-Fructose Diet-Induced Cognitive Impairment via Mediating the Microbiota–Gut–Brain Axis

“…Recent studies have shown that β-hydroxybutyric acid is not only a source of energy metabolism in the brain but also has potential therapeutic effects on neurodegenerative diseases. For example, β-hydroxybutyric acid has been shown to improve hippocampal neuronal viability, mainly benefiting from its drug interaction with N -methyl- d -aspartic acid and acetylcholinesterase, the main drug targets of cognitive impairment . In addition, β-hydroxybutyric acid alleviated hippocampal neuronal damage in epileptic mice by ameliorating oxidative stress, as well as promoting the phosphorylation of AMPK and upregulating PPARα in the hippocampus .…”