IMR Press / JIN / Volume 20 / Issue 2 / DOI: 10.31083/j.jin2002031
Open Access Original Research

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

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1 Department of Pharmacology, Faculty of Medicine, University of Jeddah, 23890 Jeddah, Saudi Arabia
2 Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
3 Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, 34212 Dammam, Saudi Arabia
4 Center for Neuroscience, Auburn University, Auburn, AL 36849, USA
5 Pharmacognosy and Pharmaceutical Chemistry Department, Faculty of Pharmacy, Taibah University, 42311 Almadinah Almunawwarah, Saudi Arabia
6 Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USA

These authors contributed equally.

J. Integr. Neurosci. 2021, 20(2), 321–329; https://doi.org/10.31083/j.jin2002031
Submitted: 16 February 2021 | Revised: 5 March 2021 | Accepted: 25 April 2021 | Published: 30 June 2021
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 β-hydroxybutyric 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 β-hydroxybutyric 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.

Keywords
β-hydroxybutyric acid
Apoptosis
Mitochondrial function
Oxidative stress
Neuro-protection
Cognitive enhancer
Computational analysis
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