The Mechanisms by Which the Ketone Body D-β-Hydroxybutyrate May Improve the Multiple Cellular Pathologies of Parkinson’s Disease
Ketone may improve Parkinson’s Disease.
Parkinson’s disease (PD), a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, is strongly associated with the death of dopaminergic neurons in the brain’s substantia nigra. Although dopamine replacement therapy temporarily helps patients manage their motor symptoms, this current standard of care fails to address the underlying network of pathologies that contribute to the persistent death of dopaminergic neurons. Thus, new treatment approaches are needed that address the underlying pathologies and, thereby, slow or halt the progression of the actual disease. D-β-hydroxybutyrate – a ketone body produced by the liver to support brain function during periods of starvation – may provide an option. Lifestyle interventions that induce endogenous D-β-hydroxybutyrate production, such as caloric restriction and ketogenic diets, are known to increase healthspan and lifespan in animal models and are used to treat neurological disorders. The efficacy of these ketosis-inducing interventions, along with the recent development of commercially available D-β-hydroxybutyrate-based nutritional supplements, should inspire interest in the possibility that D-β-hydroxybutyrate itself exerts neuroprotective effects. This review provides a molecular model to justify the further exploration of such a possibility. Herein, we explore the cellular mechanisms by which the ketone body, D-β-hydroxybutyrate, acting both as a metabolite and as a signaling molecule, could help to prevent the development, or slow the progression of, Parkinson’s disease. Specifically, the metabolism of D-β-hydroxybutyrate may help neurons replenish their depleted ATP stores and protect neurons against oxidative damage. As a G-protein-coupled receptor ligand and histone deacetylase inhibitor, D-β-hydroxybutyrate may further protect neurons against energy deficit and oxidative stress, while also decreasing damaging neuroinflammation and death by apoptosis. Restricted to the available evidence, our model relies largely upon the interpretation of data from the separate literatures on the cellular effects of D-β-hydroxybutyrate and on the pathogenesis of Parkinson’s disease. Future studies are needed to reveal whether D-β-hydroxybutyrate actually has the potential to serve as an adjunctive nutritional therapy for Parkinson’s disease.
Segregating the pathologies underlying PD is, to some extent, an arbitrary exercise because they are deeply interconnected. Energetic abnormalities cause cells, which have been unable to maintain homeostasis, and thus may have compromised genomes, to undergo apoptosis. Apoptosis can deplete the extracellular pool of neuroprotective brain-derived neurotrophic factor (BDNF), thereby increasing inflammation. The nitric oxide (NO) produced as part of the inflammatory response can induce oxidative stress, which can cause mitochondrial damage and increase the energy crisis.
Of course, PD pathology is not a simple loop, but a complex network. Oxidative stress induces DNA damage, exciting the activity of the DNA repair protein, poly ADP-ribose polymerase 1 (PARP1), which catabolizes the silent mating type information regulation 2 homolog 1 (SIRT1) cofactor, NAD+ , and thus precipitates further oxidative stress, energy crisis, and apoptosis. Reactive oxygen species (ROS) also directly induces apoptosis and nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) -mediated inflammation, the latter of which accentuates oxidative stress, causes apoptosis, and, because NFκB is induced by the cytokines that it induces, more inflammation.
The pathologies that underlay PD are synergistic. This interconnectedness undermines any intervention aimed at a single point within the network. Perhaps that is why no true preventative treatments exist and why the current standard of care remains the largely palliative option of dopamine replacement therapy. However, there is a flipside to this complexity, for any molecule that can target many points within the network, as D-β-hydroxybutyrate (βHB) can, may capitalize on the feedback loops, such that the multiple mechanisms by which it operates add up to more than the sum of their parts. In this review, we attempted to integrate the still largely independent bodies of literature on the biochemical effects of βHB and on that pathological mechanisms of PD in order to present a model for how βHB could be used to improve the multiple cellular pathologies of PD. This model, in combination with preliminary data that show the ketogenic diet may be ameliorative in PD, suggests that exogenous βHB, now available as an FDA-approved sports drink, may have therapeutic potential for the prevention and/or treatment of PD. Future studies, including those currently being conducted, will reveal the authenticity of this potential.