The Mechanisms by Which the Ketone Body D-β-Hydroxybutyrate May Improve the Multiple Cellular Pathologies of Parkinson's Disease

Abstract

Parkinson's disease, 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.

Keywords: D-β-hydroxybutyrate; Parkinson's disease; apoptosis; dopamine; energy metabolism; inflammation; oxidative stress.

Figures

Figure 1

βHB protects against PD pathologies. βHB acts as a metabolite (blue), to increase mitochondrial ATP production and bolster antioxidant defenses, and as a signaling molecule (orange), to activate the G-protein-coupled, hydroxycarboxylic acid receptor 2 (HCAR2), and inhibit class I and IIa histone deacetylases (HDACs), thereby targeting the four fundamental pathologies underlying PD.

Figure 2

βHB improves energetics. βHB decreases the NAD+/NADH ratio and increases the Q/QH2 ratio, resulting in an increase in the redox span between the two couples. More energy is liberated by the transfer of electrons from NADH to Q and, thereby, ATP production is increased. βHB also acts to circumvent the pathological blockade of complex I (CI) observed in PD by increasing flux through complex II (CII) via the production of succinate.

Figure 3

βHB decreases ROS production, increases antioxidant defenses, and increases neurotransmitter synthesis. βHB oxidizes the Q/QH2 couple to decrease the transfer of electrons from QH2 to oxygen by reverse electron transport at complex I (CI) and, thus, decrease the production of superoxide (O2•) radicals. βHB generates NADPH by (i) increasing the transfer of hydride ions from NADH to NADP+, (ii) inhibiting glycolysis, thus increasing pentose phosphate pathway flux, and (iii) increasing citrate-pyruvate and citrate-isocitrate cycle flux. NADPH, in turn, supports antioxidant defenses, including improving (reducing) the glutathione (GSH-GSSG), thioredoxin (TRX), and vitamins C and E reduced to oxidized ratios. NADPH reduces dihydrobiopterin (BH2) into tetrahydrobiopterin (BH4) and, thereby, increases the synthesis of the neurotransmitters dopamine, noradrenaline, serotonin, and melatonin.

Figure 4

βHB exerts neuroprotective effects by activating hydroxycarboxylic acid receptor 2 (HCAR2). Activation of HCAR2 promotes the downstream activation of SIRT1 and inhibition of NFκB to protect against the fundamental pathologies of PD.

Figure 5

βHB exerts neuroprotective effects by inhibiting histone deacetylases (HDACs). βHB-mediated HDAC inhibition increases BDNF and FOXO3A expression and prevents endoplasmic reticulum (ER) stress. In these ways, βHB protects neurons against energetic abnormalities, inflammation, apoptosis, and oxidative stress.

Figure 6

Summary of the interrelated pathologies of PD. Blue arrows represent activation or upregulation. Red dots represent inhibition or downregulation. Black up and down arrows represent the stimulatory or inhibitory effect of βHB on a given metabolite, ratio, protein, or process.