D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease
Kim Tieu, … , Ravichandran Ramasamy, Serge Przedborski
Kim Tieu, … , Ravichandran Ramasamy, Serge Przedborski
Published September 15, 2003
Citation Information: J Clin Invest. 2003;112(6):892-901. https://doi.org/10.1172/JCI18797.
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Article Neuroscience

D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease

Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of the nigrostriatal dopaminergic neurons accompanied by a deficit in mitochondrial respiration. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes dopaminergic neurodegeneration and a mitochondrial deficit reminiscent of PD. Here we show that the infusion of the ketone body D-β-hydroxybutyrate (DβHB) in mice confers partial protection against dopaminergic neurodegeneration and motor deficits induced by MPTP. These effects appear to be mediated by a complex II–dependent mechanism that leads to improved mitochondrial respiration and ATP production. Because of the safety record of ketone bodies in the treatment of epilepsy and their ability to penetrate the blood-brain barrier, DβHB may be a novel neuroprotective therapy for PD.

Authors

Kim Tieu, Celine Perier, Casper Caspersen, Peter Teismann, Du-Chu Wu, Shi-Du Yan, Ali Naini, Miquel Vila, Vernice Jackson-Lewis, Ravichandran Ramasamy, Serge Przedborski

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Figure 2

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Protective effect of DβHB against MPTP-induced neurodegeneration. (a–h) ...
Protective effect of DβHB against MPTP-induced neurodegeneration. (a–h) TH-positive neurons in SNpc, and (i–p) TH-positive terminals in striatum. Animals were infused subcutaneously with vehicle (saline; a, e, i, and m), DβHB (1.6 mmol/kg/d; b, d, f, h, j, l, n, and p), or LβHB (1.6 mmol/kg/d; c, g, k, and o) 1 day before receiving intraperitoneal injections of either saline (a–d and i–l) or MPTP (18 mg/kg; e–h and m–p). There is an extensive loss of TH-positive neurons (e) and terminals (m) in MPTP-injected animals. This loss is attenuated by DβHB (f and n) but not by its inactive isomer LβHB (g and o). The complex II inhibitor 3-NP was given intraperitoneally (15 mg/kg) daily for the entire period of DβHB infusion. In the presence of 3-NP, DβHB does not confer neuroprotection. Scale bars: 500 μm (a–h) and 1 mm (i–p). Please refer to Table 1 for quantification of neurons and terminals in each animal group.