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

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

doi:10.1172/jci200318797

Cited by 378 publications

(278 citation statements)

References 45 publications

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“…We conclude, therefore, that, in this paradigm, dopaminergic cells do not succumb to rotenone via oxidative stress. Consistent with our findings, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice can be attenuated by D-␤-hydroxybutyrate, which increases ATP levels, but does not have antioxidant effects (34).…”

Section: Discussionsupporting

confidence: 92%

“…ATP depletion has also been observed as a primary consequence of MPP ϩ toxicity in hepatocytes (35), brain mitochondria (36), and mouse striatum (37,38), and providing metabolites of glycolysis attenuates it (39). Similarly, supplementation with D-␤-hydroxybutyrate, as well as glucose, protects neurons from MPP ϩ toxicity in vitro and in vivo (34,40,41). Accordingly, the importance of bioenergetics in the pathogenesis of PD warrants further investigation (42).…”

Section: Discussionmentioning

confidence: 99%

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Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Kweon¹,

Marks²,

Krencik³

et al. 2004

Journal of Biological Chemistry

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The pathogenesis underlying the selective degeneration of dopaminergic neurons in Parkinson's disease (PD) 1 is not fully defined, but multiple lines of evidence implicate mitochondrial dysfunction. Thus, defects in complex I of the mitochondrial respiratory chain in the substantia nigra and evidence of oxidative stress have been noted in the brains of PD patients (1, 2). PD is also associated with exposure to pesticides (3, 4), many of which are either oxidants or mitochondrial toxins. Rapid onset of Parkinsonism in young adults following injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5) occurs through its active metabolite, 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I (6), potentially by depleting energy stores and inducing oxidative stress (7,8).Complex I is specifically and irreversibly inhibited by the neurotoxin rotenone, a hydrophobic pesticide epidemiologically linked to PD. Continuous, systemic, in vivo infusion of 2-3 mg/kg/day rotenone in rats over weeks produces relatively selective nigrostriatal dopaminergic neurodegeneration, with formation of ubiquitin-and ␣-synuclein-positive inclusions (9, 10). This low dose paradigm results in about 75% inhibition of complex I activity, and corresponds to a brain concentration of 20 -30 nM (9, 10). However, although these studies establish the principle that complex I dysfunction leads to degeneration in dopaminergic neurons, consistent levels of functional deficits related to complex I dysfunction have been difficult to reproduce (11). Accordingly, this in vivo model has not lent itself easily to the study of the mechanism of rotenone toxicity (12). Similarly, the use of primary cultures of dopaminergic neurons to study mechanisms of rotenone-induced neurodegeneration has been limited: short term, nanomolar rotenone administration in primary cultures of dopaminergic neurons does not produce selective dopaminergic damage (13). In addition, primary cultures contain a mixture of dopaminergic and nondopaminergic neurons and therefore do not lend themselves to molecular and biochemical analyses. The use of existing cell lines to study the effects of chronic rotenone exposure (14) also has shortcomings. Most cell lines do not exhibit robust dopaminergic phenotypes. In addition, the high rate of proliferation that characterize these cell lines confound the assessment of cellular susceptibility to rotenone, because proliferating cells may replace those that have succumbed to rotenone, and chronic exposure may lead to the selection of cells that become resistant to rotenone toxicity.To study the cellular mechanisms of rotenone-induced dopaminergic neuronal degeneration, we therefore developed a novel cellular model derived from immortalized midbrain MN9D cells (15), a dopaminergic neuronal cell line that has been extensively characterized as a model of dopaminergic neurons (16 -19). Using sodium butyrate (NaBu) (20) to differentiate MN9D cells and cells from a related, immortalized, non-dopaminergic midbrain neuronal cell line (MN9X ...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Kweon¹,

Marks²,

Krencik³

et al. 2004

Journal of Biological Chemistry

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“…32 In addition, KB metabolism increases the mitochondrial pool of acetylCoA and succinate. 33 The net effect of these changes is increased metabolic efficiency. The reader is referred to several reviews that extensively cover the metabolic efficiency of KB metabolism.…”

Section: Properties Of Kbmentioning

confidence: 99%

“…For example, infusion of KB into rodents protects them from glutamate toxicity, 50 ischemia, 51 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. 33 This approach has been tested in a cell culture model of AD and in human trials. Exposure of cultured hippocampal cells from 18-day embryonic rats to 5 uM A␤42 resulted in a 50% decrease in cell number.…”

Section: Ketosis and Admentioning

confidence: 99%

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

294

116

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Summary: An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, ␤-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.

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“…In clinical practice, ketogenic diet is now established in the treatment of pharmacoresistant childhood epilepsy. In addition, ketogenic diet and BHB exert a protective function in animal models of stroke, PD, AD and ALS [4][5][6][7][8] . So far small clinical trials suggest that it is also effective in neurodegenerative diseases 9 .…”

mentioning

confidence: 99%

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

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The ketone body b-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA 2 , GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2 À / À mice. We further demonstrate that nicotinic acid, a clinically used HCA 2 agonist, reduces infarct size via a HCA 2 -mediated mechanism, and that noninflammatory Ly-6C Lo monocytes and/or macrophages infiltrating the ischemic brain also express HCA 2 . Using cell ablation and chimeric mice, we demonstrate that HCA 2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA 2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD 2 production by COX1 and the haematopoietic PGD 2 synthase. Our data suggest that HCA 2 activation by dietary or pharmacological means instructs Ly-6C Lo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

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

Cited by 378 publications

References 45 publications

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Ketone Bodies as a Therapeutic for Alzheimer's Disease

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

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