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/jci18797

Cited by 222 publications

(166 citation statements)

References 48 publications

(44 reference statements)

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“…The authors show that D-BHB stimulates oxygen consumption and ATP production in isolated mitochondrial [38]. Consistent with these results, a recent in vitro study shows that D-BHB administration during hypoxia favors the maintenance of the mitochondrial membrane potential and prevents cytochrome c release and caspase-3 activation, promoting cell survival in cultured hippocampal neurons [34].…”

Section: Discussionsupporting

confidence: 64%

“…On the other hand, in vivo studies have shown preservation of ATP levels and prevention of ischemic damage by D-BHB, suggesting its utilization as an energy substrate in the ischemic brain [36,37]. Similar results have been found in mice treated with the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a wellaccepted model of Parkinson disease [38]. However, the mechanisms of protection of ketone bodies have not been completely elucidated.…”

Section: Introductionsupporting

confidence: 59%

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d-β-Hydroxybutyrate Prevents Glutamate-Mediated Lipoperoxidation and Neuronal Damage Elicited during Glycolysis Inhibition In Vivo

2006

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Excitotoxic neuronal death mediated by over-activation of glutamate receptors has been implicated in ischemia, hypoglycemia and some neurodegenerative diseases. It involves oxidative stress and is highly facilitated during impairment of energy metabolism. We have shown previously that in vivo systemic glycolysis inhibition with iodoacetate (IOA), exacerbates glutamate excitotoxicity. We have now investigated whether this effect involves oxidative damage to membrane lipids, as evaluated by the presence of thiobarbituric acid-reactive substances. We have also tested whether the ketone body, D-beta-hydroxybutyrate (D-BHB), prevents lipoperoxidation and tissue damage. Results show that glutamate intrastriatal injection in control rats transiently enhances lipoperoxidation, while in IOA-treated animals increased lipoperoxidation is sustained. Treatment with D-BHB significantly reduces striatal lesions and lipoperoxidation. Vitamin E also reduced neuronal damage and lipoperoxidation. Results suggest that glycolysis impairment favors a pro-oxidant condition and situates oxidative damage as an important mediator of in vivo induced excitotoxicity. Results provide evidence for the neuroprotective effect of D-BHB against glutamate toxicity.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionsupporting

confidence: 59%

d-β-Hydroxybutyrate Prevents Glutamate-Mediated Lipoperoxidation and Neuronal Damage Elicited during Glycolysis Inhibition In Vivo

2006

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“…Moreover, the increased ketoacidosis in fasted animals could also play an important role in reducing PON1 activity because serum acidification could alter PON1 association to HDL as well as its catalytic activity [35]. Furthermore, ketone bodies have been described to increase oxidative stress [41]; thus, they are likely to contribute to PON1 oxidative inactivation. In this sense, the acute, early increase of PON1 activity in response to fasting could be related to the previously established theory of hormesis, describing that the low-intensity biological stress given by periodically repeated short periods of fasting would elicit a defence response to help organisms to overcome adversity [25].…”

Section: Kdamentioning

confidence: 99%

Time-dependent modulation of rat serum paraoxonase 1 activity by fasting

Thomàs-Moyà

Nadal-Casellas

Gianotti

et al. 2006

Pflugers Arch - Eur J Physiol

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High-density lipoprotein-associated paraoxonase 1 (PON1) protects the endothelium from the pro-oxidant activity of oxidised low-density lipoprotein. Whereas fasting has been related to increased oxidative stress, intermittent fasting and caloric restriction are associated to increased resistance to oxidative injury. Taking into consideration that serum PON1 activity is modulated by a restriction of caloric intake and because there is no evidence regarding PON1 response to total food deprivation, we investigated whether PON1 activity is involved in the response aimed to counteract the greater oxidative stress associated to fasting and whether serum PON1 activity is altered by the length of food deprivation. Male Wistar rats were randomly divided into five groups: fed and 6-, 12-, 24- or 48-h fasted rats. Serum PON1 activity increases within the first hours of fasting, representing a prompt adaptation designed to attenuate blood lipid peroxidation that cannot be sustained when fasting is prolonged. This PON1 response to early fasting could be part of the mechanisms triggered by periodically repeated short periods of food deprivation - intermittent fasting - which result in increased resistance to stress by stimulating antioxidant defences.

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“…The administration of DbHB protects brain from damage induced by hypoxia, anoxia and ischemia in mice and rats [36]. Administration of DbHB intraperitoneally attenuates MPTP-induced the neurodegeneration of the dopaminergic neurons and the loss of striatal dopaminergic fibers and dopamine in C57BL mice [27]. 4 mM DbHB protects cultured mesencephalic dopaminergic neurons from death induced by MPP?…”

Section: Discussionmentioning

confidence: 99%

“…and b-amyloid, respectively [26]. Systemic treatment of DbHB prevents degeneration of dopaminergic neurons in mice treated with MPTP [27].…”

Section: Introductionmentioning

confidence: 99%

D-β-Hydroxybutyrate Prevents MPP+-Induced Neurotoxicity in PC12 Cells

et al. 2009

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Numerous studies show that D-beta-Hydroxybutyrate (DbetaHB) is neuroprotective. The present study was to explore the neuroprotective effects of DbetaHB against the cell death and apoptosis induced by 1-methyl-4-phenylpyridinium ion (MPP+) in PC12 cells. PC12 cells were pretreated with DbetaHB and followed by MPP+ exposure. The cell viability was determined by MTT assay. The morphological characteristics of apoptosis was observed by Acridine Orange (AO) staining and apoptotic rates were measured by flow cytometer. The product of lipid peroxidation, malondialdehyde (MDA), was measured using thiobarbituric acid method. The mitochondrial membrane potential (MMP), intracellular ROS and total glutathione were detected by microplate reader. In PC12 cells, pretreatment with DbetaHB significantly reduced MPP+-induced the decrease of cell viability. AO staining and flow cytometric analysis found DbetaHB inhibited MPP+-induced apoptosis. The measurement of MDA formation showed that DbetaHB alleviated lipid peroxidation induced by MPP+. The loss of MMP induced by MPP+ was preventive by DbetaHB. The changes of intracellular ROS and total glutathione induced by MPP+ were reversed by DbetaHB. DbetaHB protected PC12 cells against MPP+-induced death and apoptosis.

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

Cited by 222 publications

References 48 publications

d-β-Hydroxybutyrate Prevents Glutamate-Mediated Lipoperoxidation and Neuronal Damage Elicited during Glycolysis Inhibition In Vivo

d-β-Hydroxybutyrate Prevents Glutamate-Mediated Lipoperoxidation and Neuronal Damage Elicited during Glycolysis Inhibition In Vivo

Time-dependent modulation of rat serum paraoxonase 1 activity by fasting

D-β-Hydroxybutyrate Prevents MPP+-Induced Neurotoxicity in PC12 Cells

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