Experience With the Ketogenic Diet in Infants

Nordli, Douglas R.; Kuroda, Maxine M.; Carroll, Joanne; Koenigsberger, Dorcas; Hirsch, Lawrence J.; Bruner, Harlan J.; Seidel, William T.; Vivo, Darryl C. De

doi:10.1542/peds.108.1.129

Cited by 279 publications

(219 citation statements)

References 17 publications

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“…11,12 In addition, the ketogenic diet has been used for a long time for the treatment of refractory epilepsy. 4,13,14 The protective effect of KB has been mostly attributed to their conversion to AcetylCoA improving mitochondrial metabolism and preserving energy levels. [15][16][17] However, studies suggest that besides providing energy to neurons, KB reduce the production of reactive oxygen species (ROS) contributing to their protective effect.…”

Section: Introductionmentioning

confidence: 99%

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Julio-Amilpas

Montiel

Soto‐Tinoco

et al. 2015

J Cereb Blood Flow Metab

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Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury. INTRODUCTIONGlucose is the main energy source in brain. However, under certain conditions other energy substrates such as the ketone bodies (KB), acetoacetate (AcAc), and β-hydroxybutyrate (BHB) can be used by brain, including the suckling period, 1,2 prolonged fasting, 3 and the ketogenic diet; 4 all these situations are associated with increased KB levels in blood. Several studies have shown that KB can protect the brain against damage associated with diverse neurotoxic insults such as hypoxia, 5 ischemia, 6-8 hypoglycemia, 9,10 and excitotoxicity. 11,12 In addition, the ketogenic diet has been used for a long time for the treatment of refractory epilepsy. 4,13,14 The protective effect of KB has been mostly attributed to their conversion to AcetylCoA improving mitochondrial metabolism and preserving energy levels. [15][16][17] However, studies suggest that besides providing energy to neurons, KB reduce the production of reactive oxygen species (ROS) contributing to their protective effect. It has been observed in vitro that AcAc reduces ROS levels induced by glutamate exposure and glycolysis inhibition in cultured neurons, 12,16 and previous in vivo studies have shown that BHB decreases hypoglycemia and glutamate-mediated lipoperoxidation in the rat brain. 10,18 The mechanism underlying the reduction of ROS by BHB has not been elucidated but we have previously reported that KB display a scavenging action of ROS, in particular of the hydoxyl radical ( • OH). 10 The physiologic and the

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Section: Introductionmentioning

confidence: 99%

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Julio-Amilpas

Montiel

Soto‐Tinoco

et al. 2015

J Cereb Blood Flow Metab

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“…In myocardial cells, AA is involved in regulating the incorporation of glucose into glycogen and mediating the relative contributions of exogenous glucose and endogenous carbohydrate to myocardial energy metabolism (52). Interestingly, a ketogenic diet has long been known to be beneficial for the treatment of children with intractable seizures by unknown mechanisms (53,54). These tantalizing reports not only suggest that AA may play important roles in various biological processes but also suggest that it may have regulatory functions in addition to its involvement in energy production.…”

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confidence: 99%

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.Satellite cells, which are among the most abundant well defined adult stem cell types in skeletal muscle, play functionally important roles in postnatal growth, repair, and the regeneration of skeletal muscle (1-6). Because of their powerful ability to regenerate in vivo in response to muscle damage and various stimuli, satellite cells represent important targets for the treatment of muscular diseases (7-10). The recent development of stem cell-based regenerative medicine strategies has brought enormous interest in the discovery of regulatory factors capable of controlling satellite cell functions, such as activation, proliferation, differentiation, and self-renewal (11-13). Identification of such factors is expected to not only improve our understanding of the regulatory mechanisms that govern satellite cell functions, but also to facilitate the development of stem cell-based therapies for the treatment of muscular dystrophy or other chronic diseases associated with muscle wasting.Recent studies demonstrating a close correlation between cell proliferation and metabolic alterations in various tumor types have drawn attention to the significance of intrinsic small metabolites as signaling molecules responsible for regulating various cellular activities (14, 15). Although only a very limited number of such metabolites have been identified to date, accumulating evidence suggests that these metabolites can be oncogenic and alter cell signaling through epigenetic regulation. For example, 2-hydroxyglutarate (2-HG), 4 succinate, and fumarate, which are the best characterized small metabolites with oncogenic function, have come to be regarded as oncometabolites (16 -19). In tumor cells, 2-HG is generated by mutant forms of isocitrate dehydrogenase (IDH1 and IDH2) (20 -23), whereas succinate and fumarate accumulate via mutant forms of succinate dehydrogenase and fumarate hydratase, respectively (24 -27). It has been clearly demonstrated that increases in the levels of these oncometabolites play causal roles in tumorigenesis (26 -34). Recent studies of the molecular mechanisms underlying their action have revealed that 2-HG and elevated levels of succinate ...

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“…The ketogenic diet was stopped during the first month in seven patients: in two (10, 15) because of inefficacy after 10 days and 3 weeks respectively, and in the five others (3,8,9,20,21) because of adverse events (severe vomiting and fatigue). Although they tolerated the ketogenic diet poorly, these five patients were responders at 1 week, including two who became seizure-free, with seizure control maintained at 1 month (3,9).…”

Section: Results (mentioning

confidence: 99%

“…1,2 Many investigators have confirmed the benefits that this treatment can offer to young patients with epilepsy, [3][4][5][6] including infants. 7,8 However, the best indications for using the diet have not been clearly defined since it was shown to be helpful in treating a large range of different seizure types and epilepsy syndromes. Special interest has been given to various conditions associated with epilepsy including myoclonic astatic epilepsy, 5,9 infantile spasms, 7 Dravet syndrome, 10 atypical absences, 11 acquired epileptic aphasia, 12 tuberous sclerosis, 13 and Rett syndrome.…”

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confidence: 99%

The ketogenic diet improves recently worsened focal epilepsy

Villeneuve

Pinton

Bahi‐Buisson

et al. 2009

Develop Med Child Neuro

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Aim We observed a dramatic response to the ketogenic diet in several patients with highly refractory epilepsy whose seizure frequency had recently worsened. This study aimed to identify whether this characteristic was a useful indication for the ketogenic diet. Method From the 70 patients who received the ketogenic diet during a 3‐year period at our institution, we retrospectively selected patients with focal epilepsy. There were 22 children, 13 females and nine males, aged from 5 months to 18 years 6 months (mean 6y 9mo, SD 5y 11mo). Fifteen had symptomatic and seven had cryptogenic focal epilepsy. Seizure frequency 1 week before initiating the ketogenic diet was compared with that at 1 month and at the last visit on the diet. Results Eleven patients were responders (defined as reduction of seizures by more than 50%) at 1 month. Responders were higher (p=0.046) in the group with a recent worsening of seizures than in those with stable seizure frequency. Seven patients were still seizure‐free at 6 months on the diet. Tolerability was excellent in 10 patients. Five patients stopped the diet because of early side effects. Interpretation The ketogenic diet may be a valuable therapeutic option for children with pharmacoresistant focal epilepsy, particularly those with a recent deterioration of seizure control and neurological status. Because of its rapid effect, the ketogenic diet may be a useful support to intravenous emergency drugs in such a situation.

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Experience With the Ketogenic Diet in Infants

Abstract: The ketogenic diet should be considered safe and effective treatment for infants with intractable seizures.

Cited by 279 publications

References 17 publications

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

The ketogenic diet improves recently worsened focal epilepsy

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