An anticonvulsant profile of the ketogenic diet in the rat

Bough, Kristopher J.; Gudi, Kirana; Han, Frederick T.; Rathod, Alyssa H; Eagles, Douglas A.

doi:10.1016/s0920-1211(02)00086-4

Cited by 66 publications

(46 citation statements)

References 47 publications

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“…Anticonvulsant properties of the ketogenic diet have been documented in acute seizure models in rodents (Appleton and De Vivo, 1973;Huttenlocher, 1976;Hori et al, 1997;Stafstrom, 1999;Likhodii et al, 2000;Thavendiranathan et al, 2000Thavendiranathan et al, , 2003Bough et al, 2002). Moreover, there is accumulating evidence from studies in models of chronic epilepsy that the ketogenic diet has antiepileptogenic properties that extend beyond its anticonvulsant efficacy.…”

Section: Epilepsymentioning

confidence: 99%

Neuroprotective and disease-modifying effects of the ketogenic diet

Gąsior¹,

Rogawski²,

Hartman³

2006

Behavioural Pharmacology

402

324

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The ketogenic diet has been in clinical use for over 80 years, primarily for the symptomatic treatment of epilepsy. A recent clinical study has raised the possibility that exposure to the ketogenic diet may confer long-lasting therapeutic benefits for patients with epilepsy. Moreover, there is evidence from uncontrolled clinical trials and studies in animal models that the ketogenic diet can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, and may also be protective in traumatic brain injury and stroke. These observations are supported by studies in animal models and isolated cells that show that ketone bodies, especially β-hydroxybutyrate, confer neuroprotection against diverse types of cellular injury. This review summarizes the experimental, epidemiological and clinical evidence indicating that the ketogenic diet could have beneficial effects in a broad range of brain disorders characterized by the death of neurons. Although the mechanisms are not yet well defined, it is plausible that neuroprotection results from enhanced neuronal energy reserves, which improve the ability of neurons to resist metabolic challenges, and possibly through other actions including antioxidant and anti-inflammatory effects. As the underlying mechanisms become better understood, it will be possible to develop alternative strategies that produce similar or even improved therapeutic effects without the need for exposure to an unpalatable and unhealthy, high-fat diet.

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Section: Epilepsymentioning

confidence: 99%

Neuroprotective and disease-modifying effects of the ketogenic diet

Gąsior¹,

Rogawski²,

Hartman³

2006

Behavioural Pharmacology

402

324

View full text Add to dashboard Cite

show abstract

“…In contrast, the ketogenic diet was found to be protective in the pentylenetetrazol test in rats [25][26][27][28]. The diet also was effective against seizures induced by the GABA A receptor antagonists bicuculline and picrotoxin in rats [31], but did not confer sustained protection against fully kindled seizures in the rat amygdala kindling model [21,22]. Anticonvulsant treatments that act through effects on GABA mechanisms are generally active in these models.…”

Section: Gaba Systemsmentioning

confidence: 99%

The Neuropharmacology of the Ketogenic Diet

Hartman

Gąsior

Vining

et al. 2007

Pediatric Neurology

280

169

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The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease.

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“…It has been shown that ketone bodies are neuroprotective as they induce a consistent increase in mitochondrial biogenesis regulating the synaptic function, and also generate ATP increases, thus reducing the reactive oxygen species production in neurological tissues [9,10], and notably inhibit superoxide synthesis in primary rat neuronal cultures exposed to hyperoxia [11]. Moreover, the main reason why the KD has been proven so effective as an anticonvulsant aFpproach is because it significantly reduces the metabolism of glucose [12]. In addition, Ma and colleagues [13] demonstrated that, at physiological concentrations, BHB and AcAc reduce spontaneous discharges of GABAergic neurons in the rat substantia nigra, through ATP-sensitive potassium channels.…”

Section: Editorialmentioning

confidence: 99%

The Ketogenic Diet Approach as Metabolic Treatment for a Variety of Diseases

Pilla¹

2016

J Epilepsy

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EditorialHuman brain derives over 60% of its energy from ketones when glucose availability is limited. After prolonged periods of fasting or Ketogenic Diet (KD), the whole body utilizes energy obtained from Free Fatty Acids (FFAs) released from adipose tissue. However, the brain is not capable to obtain significant energy from FFAs, thus hepatic ketogenesis converts them into ketone bodies: β-Hydroxybutyrate (BHB) and acetoacetate (AcAc), while a percentage of AcAc spontaneously decarboxylates to acetone [1]. To date, it has been broadly demonstrated how the metabolic state of mild ketosis, which can be induced through KD administration, calorie restriction or fasting, represents a valid tool for the metabolic management of epilepsy and a number neurodegenerative diseases [2], Amyotrophic Lateral Sclerosis (ALS) [3], and some types of cancer [4,5]. In addition, nutritional treatments represent an effective alternative where pharmaceutical approaches fail or produce unbearable side effects and costs for public health worldwide. However, before analyzing how benefits from therapeutic ketosis could be exploited, let us mention some pivotal concepts about metabolism. Under normal conditions and mostly in western societies, a healthy brain utilizes glucose as primary energy source, which unbalance can lead to a number of neurodegenerative disorders often associated with mitochondrial impairment and glucose transport-related dysfunctions, such as in epilepsy, Traumatic Brain Injury (TBI), Parkinson's and Alzheimer's diseases [6,7]. Ketone bodies and Krebs cycle intermediates represent the best fuels for brain and other organs. In fact, through their utilization, impaired glucose metabolism may be bypassed and their neuroprotective properties may be exploited [8]. However, neuroprotective mechanisms of ketosis are currently object of studies as mechanisms of action are still not sufficiently understood. It has been shown that ketone bodies are neuroprotective as they induce a consistent increase in mitochondrial biogenesis regulating the synaptic function, and also generate ATP increases, thus reducing the reactive oxygen species production in neurological tissues [9,10], and notably inhibit superoxide synthesis in primary rat neuronal cultures exposed to hyperoxia [11]. Moreover, the main reason why the KD has been proven so effective as an anticonvulsant aFpproach is because it significantly reduces the metabolism of glucose [12]. In addition, Ma and colleagues [13] demonstrated that, at physiological concentrations, BHB and AcAc reduce spontaneous discharges of GABAergic neurons in the rat substantia nigra, through ATP-sensitive potassium channels.Also, a reduction of total CNS aspartate levels in association with an increase of glutamate concentrations was found during ketosis, observing a significant increase of decarboxylated glutamate to GABA, the main inhibitory neurotransmitter [14,15]. Moreover, a remarkable increase in mitochondrial transcription enzymes and proteins was observed in rat hippocampus after the...

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An anticonvulsant profile of the ketogenic diet in the rat

Cited by 66 publications

References 47 publications

Neuroprotective and disease-modifying effects of the ketogenic diet

Neuroprotective and disease-modifying effects of the ketogenic diet

The Neuropharmacology of the Ketogenic Diet

The Ketogenic Diet Approach as Metabolic Treatment for a Variety of Diseases

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