The protective effect of a ketogenic diet on kainic acid-induced hippocampal cell death in the male ICR mice

Noh, Hae Sook; Kim, Yoon Sook; Lee, Hee Po; Chung, Ki Myung; Kim, Dong Wook; Kang, Sang Soo; Cho, Gyeong Jae; Choi, Wan Sung

doi:10.1016/s0920-1211(02)00262-0

Cited by 103 publications

(73 citation statements)

References 42 publications

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“…For example, the diet was protective against apoptotic cell death in mice induced by the glutamate receptor agonist and excitotoxin kainate, as evidenced by reductions of markers of apoptosis, including terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling and caspase-3 staining, in neurons in the CA1 and CA3 regions of the hippocampus (Noh et al, 2003). Activation of caspase-3, a member of a larger family of cysteine proteases, has been implicated in neuronal cell death produced by different brain insults including seizures and ischemia (Gillardon et al, 1997;Chen et al, 1998).…”

Section: Effects On Programmed Cell Deathmentioning

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: Effects On Programmed Cell Deathmentioning

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

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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%

“…Indeed, Noh et al identified a protective effect of ketosis on the hippocampus in an animal model. 21 This might explain the better response in patients with status epilepticus and nearly continuous seizure activity than in patients with stable sporadic seizures.…”

Section: Discussionmentioning

confidence: 99%

“…3 However, studies that addressed the effects of the ketogenic diet according to the type of seizures or epilepsy failed to identify any significant difference. 17,18 Animal studies have concentrated more on models for generalized convulsions 19,20 than on focal seizures, 21 although in both instances ketosis proved to be efficient. These models failed to generate any hypothesis regarding possible mechanisms of antiepileptic and anticonvulsive properties, despite the increase in neurogenesis after kainic-acid-induced seizures in mice.…”

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confidence: 99%

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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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“…On another note, ketones show a neuroprotective effect also against neurodegenerative pathologies characterized by deficits in glucose metabolism, since impairment of mitochondrial function represents the main cause of a high number of neurological diseases. In fact, the following findings were published in response to ketosis: Increased cell survival and decreased seizure frequency in kainate-induced seizure models [21]; consistent reduction in lesion volume after TBI induction [22]; suppressed inflammatory cytokines and chemokines in an experimental model of multiple sclerosis [23] increase in motor neuron number in ALS transgenic models [3,24]. Notably, studies on ALS mouse models have suggested that targeting energy metabolism with metabolic therapy may prolong survival and quality of life in ALS patients.…”

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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The protective effect of a ketogenic diet on kainic acid-induced hippocampal cell death in the male ICR mice

Cited by 103 publications

References 42 publications

Neuroprotective and disease-modifying effects of the ketogenic diet

Neuroprotective and disease-modifying effects of the ketogenic diet

The ketogenic diet improves recently worsened focal epilepsy

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

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