The role of the ketogenic diet in the effective treatment of some neurological diseases has been demonstrated over the past decade. It is used to treat epilepsy, migraines, Alzheimer’s or Parkinson’s disease, lateral amyotrophic sclerosis, autism, and sleep disorders. Although there is a limited amount of data about the diet ’s mechanism of action, it has been proven that this dietary therapy modifies cellular metabolism. Its effectiveness is being studied intensely while treating patients with the refractory type of epilepsy. Appropriate application of the ketogenic diet has fewer side effects than well-known pharmaceuticals given to patients.
The ketogenic diet was developed in the 1920’s as a treatment for epilepsy that mimics the elevation in the circulation of ketone bodies – compounds produced during metabolism of fats which occurs when the body runs low on glucose, such as in fasting or in a low carbohydrate intake.. The diet consists mainly of fats, which are in the ratio of 4:1 to carbohydrates with proteins in the most classical type of the diet . Due to a specific flavor of meals, the ketogenic diet initially had low interest and only started as a non-pharmacological way of treating epilepsy. The breakthrough that raised questions about the diet’s properties was the story of a two-year-old boy with refractory epilepsy, Charlie, who, when treated with the ketogenic diet under medical supervision, became free of epileptic seizures and achieved neuro-developmental recovery . His case drew attention to the role of a ketogenic diet and originated a new era of research, focused on possible neuroprotective aspects of it. Today, this diet serves to treat many patients with epilepsy, and its benefits seem to be promising in the treatment of other neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease.
Today, there are many different varieties of the ketogenic diet, some restrictive and some less so. The classic one requires eating about 20 to 50 g of carbohydrates per day, while 90% of the calories come from fats. This reduction of carbohydrates intake causes the nervous system to find an alternative source of energy, which is the ketone bodies produced in a process called ketogenesis occurring in the liver. Three of the ketone bodies are 3-hydroxybutyrate, acetoacetate, and acetone . In normal conditions, the concentration of the ketone bodies is about 0.3 mmol/L; during the stage of ketosis, it even raises up to 8 mmol/L. The ketone bodies start to be utilized as an energy source when the concentration reaches above 4 mmol/l. Then, due to the lack of a mitochondrial enzyme in the liver that transforms acetoacetate into acetoacetyl-CoA, this activation does not happen, and the ketone bodies start to be used as an energy source by tissues, mainly the brain . It has been proven that the ketogenic diet also stimulates the biogenesis of mitochondria, and causes higher expression of genes that code enzymes essential in cellular respiration, resulting in the higher affluence of the ATP in the brain . Moreover, it influences the mitochondrial uncoupling protein levels and activity; the maximum cellular respiration rates are higher in animals treated with the ketogenic diet, which causes the significantly lower production of radical oxygen species than in standard diet controls. These data suggest that the dietary therapy by diminishing radical oxygen species production may have neuroprotective effects . There are also assumptions that the ketogenic diet influences the neuron excitability by inhibiting glutaminergic transmission and strengthening the GABAergic one .
The Ketogenic Diet and Epilepsy
The ketogenic diet is most intensively studied regarding epilepsy, usually the refractory type of the disease. In this type of epilepsy, seizures fail to be controlled with anti-seizure medications, which make required therapy much more troublesome. Difficulty can result from not tolerating seizure medications or not responding to the medicines. The perfect aim is to keep the seizures under control without side effects. Throughout the years of research, the dietary treatment has shown the effectiveness resulting in a reduction of seizures by 50% on average. A number of patients, who were previously resistant to antiepileptic medicine, became seizure-free or presented significantly less frequent seizures even after discontinuation of the diet, which suggests that the ketogenic diet may exert long-term remedial effects on some people with the disease . No clinical factors can predict which patients will benefit the most. The therapy may also be useful in myoclonic-astatic epilepsy known as Doose syndrome, which is characterized by developmental neurological delays and falling preceded immediately by myoclonic and astatic seizures. Early dietary treatment demonstrated high effectiveness both clinically and electrographically; studies have shown that over half of patients treated experienced a reduction in seizures of more than 50%. Use of the diet in the disease is very promising and has been considered to be the first-line therapy for Doose syndrome. As a result of research, the Doose syndrome was listed by the expert consensus guideline for the optimal use of the ketogenic diet as one of the eight probable indications for the diet .
(Figure 1.) An animal fed with the ketogenic diet has increased level of ketone bodies and decreased glucose level. Ketone bodies lead to a higher concentration of ATP that is released into extracellular space and broken down to adenosine. Hyperpolarization occurs due to the opening of ATP-sensitive potassium channels and results in the antiepileptic effects of the diet.
Effects on Parkinson’s disease
As suggested by studies, the cause of Parkinson’s disease is degeneration of dopaminergic neurons, as well as impairment of mitochondrial function in the substantia nigra that contributes to the progression of the disease. These lead to slow abnormal movement, impaired posture, cognitive decline and other cortical function disorders . When utilizing the ketogenic diet, production of ketone bodies enhances mitochondrial function and ATP production, which then protects cells by enabling the use of high levels of energy when demanded. It has also been shown to cause the expression of many enzymes involved in mitochondrial metabolic pathways and an increase of biogenesis of mitochondria in the
hippocampus . In a model of Parkinson’s disease, neurons of the substantia nigra are injured from the application of 1-methyl-4-phenylpyridinium (MPP+), a neurotoxin which inhibits mitochondrial oxidative functions and causes symptoms of Parkinson’s disease. Treatment with one of the ketone bodies, 3-hydroxybutyrate, protects dopaminergic cells in the substantia nigra from degeneration induced by the application of MPTP, the precursor of MPP+, as it enhances oxidative phosphorylation in the mitochondria and thus the production of ATP . It also seems to cause a decrease in the levels of pro-inflammatory cytokines in the substantia nigra. Thus, it has been concluded that the ketogenic diet has neuroprotective and anti-inflammatory function against neurotoxicity induced by MPTP .
The ketogenic diet also seems to have neuroprotective effects for those with Alzheimer’s disease. The pathogenesis of this progressive dementia is thought to be extracellular “senile” plaques containing the amyloid protein, together with neurofibrillary tangles made of tau protein. Protective functions of one of the ketone bodies, 3-hydroxybutyrate, have been demonstrated by addition of fragments of the amyloid-beta protein (Aβ) in hippocampal neurons. The results have shown that the 3-hydroxybutyrate successfully protect against the deposition of amyloid in the rat model . The ketone bodies also may affect Alzheimer’s disease by allowing the cell to overcome amyloid-induced apoptosis . Other effects associated with the ketogenic diet such as reduced inflammation and enhanced mitochondrial metabolism have been shown to improve neurocognitive function in this type of dementia. Ingestion of carbohydrates can worsen memory, while higher ketone levels are positively correlated with memory performance. It has been suggested that insufficient carbohydrate intake contributes to the improvement of memory in adults who have an increased risk for Alzheimer’s disease . In addition, an increased level of fatty acids resulting from the ketogenic diet can improve cognitive function by having a beneficial effect on preventing memory decline, thus raising the possibility of having neuromodulatory functions of their own .
Despite the lack of clinical data about the diet’s mechanism of action, the ketogenic diet is broadly used against a variety of neurological diseases. One fundamental idea is that the energy metabolism shifts may contribute to the neuroprotective function of dietary therapy. However, the details of how that altered metabolism results in reduced degeneration of neurons or alleviates functional impairment remain a scientific mystery requiring further investigation in this field. This growing interest in studying the mechanism of ketogenic diet action gives rich opportunities for research, in both laboratory and clinic.
Natalia - a girl from Poland who fell in love with neuroscience after participating in the Brain Bee Championship. She became obsessed with everything connected to the nervous system and decided to pursue career as a neuroscientist in the future. Her main interests are the molecular basis of memory and circadian rhythm. As a high school student, she had an opportunity to conduct research on the long-term depression and long-term potentiation. Because of her interest in deep learning and artificial intelligence, she learns programming as well. Her other obsessions include practicing martial arts, traveling, and exploring various memory techniques.