The Ketogenic Diet As A Treatment For Neurological Disorders
While the mechanisms underlying the anticonvulsant effects of the ketogenic diet are unknown, there is growing experimental evidence for its broad neuroprotective properties and, as a result, emerging data supporting its use in a variety of neurological diseases.
Even in medically refractory epilepsy patients who have been seizure-free for 2 years or more on the ketogenic diet, clinicians frequently report that both anticonvulsant medications and the diet can be successfully discontinued without seizures resuming.
The hypothesis that the ketogenic diet may have anti-epileptogenic properties is based on this fascinating clinical observation.
Several mechanisms through which the ketogenic diet may provide neuroprotective activity have been discovered over the last decade by researchers.
COPYRIGHT_OAPL: Published on https://www.oapublishinglondon.com/pop/the-ketogenic-diet/ by Alexander McCaslin on 2022-06-06T12:26:00.930Z
The rise in ketone body production by the liver and a decrease in blood glucose levels are two hallmark features of ketogenic diet treatment. Ketones are primarily produced as a result of fatty acid oxidation. Polyunsaturated fatty acids (PUFAs) like arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid may regulate neuronal membrane excitability by blocking voltage-gated sodium and calcium channels, reducing inflammation by activating peroxisome proliferator-activated receptors (PPARs), or inducing expression of mitochondrial uncoupling proteins that reduce reactive oxygen species (ROS) production.
The reduction in glycolytic flux is the second major biochemical feature of the ketogenic diet. Reduced glycolysis is a key feature of calorie restriction, which has been shown to reduce seizures and extend the lifespan in a variety of animals, including primates. While the link between calorie restriction and ketogenic diet mechanisms is still debated, it is clear that both treatments lower blood glucose levels, most likely due to a reduction in glycolytic flux.
Finally, many other mechanisms are likely to play a role in the ketogenic diet's neuroprotective effects. Many of these mechanisms are thought to be related to the anticonvulsant effects of the ketogenic diet, but some, if not all, could also contribute to cellular homeostasis and neuronal injury or dysfunction prevention.
The ketogenic diet, explained
There is no doubt that the ketogenic diet can help patients with medically refractory epilepsy, particularly children. The ketogenic diet was first and second-line treatment for severe childhood epilepsy after its introduction in 1920. The ketogenic diet fell out of favor after the introduction of anticonvulsant medications in pill form, only to resurface in the early 1990s, thanks in part to the efforts of concerned parents who reintroduced the diet to the general public.
In recent years, there has been a significant increase in ketogenic diet research, both in terms of basic science and clinical protocols and trials. Most major epilepsy centers around the world now use the ketogenic diet as part of their arsenal of treatments.
Neurons and neural circuits gradually lose function and, in some cases, completely degenerate as people age. It's possible that slowing the degeneration of certain neural structures and functions could be accomplished by altering energy metabolism with the ketogenic diet. Ketogenic diets, on the other hand, may have different morphological effects in structures like the hippocampus, possibly as a result of region-specific neuronal vulnerability during the late stages of aging.
The medium-chain triglyceride (MCT) form of the ketogenic diet, in particular, has been shown to cause negative synaptic changes in the CA1 stratum moleculare while having positive effects in the dentate gyrus' outer molecular layer.
There is a growing understanding that neuronal excitability is increased in Alzheimer's disease patients. While neuronal degeneration and the accumulation of abnormal cellular products such as fibrillary plaques and tangles are important pathological processes in Alzheimer's disease, recent evidence suggests that the function of existing neural circuits and mitochondrial homeostasis are also important.
The fact that patients with Alzheimer's disease have a higher rate of seizures than the general population supports this hypothesis. As a result, in addition to the potential benefits to the aging process mentioned above, there is a rationale for hypothesizing that the ketogenic diet may be beneficial in patients with Alzheimer's disease.
Importantly, if ketone bodies are the primary mediators in Alzheimer's disease, the ketogenic diet should be moderated by age-related differences in ketones production and extraction, as well as age-specific regional differences in ketone utilization within the brain.
The primary pathophysiology of Parkinson's disease is excitotoxic degeneration of dopaminergic neurons in the substantia nigra, which causes abnormalities in movement, cognition, and other cortical functions. What are the potential benefits of a ketogenic diet for Parkinson's disease patients?
A small clinical study found that 5 of 7 affected patients improved their scores on a standard Parkinson's disease rating scale, based on the recognition that ketone bodies may bypass defects in mitochondrial complex I activity that have been implicated in Parkinson's disease. However, a placebo effect cannot be ruled out given the small sample size.
BHB treatment reduced mitochondrial respiratory chain damage in animal models of Parkinson's disease caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Amyotrophic lateral sclerosis (ALS) is a disease that causes the cortex and anterior horn of the spinal cord to degenerate. As a result, voluntary motor activity deteriorates over time, leaving the affected individual profoundly weak despite maintaining a high level of cognitive function. The fundamental pathophysiological mechanisms that underpin this relentless disorder are still unknown, but, as with other neurodegenerative disorders, energy-producing systems are likely to play a role, and mitochondrial dysfunction is likely to contribute to disease pathogenesis.
In this regard, a mouse model of ALS created by knocking out the gene encoding the copper/zinc superoxide dismutase SOD1-G93A, causing progressive muscle weakness and death by respiratory failure, suggests that the ketogenic diet could be a promising adjunctive treatment for this devastating disease.
In comparison to non-ketogenic diet fed animals, feeding these mutant mice a ketogenic diet improved their histological and functional outcomes. In comparison to control mice fed a non-ketogenic diet, the ketogenic diet did not extend survival time. Mitochondria from these mutant mice produced more ATP, which counteracted the electron transport chain's complex I inhibition.
Autism is a neurodevelopmental disorder that affects social interaction and language development. Apart from symptomatic treatment of autism-related behaviors like aggression or anxiety, the development of a universally beneficial treatment has been hampered by the heterogeneous etiologies leading to autism spectrum disorders, as well as the uncertainty about what causes autism in the majority of "idiopathic" cases. Limited clinical evidence now suggests that the ketogenic diet could help children with autism spectrum disorders manage some of their abnormal behaviors.
After a 6-month trial of providing the ketogenic diet for 4 weeks of ketogenic diet treatment alternating with 2 weeks of normal diet in 6-week cycles, 10 of 18 autistic children showed moderate or significant behavioral improvement using a ketogenic diet variant containing MCT. This research was conducted on the Greek island of Crete, where there is a high prevalence of autism but also a high risk of genetic inbreeding.
The ketogenic diet increases mitochondrial mass while also upregulating mitochondrial genes and genes involved in metabolism. These boost brain cells' capacity to protect them from strokes and neurodegenerative diseases like Alzheimer's.
Ketogenic diets, which are extremely low in carbohydrates, have long been used to reduce seizure frequency and are now being promoted for a variety of health problems, including obesity, diabetes, and liver disease. Ketogenic diets may help manage symptoms of some chronic diseases and provide short-term relief.
According to new research from UC San Francisco scientists, ketogenic diets – extremely low-carbohydrate, high-fat diets that have long been known to help people with epilepsy and other neurological disorders – may work by reducing inflammation in the brain.
Because of their more efficient pathway, Ketones turned out to be a far better energy source for the brain than Glucose. Ketones produce more ATP per molecule than Glucose when used to produce energy using oxygen.
Despite a paucity of clinical evidence, there is growing evidence that the ketogenic diet can be used to treat a wide range of neurological disorders. The basic idea behind these preliminary studies is that metabolic changes may lead to neuroprotective effects.
A common theme appears to be changes in energy metabolism. While the mechanisms by which the ketogenic diet produces these effects are likely to be diverse, there may be one or more mechanistically shared final pathways.