The ketogenic diet is an alternative therapeutic strategy that may improve the survival and function of motor neurons, the nerve cells that control the movement of muscles, in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. It is a diet high in fat (80%–90%), and low in carbohydrates and protein.

How the ketogenic diet works

The ketogenic diet may have an impact on many mechanisms that regulate the survival of motor neurons in ALS.

The breakdown or metabolism of fats produces polyunsaturated fatty acids (PUFA) and ketone bodies, which are used as an alternative energy source to the glucose derived from a carbohydrate-rich diet. PUFA and ketone bodies are energy-rich molecules that enhance the function of mitochondria, which can then produce more cellular energy in the form of adenosine triphosphate (ATP).

The ketogenic diet also activates the antioxidant defense mechanism in nerve cells, which significantly reduces the production of reactive oxygen species (mostly in the mitochondria), thereby reducing damage to proteins, membranes, and genetic material (DNA).

Furthermore, the ketogenic diet increases the production of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and reduces the production of the excitatory neurotransmitter, glutamate. Therefore, the diet is thought to fix the imbalance between glutamate and GABA in the brains of ALS patients — an imbalance that causes hyper-excitation, damage, and death to motor neurons.

In ALS patients, brain-resident immune cells such as microglia and astrocytes are overactive, and other immune cells such as T-cells infiltrate the brain. These immune cells produce pro-inflammatory cytokines (cell-signaling molecules secreted by activated immune cells), which can induce neuronal cell death in ALS.

Therefore, a reduction in neuroinflammation would enhance the survival and function of neuronal cells. The ketogenic diet has been shown to reduce inflammation in the brain by reducing oxidative stress, lowering levels of damaging reactive oxygen species, and decreasing the glucose metabolism that activates pro-inflammatory pathways.

The ketogenic diet in clinical trials

A study in a mouse model of ALS demonstrated that the ketogenic diet increases motor neuron survival and function by positively modulating mitochondrial energy production.

In another study, ALS model mice fed with caprylic triglyceride showed significant improvement in motor function because of reduced motor neuron loss. Caprylic triglyceride can cross the blood-brain barrier and is metabolized into ketone bodies, which serve as an alternative energy substrate for neuronal metabolism and improve motor neuron survival in the ALS mouse models.

A Phase 3 clinical trial (NCT01016522) aimed to evaluate the safety and tolerability of the ketogenic diet in ALS patients. However, this trial was terminated for reasons that are not listed.

A prospective, multicenter, randomized, double-blind, placebo-controlled trial (NCT02306590) investigated whether a high-calorie fatty diet can be effective as an add-on therapy to extend survival time in riluzole-treated ALS patients. The study also monitored secondary outcomes such as changes in total ALS functional rating scale-revised (ALSFRS-R), body mass index (BMI), quality of life, and slow vital capacity (a measure of lung function). The trial was completed by September 2018, but no results have been published yet.

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