Effects of ketogenic diet on neuroinflammation in neurodegenerative diseases

Since there is currently no cure or effective disease-remitting therapy for most neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), it is critical
to develop effective treatment strategies.
Neuroinflammation is known to play a significant role
in the complex pathogenesis of neurodegenerative diseases.
Therefore, intervention in neuroinflammation can be one of the strategies for the treatment of
neurodegenerative diseases.

Recently, emerging evidence has highlighted the pathophysiological and clinical benefits of the Ketogenic Diet (KD) in neurodegenerative diseases, suggesting that KD is a possible treatment option
for neurological disorders.
KD is known to be a dietary intervention
high in fat, low in carbohydrates and moderate protein.
As a form of fasting, KD allows the body to replace carbohydrates with fat as a source of
energy.
Well, whether KD fights neurodegenerative diseases by influencing neuroinflammation is unclear
.

On July 11, 2022, Wang Zhenfu's research group of the Second Medical Center of the Chinese People's Liberation Army General Hospital published a review article entitled "Effects of Ketogenic Diet on Neuroinflammation in Neurodegenerative Diseases" on Aging Dis, which introduced the physiological basis of KD.
To summarize the latest research data on KD's fight against various neurodegenerative diseases through neuroinflammatory mechanisms, and to summarize the latest experimental and clinical evidence
supporting the potential therapeutic role of KD in the treatment of normal brain aging and neuroinflammation specifically targeting neurodegenerative diseases.

Research results

1.
Biochemical and physiological functions of KD

Previous studies have shown elevated levels of ketone bodies (KB), β-hydroxybutyric acid (βHB), and acetone in healthy subjects who are fasting or on a low-carbohydrate and high-fat diet, and that special diets based on high fat and low carbohydrates help improve seizure control
in patients with drug-resistant epilepsy.
Figure 1 shows the macronutrient composition of classic KD and its common modifications
.
The ultimate goal of KD is to produce KBs, which can be measured by blood or urine samples to ensure the adequacy of their dietary intervention
.

Figure 1: Features of the classic ketogenic diet and its common modifications
.

2.
Ketolytic effect in the brain and neuroprotective effect of KD

At the beginning of a carbohydrate or energy-restricted diet, glucose stored in the brain provides adenosine triphosphate (ATP) only within minutes, and KBs can enter brain tissue through monocarboxylic acid transporters (MCTs) on microvascular endothelial cells and astrocytes, depending on the concentration
of KBs in circulation.
In general, neurons can take up betaHB, while glial cells can release or take up betaHB.

KD inhibits glycolysis and produces KB through four pathways, thereby exerting neuroprotective effects
in the CNS.
First, inhibition of glycolysis regulates insulin secretion and improves insulin sensitivity and glucose tolerance, thereby delaying the onset of age-related diseases and extending the lifespan
of species.
Second, KBs compensate for mitochondrial dysfunction in neurons and glial cells by improving the function of the mitochondrial respiratory chain and increasing the production of mitochondrial ATP
.
Third, KD reduces the production of reactive oxygen species (ROS) and reduces inflammation through
various signaling pathways.
Fourth, KD can prevent neuronal apoptosis
through the SIRT-1 signaling pathway.

3.
Possible anti-inflammatory mechanisms of KD

Inflammation is a series of integrated biological processes
that occur when the cells or tissues of an organism respond to external damage.
Microglia and astrocytes are innate immune cells
primarily involved in neuroinflammation.
Microglia are resident macrophages in the brain and are key players in neuroinflammation; Astrocytes are the most common type of glial cell and can form unique perivascular channels to eliminate potential nerve agents
.
There is increasing evidence that KD plays a neuroprotective and disease-modifying role in neurodegenerative diseases
by modulating central and peripheral inflammatory mechanisms.
Figure 2 illustrates the multidimensional underlying mechanisms
related to the anti-inflammatory properties of KD.

Figure 2: Specific anti-inflammatory mechanisms
mediated by the ketogenic diet.

4.
KBs as signal mediators

In addition to acting as energy substrates, KBs function as mediators of intracellular signaling, participating in intracellular signaling cascades and directly or indirectly regulating neuroinflammation, especially βHB.

Figure 3 shows the specific anti-inflammatory mechanism
of βHB mediated by cell signaling pathways.
In activated primary microglia pretreated with βHB and stimulated with lipopolysaccharide (LPS), βHB can bind to HCA2 to further inhibit the production
of pro-inflammatory cytokines and enzymes via the NF-κB pathway.
However, activation of HCA2 by βHB also alleviates the inflammatory response
in part by reducing endoplasmic reticulum (ER) stress, nucleotide binding domain-like receptor protein 3 (NLRP3) inflammasome activity, and IL-1β and IL-18 levels.

Figure 3: Intracellular molecular mechanisms
of β-hydroxybutyric acid (βHB)-mediated neuroinflammation.

5.
Effects of KD on normal brain aging and neurodegenerative diseases

Previous studies have identified the effects of
KD on normal brain aging and neurodegenerative diseases.
KD is increasingly seen as a potential alternative to
a range of neurodegenerative diseases.
In this review, the authors summarize the main published experimental and clinical evidence (Table hyperlink) related to the role of KD in normal brain aging and neurodegenerative diseases, in particular the involvement of neuroinflammatory mechanisms
.

In summary, recognizing that KD is not only a traditional treatment for epilepsy, but also plays a neuroprotective role in neurodegenerative diseases, it has been suggested that KD may be a promising way to prevent multiple symptoms
of neurodegenerative diseases.

Numerous studies have shown that KD promotes energy metabolism, oxidative stress, neuroinflammation and apoptosis
in neurodegenerative diseases through pleiogenic mechanisms.
Although the current findings suggest that KD offers a promising treatment for neurodegenerative diseases, further preclinical studies are needed to determine the impact
of KD on the pathophysiology of neurodegenerative diseases.