Impact of the Ketogenic Diet on Neurological Diseases: A Review

Abstract

Background: The ketogenic diet (KD), high in fat and low in carbohydrates, was introduced in the 1920s as a non-pharmacological treatment for refractory epilepsy. Although its mechanism of action is not fully understood, beneficial effects have been observed in neurological diseases such as epilepsy, Alzheimer's disease, and Parkinson's disease.

Objective: This review examines the impact of the ketogenic diet and its molecular and neuroglial effects as a complementary therapy for neurological diseases.

Discussion: KD is associated with neuroprotective and antioxidant effects that improve mitochondrial function, regulate neurotransmitter flow, and reduce neuroinflammation and oxidative stress. Glial cells play an essential role in the utilization of ketone bodies (KBs) within the central nervous system's metabolism, particularly during ketosis induced by the KD. Thus, the KD represents a broad and promising strategy that involves both neurons and glial cells, with a molecular impact on brain metabolism and neuroinflammatory homeostasis.

Conclusion: Multiple molecular mechanisms have been identified to explain the benefits of the KD in neurological diseases; however, further experimental and clinical studies are needed to address various molecular pathways in order to achieve conclusive results.

Keywords: ketogenic diet; neuroglia; neuroinflammation; neurological diseases.

Figure 1

Effects of the ketogenic diet on neuroinflammation and oxidative stress. 1. The ketogenic diet bypasses the mechanistic failure of the electron transport chain, thereby providing an alternative energy source (ATP) through ketone bodies. 2. It reduces intestinal inflammation and modifies the gut microbiota. 3. Ketone bodies promote an increase in BDNF, GDNF, and NT-3, leading to a reduction in demyelination and axonal degeneration. 4. There is suppression of the M1 microglial phenotype, while the M2 phenotype is enhanced and activated, reducing and inhibiting inflammation and promoting angiogenesis through VEGF expression. 5. It increases mitochondrial biogenesis, enhancing superoxide dismutase (SOD) levels and activating anti-inflammatory pathways such as Nrf2 and its respective signal transduction and gene expression. 6. It decreases reactive oxygen species (ROS), inhibiting inflammatory cytokines such as IL-1, IL-6, IL-1β, and TNFα. Additionally, it can activate MAPK pathways, inhibit the mTOR pathway, and suppress the NF-κB pathway and the NLRP3 inflammasome. Created with https://www.biorender.com/.

Figure 2

Effects of the ketogenic diet on neurological diseases. 1. Ketone bodies cross the blood–brain barrier through monocarboxylate transporters. 2. Beta-hydroxybutyrate and acetate enter the mitochondria and, through the Krebs cycle, facilitate the production of NADH and consequently ATP via the electron transport chain. This alternative energy production compensates for the energy deficiency present in neurological diseases. 3. It enables excitatory–inhibitory regulation by modulating neurotransmitters, primarily by regulating glutamate through the inhibition of vesicular glutamate transporter 1 and AMPA receptor activity. 4. Astrocytes participate in the glutamate-glutamine cycle by recapturing glutamate released into the postsynaptic space and converting it into glutamine via glutamine synthetase, which is then released and recaptured by presynaptic terminals. 5. It increases the expression of GABA_A receptors and enhances their uptake through glutamine transaminase, thereby allowing greater Cl⁻ influx and inducing hyperpolarization. 6. There is a marked increase in ATP-sensitive Potassium channels, further raising the seizure threshold. 7. Ketone bodies reduce type 1 microglial activation. 8. There is a significant increase in the expression of type 2 microglia, leading to decreased expression of pro-inflammatory cytokines such as IL-1β, IL-6, and TNFα, as well as anti-inflammatory cytokines like TGF-β and pro-angiogenic factors such as VEGF. Blood–brain barrier (BBB), acetate (AcAc), Nicotinamide Adenine Dinucleotide Reduced (NADH), Adenosine Triphosphate (ATP), vesicular glutamate transporter 1 (VGLUT1), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), Gamma-Aminobutyric Acid Type A (GABA_A), ATP-sensitive Potassium Channels (K_ATP), type 1 microglia (M1), type 2 microglia (M2), Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), Tumor Necrosis Factor alpha (TNFα), Transforming Growth Factor beta (TGF-β), Vascular Endothelial Growth Factor (VEGF). Created with https://www.biorender.com/.