Ketogenic diet ameliorates inflammation by inhibiting the NLRP3 inflammasome in osteoarthritis.
Arthritis research & therapy
BACKGROUND:The nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been reported to be involved in the pathological process of osteoarthritis (OA) inflammation. Here, we investigated the ketogenic diet (KD), which has been previously demonstrated to inhibit NLRP3 inflammasome activation, to elucidate its protective mechanism against OA in rats. METHODS:Anterior cruciate ligament transaction (ACLT) together with partial medial meniscectomy was used to create a rat knee joint OA model. After treatment with KD or standard diet (SD) for 8 weeks, the knee specimens were obtained for testing. RESULTS:The KD significantly increased the content of β-hydroxybutyrate (βOHB) in rats. Compared to the SD group, the KD significantly reduced the damage caused by OA in the articular cartilage and subchondral bone. The NLRP3 inflammasome and inflammatory cytokines interleukin-1 β (IL-1β) and IL-18 were significantly increased in the SD group compared with the sham group, while their expression was significantly decreased in rats treated with the KD. In addition, MMP13 was significantly decreased in the KD group compared to that in the SD group, while COL2 was significantly increased. CONCLUSIONS:KD can protect the articular cartilage and subchondral bone in a rat OA model by inhibiting NLRP3 inflammasome activation and reducing the OA inflammatory response.
10.1186/s13075-022-02802-0
Electrical Control in Neurons by the Ketogenic Diet.
Frontiers in cellular neuroscience
The ketogenic diet is used as a diet treatment for drug-resistant epilepsy, but there are no antiepileptic drugs based on the ketogenic diet. The ketogenic diet changes energy metabolites (ketone bodies, glucose and lactate) in the brain, which consequently changes electrical activities in neurons and ultimately suppresses seizures in epileptic patients. In order to elucidate the antiseizure effects of the ketogenic diet, it is important to clarify the mechanism by which these metabolic changes are converted to electrical changes in neurons. In this review, we summarize electrophysiological studies focusing on electrical control in neurons by the ketogenic diet. Recent studies have identified electrical regulators driven by the ketogenic diet: ion channels (ATP-sensitive K channels and voltage-dependent Ca channels), synaptic receptors (AMPA-type glutamate receptors and adenosine A receptors), neurotransmitter transporters (vesicular glutamate transporters), and others (BCL-2-associated agonist of cell death and lactate dehydrogenase). Thus, the ketogenic diet presumably elicits neuronal inhibition via the combined actions of these molecules. From the viewpoint of drug development, these molecules are valuable as targets for the development of new antiepileptic drugs. Drug therapy to mimic the ketogenic diet may be feasible in the future, through the combination of multiple antiepileptic drugs targeting these molecules.
10.3389/fncel.2018.00208
The Impact of the Ketogenic Diet on Glial Cells Morphology. A Quantitative Morphological Analysis.
Gzielo K,Soltys Z,Rajfur Z,Setkowicz Z K
Neuroscience
Ketogenic diet is reported to protect against cognitive decline, drug-resistant epilepsy, Alzheimer's Disease, damaging effect of ischemic stroke and many neurological diseases. Despite mounting evidence that this dietary treatment works, the exact mechanism of its protective activity is largely unknown. Ketogenic diet acts systemically, not only changing GABA signaling in neurons, but also influencing the reliance on mitochondrial respiration, known to be disrupted in many neurological diseases. Normally, human body is driven by glucose while ketogenic diet mimics starvation and energy required for proper functioning comes from fatty acids oxidation. In the brain astrocytes are believed to be the sole neural cells capable of fatty oxidation. Here we try to explain that not exclusively neurons, but also morphological changes of astroglia and/or microglia due to different metabolic state are important for the mechanism underlying the protective role of ketogenic diet. By quantifying different parameters describing cellular morphology like ramification index or fractal dimension and using Principal Component Analysis to discover the regularities between them, we demonstrate that in normal adult rat brain, ketogenic diet itself is able to change glial morphology, indicating an important role of these underappreciated cells in the brain metabolism.
10.1016/j.neuroscience.2019.06.009
Role of the ketogenic diet in acute neurological diseases.
Arora Niraj,Mehta Tejas R
Clinical neurology and neurosurgery
The current review outlines the role of ketogenic diet (KD) in the management of acute neurological conditions namely traumatic brain injury, ischemic stroke, status epilepticus and primary aggressive brain tumor. An overview of the scientific literature- both clinical and pre-clinical studies is presented along with the proposed mechanism of ketogenic diet. The review also describes different formulations of commercially available ketogenic diets along with the common adverse effects and dosing recommendations.
10.1016/j.clineuro.2020.105727
Selenium and antioxidant levels in children with intractable epilepsy receiving ketogenic diet.
El-Rashidy Omnia F,Youssef Mai M,Elgendy Yasmin G,Mohsen Manal A,Morsy Safaa M,Dawh Sarah A,Saad Khaled
Acta neurologica Belgica
Ketogenic diet is a high-fat, low-carbohydrate, and adequate-protein diet. It is well-established as a treatment option for drug-resistant childhood epilepsies. Our study aimed to evaluate Selenium levels and oxidative stress in children receiving ketogenic diet for intractable seizures for 6 months. This is a comparative case-control study included 90 children under 6 years age. They were subdivided into three groups. Group I: Thirty patients with drug-resistant epilepsy under antiepileptic drugs only. Group II: Thirty patients with drug-resistant epilepsy under treatment with ketogenic diet for 6 months and antiepileptic drugs. Group III: Thirty age and sex-matched healthy children as controls. Full history taking with special emphasis on severity and frequency of seizures, neurological examination, anthropometric measurements and laboratory analysis for serum Malonaldehyde, and total antioxidant capacity and Selenium were done for all participants. The frequency and severity of seizures were significantly lower in group II receiving ketogenic diet than group I on antiepileptic drugs only. Selenium levels were significantly lower in epileptic patients in comparison to controls. However, it was markedly lower in the ketogenic diet group. Malonaldehyde levels were significantly higher in epileptic children in comparison to controls, with lower values among ketogenic diet group when compared to patients on antiepileptic drugs only. Total antioxidant capacity levels were significantly lower in epileptic patients in comparison to controls, with higher values among ketogenic diet group as compared to epileptic patients on pharmacological treatment. Ketogenic diet is an effective treatment for refractory epilepsy for its anti-epileptic mechanism. It also may exert antioxidant effects. The nutrient content of the ketogenic diet may not meet the recommended daily allowance for selenium. So, this should be taken into consideration for supplementation of minerals in adequate amounts for patients receiving this diet.
10.1007/s13760-020-01310-9
A gut feeling about the ketogenic diet in epilepsy.
Pittman Quentin J
Epilepsy research
The ketogenic diet has been used to treat intractable epilepsy for many years, yet the mechanism(s) underlying its effectiveness have not been completely elucidated. However, emerging evidence indicates that the ketogenic diet may correct or otherwise alter a 'dystopic' gut microbiota that exhibits altered fecal microbial composition compared to healthy individuals. Recent studies in animal seizure models also reveal altered gut microbiome, as well as changes in the composition of the microbiota after ingestion of a ketogenic diet. The effectiveness of the ketogenic diet in these animal models appears to be absolutely dependent upon the presence of gut microbiota. Further evidence suggests that effectiveness of the ketogenic diet in controlling seizures may be reliant upon the ability of specific bacterial populations to alter gamma glutamylation of amino acids and thus alter their uptake into the central nervous system. These studies suggest new directions for research in patients with epilepsy.
10.1016/j.eplepsyres.2020.106409
A unifying mechanism of ketogenic diet action: The multiple roles of nicotinamide adenine dinucleotide.
Elamin Marwa,Ruskin David N,Sacchetti Paola,Masino Susan A
Epilepsy research
The ability of a ketogenic diet to treat seizures and render a neuronal network more resistant to strong electrical activity has been observed for a century in clinics and for decades in research laboratories. Alongside ongoing efforts to understand how this therapy works to stop seizures, metabolic health is increasingly appreciated as critical buffer to resisting and recovering from acute and chronic disease. Accordingly, links between metabolism and health, and the broader emerging impact of the ketogenic diet in improving diverse metabolic, immunological and neurological conditions, have served to intensify the search for its key and/or common mechanisms. Here we review diverse evidence for increased levels of NAD, and thus an altered ratio of NAD/NADH, during metabolic therapy with a ketogenic diet. We propose this as a potential unifying mechanism, and highlight some of the evidence linking altered NAD/NADH with reduced seizures and with a range of short and long-term changes associated with the beneficial effects of a ketogenic diet. An increase in NAD/NADH is consistent with multiple lines of evidence and hypotheses, and therefore we suggest that increased NAD may be a common mechanism underlying beneficial effects of ketogenic diet therapy.
10.1016/j.eplepsyres.2020.106469
Anticonvulsant mechanisms of the ketogenic diet and caloric restriction.
Rudy Luna,Carmen Rubio,Daniel Rojas,Artemio Rosiles,Moisés Rubio-Osornio
Epilepsy research
Many treatments have been proposed to control epileptic seizures, such as the ketogenic diet and caloric restriction. However, seizure control has not yet been improved completely in all patients. Probably, due to the lack of understanding regarding this neurological disorder pathogenesis or pathophysiology, including its molecular approach. Currently, there is not much information about the molecular processes and genes involved, and their relation to the possible beneficial effects of diet therapy on epilepsy. The ketogenic diet and caloric restriction are implicated in potential anti-seizure mechanisms related to the gut microbiome, metabolic pathways, hormones and neurotransmitters, mitochondria improvement, a role in inflammation, and oxidative stress, among others. In this review, we pretend to describe the molecular mechanism and the possible genes involved in the different ketogenic diet and caloric restriction mechanisms of action described to decrease neural excitability and, therefore, epileptic seizures, especially when conventional treatment is not enough to achieve control of epilepsy.
10.1016/j.eplepsyres.2020.106499
Ketogenic diet – mechanism of action and perspectives for the use in the therapy: data from clinical studies
Pondel Natalia,Liśkiewicz Daniela,Liśkiewicz Arkadiusz
Postepy biochemii
Ketogenic diet is a high fat and very low-carbohydrate nutritional approach that induces increased production of ketone bodies, which serve as an alternative to glucose energetic substrates. Since almost a century ketogenic diet has been used in the therapy of refractory epilepsy, especially in children. Because of the pleiotropic effect of ketogenic diet on physiology, including inflammation, oxidative stress, energy balance and signaling pathways, in recent years scientists have been intensively exploring the use of it in the treatment of other diseases. In the present article current clinical studies regarding the possibility of using the ketogenic diet in the treatment of obesity, diabetes, neurological disorders and cancer has been reviewed alongside with potential mechanisms responsible for the therapeutic effect of ketogenic diet in these diseases. The metabolic processes engaged in nutritional ketosis and practicals aspects of ketogenic dieting have been also discussed.
10.18388/pb.2020_342
Altered cytokine levels in cerebrospinal fluid following ketogenic diet of children with refractory epilepsy.
Wickström Ronny,Ygberg Sofia,Lindefeldt Marie,Dahlin Maria
Epilepsy research
Ketogenic diet is an effective treatment which has the potential to achieve a significant seizure reduction in drug-resistant epilepsy. The mechanism behind this effect is unclear, but one hypothesis is that the mechanism is anti-inflammatory. In this prospective study on pediatric patients we compared levels of cytokines and chemokines in the cerebrospinal fluid before and after three months on treatment to evaluate a possible anti-inflammatory effect. We analyzed 34 cytokines and chemokines in the cerebrospinal fluid of pediatric patients (n = 21) with refractory epilepsy by a multiplex assay. Beta-hydroxybutyric acid was measured in blood and cerebrospinal fluid. Seizure frequency in relation to diet treatment was assessed. For 9 different cytokines (CCL 7, CCL 21, CCL 22, CCL 25, CCL 27, IL-2, IL-10, CX3CL1 and MIF), a significant decrease ranging from 7 to 27% was seen after three months as compared to levels before the diet. In contrast, no cytokine displayed a significant increase during diet. A seizure reduction ≥ 50 % was seen in 15/21 patients (71 %) but no significant differences in cytokine decreases were found between responders and non-responders during treatment. A non-significant trend towards higher initial pre-treatment levels of cytokines was seen in responders, which were reduced following treatment. The levels of betahydroxybutyric acid were not related to seizure response. We conclude that while it is not possible to state a primary anti-inflammatory effect by dietary treatment from these data, an unequivocal immunological effect is seen and may be a part of the mechanism of ketogenic dietary treatment.
10.1016/j.eplepsyres.2021.106775
Ketogenic diet prevents methylglyoxal-evoked nociception by scavenging methylglyoxal.
Pain
ABSTRACT:Methylglyoxal (MGO) is a reactive dicarbonyl byproduct of glycolysis implicated in a growing number of neuropathic pain conditions, including chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, and radiculopathy with lumbar disk herniation. Recent studies show success in preclinical models treating these disorders with an interventional ketogenic diet. Here, we tested the hypothesis that a ketogenic diet modifies pathological MGO signaling as a mechanism underlying neuropathy improvement. We found that mice injected with MGO displayed nocifensive behaviors, whereas mice prefed a ketogenic diet were resistant to mechanical allodynia elicited by MGO. In addition, levels of circulating MGO were reduced in ketogenic diet-fed mice and negatively correlated with levels of the ketone body β-hydroxybutyrate (β-HB). Methylglyoxal is normally scavenged by the glyoxalase system, and ketogenic diet-fed mice displayed increased glyoxalase 1 activity compared with chow-fed control mice. Recent studies also suggest that ketone bodies contribute to MGO detoxification, consistent with a negative correlation between β-HB and MGO. To assess whether ketone bodies modified MGO-evoked nociception through direct MGO detoxification, we coincubated either acetoacetate or β-HB with MGO before injection. Mice receiving intraplantar MGO injection exhibit increased nociceptive behavior (lifting, licking, biting, and scratching), which was significantly reduced by coincubation with either acetoacetate or β-HB. Methylglyoxal increased phospho-extracellular signal-regulated kinase-positive cells in the spinal dorsal horn, and this evoked spinal activation was ameliorated by preincubation with acetoacetate or β-HB. These results suggest that a ketogenic diet and ketone bodies ameliorate MGO-evoked nociception, partially through detoxification of MGO, and provide rationale for therapeutic intervention with a ketogenic diet in MGO-driven pathologies.
10.1097/j.pain.0000000000002667