Control of seizure-like dynamics in neuronal populations with excitability adaptation related to ketogenic diet.

We consider a heterogeneous, globally coupled population of excitatory quadratic integrate-and-fire neurons with excitability adaptation due to a metabolic feedback associated with ketogenic diet, a form of therapy for epilepsy. Bifurcation analysis of a three-dimensional mean-field system derived in the framework of next-generation neural mass models allows us to explain the scenarios and suggest control strategies for the transitions between the neurophysiologically desired asynchronous states and the synchronous, seizure-like states featuring collective oscillations. We reveal two qualitatively different scenarios for the onset of synchrony. For weaker couplings, a bistability region between the lower- and the higher-activity asynchronous states unfolds from the cusp point, and the collective oscillations emerge via a supercritical Hopf bifurcation. For stronger couplings, one finds seven co-dimension two bifurcation points, including pairs of Bogdanov-Takens and generalized Hopf points, such that both lower- and higher-activity asynchronous states undergo transitions to collective oscillations, with hysteresis and jump-like behavior observed in vicinity of subcritical Hopf bifurcations. We demonstrate three control mechanisms for switching between asynchronous and synchronous states, involving parametric perturbation of the adenosine triphosphate (ATP) production rate, external stimulation currents, or pulse-like ATP shocks, and indicate a potential therapeutic advantage of hysteretic scenarios.

Ketogenic Diet in the Treatment of Epilepsy.

Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Ketogenic Diet Protects from Experimental Colitis in a Mouse Model Regardless of Dietary Fat Source.

While ketogenic diets (KDs) may have potential as adjunct treatments for gastrointestinal diseases, there is little knowledge on how the fat source of these diets impacts intestinal health. The objective of this study was to investigate how the source of dietary fat of KD influences experimental colitis. We fed nine-week-old male C57BL/6J mice (n = 36) with a low-fat control diet or KD high either in saturated fatty acids (SFA-KD) or polyunsaturated linoleic acid (LA-KD) for four weeks and then induced colitis with dextran sodium sulfate (DSS). To compare the diets, we analyzed macroscopic and histological changes in the colon, intestinal permeability to fluorescein isothiocyanate-dextran (FITC-dextran), and the colonic expression of tight junction proteins and inflammatory markers. While the effects were more pronounced with LA-KD, both KDs markedly alleviated DSS-induced histological lesions. LA-KD prevented inflammation-related weight loss and the shortening of the colon, as well as preserved Il1b and Tnf expression at a healthy level. Despite no significant between-group differences in permeability to FITC-dextran, LA-KD mitigated changes in tight junction protein expression. Thus, KDs may have preventive potential against intestinal inflammation, with the level of the effect being dependent on the dietary fat source.

Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use.

Cardiac arrest survivors suffer the repercussions of anoxic brain injury, a critical factor influencing long-term prognosis. This injury is characterised by profound and enduring metabolic impairment. Ketone bodies, an alternative energetic resource in physiological states such as exercise, fasting, and extended starvation, are avidly taken up and used by the brain. Both the ketogenic diet and exogenous ketone supplementation have been associated with neuroprotective effects across a spectrum of conditions. These include refractory epilepsy, neurodegenerative disorders, cognitive impairment, focal cerebral ischemia, and traumatic brain injuries. Beyond this, ketone bodies possess a plethora of attributes that appear to be particularly favourable after cardiac arrest. These encompass anti-inflammatory effects, the attenuation of oxidative stress, the improvement of mitochondrial function, a glucose-sparing effect, and the enhancement of cardiac function. The aim of this manuscript is to appraise pertinent scientific literature on the topic through a narrative review. We aim to encapsulate the existing evidence and underscore the potential therapeutic value of ketone bodies in the context of cardiac arrest to provide a rationale for their use in forthcoming translational research efforts.

Ketogenic diet induces p53-dependent cellular senescence in multiple organs.

A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that leads to the generation of ketones. While KDs improve certain health conditions and are popular for weight loss, detrimental effects have also been reported. Here, we show mice on two different KDs and, at different ages, induce cellular senescence in multiple organs, including the heart and kidney. This effect is mediated through adenosine monophosphate-activated protein kinase (AMPK) and inactivation of mouse double minute 2 (MDM2) by caspase-2, leading to p53 accumulation and p21 induction. This was established using p53 and caspase-2 knockout mice and inhibitors to AMPK, p21, and caspase-2. In addition, senescence-associated secretory phenotype biomarkers were elevated in serum from mice on a KD and in plasma samples from patients on a KD clinical trial. Cellular senescence was eliminated by a senolytic and prevented by an intermittent KD. These results have important clinical implications, suggesting that the effects of a KD are contextual and likely require individual optimization.

Dietas populares y su impacto en la piel. Una revisión narrativa / Popular Diets and Skin Effects: A Narrative Review

Se han popularizado diversas dietas para perder peso, incrementar la capacidad física y para el manejo de múltiples enfermedades crónicas: cardiovasculares, neurológicas o cutáneas. Destacan la dieta cetogénica y el ayuno intermitente, con resultados prometedores en la medicina tradicional y deportiva. Además, la dieta mediterránea se ha consolidado como una forma de alimentación de impacto positivo muy significativo en la salud. Otras dietas populares son la dieta «paleo», la dieta vegana y la libre de gluten. La dieta cetogénica, el ayuno intermitente y la dieta mediterránea aportan resultados favorables en dermatosis inflamatorias como la psoriasis, dermatitis atópica, hidradenitis supurativa o acné. La dieta mediterránea podría actuar también como factor protector para el desarrollo de algunas neoplasias cutáneas. En este artículo presentamos una revisión del papel de diversas dietas populares en el manejo de dermatosis. (AU)

Numerous diets for losing weight, building strength, and managing a range of cardiovascular, neurologic, and skin diseases have become popular in recent years. The ketogenic diet and intermittent fasting in particular have shown promising results in clinical and sports medicine. The Mediterranean diet, in turn, is widely recognized for its numerous health benefits. Also popular are the paleo diet and vegan and gluten-free diets. Positive effects on inflammatory conditions, such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and acne, have been observed in patients who practice intermittent fasting or follow ketogenic or Mediterranean diets. This last choice may also protect against certain skin cancers. We review the role of several popular diets in the management of skin disorders. (AU)

[Translated article] Popular Diets and Skin Effects: A Narrative Review / Dietas populares y su impacto en la piel. Una revisión narrativa

Numerous diets for losing weight, building strength, and managing a range of cardiovascular, neurologic, and skin diseases have become popular in recent years. The ketogenic diet and intermittent fasting in particular have shown promising results in clinical and sports medicine. The Mediterranean diet, in turn, is widely recognized for its numerous health benefits. Also popular are the paleo diet and vegan and gluten-free diets. Positive effects on inflammatory conditions, such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and acne, have been observed in patients who practice intermittent fasting or follow ketogenic or Mediterranean diets. This last choice may also protect against certain skin cancers. We review the role of several popular diets in the management of skin disorders. (AU)

Se han popularizado diversas dietas para perder peso, incrementar la capacidad física y para el manejo de múltiples enfermedades crónicas: cardiovasculares, neurológicas o cutáneas. Destacan la dieta cetogénica y el ayuno intermitente, con resultados prometedores en la medicina tradicional y deportiva. Además, la dieta mediterránea se ha consolidado como una forma de alimentación de impacto positivo muy significativo en la salud. Otras dietas populares son la dieta «paleo», la dieta vegana y la libre de gluten. La dieta cetogénica, el ayuno intermitente y la dieta mediterránea aportan resultados favorables en dermatosis inflamatorias como la psoriasis, dermatitis atópica, hidradenitis supurativa o acné. La dieta mediterránea podría actuar también como factor protector para el desarrollo de algunas neoplasias cutáneas. En este artículo presentamos una revisión del papel de diversas dietas populares en el manejo de dermatosis. (AU)

Decimocuarta lección Jesús Culebras. Dieta cetogénica, un tratamiento a medio descubrir / Fourteenth Jesús Culebras Lecture. Ketogenic diet, a half-discovered treatment

La dieta cetogénica constituyó desde su inicio un planteamiento sorprendente para el tratamiento de la epilepsia. Someter al organismo a un cambio en la obtención de energía, pasando de depender de los carbohidratos a hacerlo de las grasas, pone en marcha toda una serie de rutas bioquímicas que, de forma independiente pero también complementaria, dan lugar a un conjunto de efectos que benefician al paciente. Esta búsqueda de su mecanismo de acción, de idear cómo mejorar el cumplimiento y de aprovecharla para otras enfermedades ha marcado su trayectoria. En este artículo se revisan someramente estos aspectos, haciendo hincapié en la importancia de seguir realizando investigación básica y clínica para que este tratamiento pueda aplicarse con bases científicas sólidas.(AU)

The ketogenic diet was an amazing approach to treating epilepsy from its beginning. The body undergoes a change in obtaining energy, going from depending on carbohydrates to depending on fats, and then a whole series of biochemical routes are launched that, independently but also complementary, give rise to a set of effects that benefit the patient. This search for its mechanism of action, of devising how to improve compliance and take advantage of it for other diseases has marked its trajectory. This article briefl y reviews these aspects, emphasizing the importance of continuing to carry out basic and clinical research so that this treatment can be applied with solid scientific bases.(AU)

Impact of Ketogenic and Low-Glycemic Diets on Inflammatory Skin Conditions.

Diet plays an emerging role in dermatologic therapy. The ketogenic and low-glycemic diets have potential anti-inflammatory and metabolic effects, making them attractive for treating inflammatory skin conditions. We provide an overview of the current evidence on the effects of ketogenic and low-glycemic diets on inflammatory skin conditions including acne, psoriasis, seborrheic dermatitis (SD), atopic dermatitis (AD), and hidradenitis suppurativa (HS). We conclude that low-glycemic diets show promise for treating acne, while the evidence for ketogenic diets in treating other inflammatory skin conditions is limited. Randomized clinical trials are needed to explore the efficacy of these diets as stand-alone or adjunctive treatments for inflammatory skin conditions.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD). OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

Very low-calorie ketogenic diet (VLCKD): a therapeutic nutritional tool for acne?

BACKGROUND: Acne, a chronic inflammatory disease impacting the pilosebaceous unit, is influenced significantly by inflammation and oxidative stress, and is commonly associated with obesity. Similarly, obesity is also associated with increased inflammation and oxidation. The role of diet in acne remains inconclusive, but the very low-calorie ketogenic diet (VLCKD), known for weight loss and generating anti-inflammatory ketone bodies, presents promising potential. Despite this, the effects of VLCKD on acne remain underexplored. This study aimed to investigate the efficacy of a 45-day active phase of VLCKD in reducing the clinical severity of acne in young women with treatment-naïve moderate acne and grade I obesity. METHODS: Thirty-one women with treatment-naïve moderate acne, grade I obesity (BMI 30.03-34.65 kg/m2), aged 18-30 years, meeting inclusion/exclusion criteria, and consenting to adhere to VLCKD were recruited. Baseline and post-intervention assessments included anthropometric measurements, body composition, phase angle (PhA), trimethylamine N-oxide (TMAO) levels, and reactive oxygen metabolite derivatives (dROMs) as markers of inflammation, dysbiosis, and oxidative stress, respectively. A comprehensive dermatological examination, incorporating the Global Acne Grading System (GAGS) and the Dermatology Life Quality Index (DLQI), was conducted for all women. RESULTS: VLCKD resulted in general improvements in anthropometric and body composition parameters. Significantly, there were significant reductions in both the GAGS score (Δ%: - 31.46 ± 9.53, p < 0.001) and the DLQI score (Δ%: - 45.44 ± 24.02, p < 0.001) after the intervention. These improvements coincided with significant decreases in TMAO (p < 0.001) and dROMs (p < 0.001) levels and a significant increase in PhA (Δ%: + 8.60 ± 7.40, p < 0.001). Changes in the GAGS score positively correlated with changes in dROMs (p < 0.001) and negatively with PhA (p < 0.001) even after adjusting for Δ% FM. Changes in the DLQI score positively correlated with changes in dROMs (p < 0.001) and negatively with PhA (p < 0.001) even after adjustment for Δ% FM. CONCLUSION: Given the side effects of drugs used for acne, there is an increasing need for safe, tolerable, and low-cost treatments that can be used for acne disease. The 45-day active phase of VLCKD demonstrated notable improvements in acne severity, and these improvements seemed to be attributable to the known antioxidant and anti-inflammatory effects of VLCKD.

Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis.

BACKGROUND: The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor ß-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis. METHODS: Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes. RESULTS: KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism. CONCLUSION: KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis.

High Fat Diet and Polycystic Ovary Syndrome (PCOS) in Adolescence: An Overview of Nutritional Strategies.

Polycystic ovary syndrome (PCOS) is a multifaceted and heterogeneous disorder, linked with notable reproductive, metabolic, and psychological outcomes. During adolescence, key components of PCOS treatment involve weight loss achieved through lifestyle and dietary interventions, subsequently pursued by pharmacological or surgical therapies. Nutritional interventions represent the first-line therapeutic approach in adolescents affected by PCOS, but different kinds of dietary protocols exist, so it is necessary to clarify the effectiveness and benefits of the most well-known nutritional approaches. We provided a comprehensive review of the current literature concerning PCOS definition, pathophysiology, and treatment options, highlighting nutritional strategies, particularly those related to high-fat diets. The high-fat nutritional protocols proposed in the literature, such as the ketogenic diet (KD), appear to provide benefits to patients with PCOS in terms of weight loss and control of metabolic parameters. Among the different types of KD studies, very low-calorie ketogenic diets (VLCKD), can be considered an effective dietary intervention for the short-term treatment of patients with PCOS. It rapidly leads to weight loss alongside improvements in body composition and metabolic profile. Even though extremely advantageous, long-term adherence to the KD is a limiting factor. Indeed, this dietary regimen could become unsustainable due to the important restrictions required for ketosis development. Thus, a combination of high-fat diets with more nutrient-rich nutritional regimens, such as the Mediterranean diet, can amplify positive effects for individuals with PCOS.

The impact of continuous and intermittent ketogenic diets on cognitive behavior, motor function, and blood lipids in TgF344-AD rats.

Studies suggest that ketogenic diets (KD) may improve memory in mouse models of aging and Alzheimer's disease (AD). This study determined whether a continuous or intermittent KD (IKD) enhanced cognitive behavior in the TgF344-AD rat model of AD. At 6 months-old, TgF344-AD and wild-type (WT) littermates were placed on a control (CD), KD, or IKD (morning CD and afternoon KD) provided as two meals per day for 2 or 6 months. Cognitive and motor behavior and circulating ß-hydroxybutyrate (BHB), AD biomarkers and blood lipids were assessed. Animals on a KD diet had elevated circulating BHB, with IKD levels intermediate to CD and KD. TgF344-AD rats displayed impaired spatial learning memory in the Barnes maze at 8 and 12 months of age and impaired motor coordination at 12 months of age. Neither KD nor IKD improved performance compared to CD. At 12 months of age, TgF344-AD animals had elevated blood lipids. IKD reduced lipids to WT levels with KD further reducing cholesterol below WT levels. This study shows that at 8 or 12 months of age, KD or IKD intervention did not improve measures of cognitive or motor behavior in TgF344-AD rats; however, both IKD and KD positively impacted circulating lipids.

A maternal ketogenic diet alters oviduct fluid nutrients and embryo histone acetylation in mice.

In brief: A ketogenic diet (KD) elevates blood ß-hydroxybutyrate to concentrations that are known to perturb the development, metabolism, histone acetylation and viability of preimplantation mouse embryos in culture. This study shows that a maternal KD changes available nutrient levels in the oviduct, leading to altered embryo development and epigenetic state in vivo. Abstract: A ketogenic diet elevates blood ß-hydroxybutyrate to concentrations that perturb the development, metabolism, histone acetylation (H3K27ac) and viability of preimplantation mouse embryos in vitro. However, whether a ketogenic diet alters ß-hydroxybutyrate concentrations within female reproductive fluid is unknown. This study aimed to quantify glucose and ß-hydroxybutyrate within mouse blood and oviduct fluid following standard diet and ketogenic diet consumption and to assess whether a maternal periconceptional ketogenic diet impacts in vivo embryo development and blastocyst H3K27ac. Female C57BL/6 × CBA mice were fed a standard or ketogenic diet (n = 24 each) for 24-27 days. Glucose and ß-hydroxybutyrate were quantified in blood via an electronic monitoring system and in oviduct fluid via ultramicrofluorescence. The developmental grade of flushed blastocysts was recorded, and blastocyst cell number and H3K27ac were assessed via immunofluorescence. A maternal ketogenic diet elevated ß-hydroxybutyrate in day 24 blood (P < 0.001) and oviduct fluid (P < 0.05) compared with a standard diet, whereas glucose was unchanged. A periconceptional ketogenic diet did not impact blastocyst cell number; however, it significantly delayed blastocyst development (P < 0.05) and reduced trophectoderm-specific H3K27ac (P < 0.05) compared with standard diet-derived embryos. Maternal ketogenic diet consumption is, therefore, associated with reproductive tract nutrient changes and altered embryonic development and epigenetics in vivo. Future studies to assess whether periconceptional/gestational ketogenic diet consumption impacts human preimplantation, fetal, and long-term offspring development and health are warranted.

Protein acylations induced by a ketogenic diet demonstrate diverse patterns depending on organs and differ between histones and global proteins.

An essential ketone body, ß-hydroxybutyrate (BOHB), plays various roles in physiological regulations via protein acylations such as lysine acetylation and ß-hydroxybutyrylation. Here, to understand how BOHB systemically regulates acylations from an overarching perspective, we administered a ketogenic diet to mice to increase BOHB concentration and examined acylations. We found that global acetylation and ß-hydroxybutyrylation dramatically increase in various organs except for the brains, where the increase was much smaller than in the other organs. Interestingly, we observe no increase in histone acetylation in the organs where significant global protein acetylation occurs despite a substantial rise in histone ß-hydroxybutyrylation. Finally, we compared the transcriptome data of the mice's liver after the ketogenic diet to the public databases, showing that upregulated genes are enriched in those related to histone ß-hydroxybutyrylation in starvation. Our data indicate that a ketogenic diet induces diverse patterns of acylations depending on organs and protein localizations, suggesting that different mechanisms regulate acylations and that the ketogenic diet is associated with starvation in terms of protein modifications.