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The Ketogenic Diet Increases Mitochondrial Uncoupling Protein Levels and Activity

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Abstract

Fatty acids are known to enhance mitochondrial uncoupling protein (UCP) activity. We asked whether a high-fat ketogenic diet (KD) increases UCP levels and activity in hippocampi of juvenile mice. Maximum mitochondrial respiration rates were significantly (p < 0.001) higher in KD- versus standard diet (SD)-treated animals, indicating increased UCP-mediated proton conductance that can reduce reactive oxygen species (ROS) production. Western blots showed significant (p < 0.05) or borderline significant increases in UCP2, UCP4, and UCP5 protein levels, and increased immunoreactivity to these three UCP isoforms was most prominently seen in the dentate gyrus of KD-fed mice. Finally, we found that oligomycin-induced ROS production was significantly (p < 0.05) lower in KD-fed mice than in SD controls. Collectively, our data suggest that a KD may exert neuroprotective effects by diminishing ROS production through activation of mitochondrial UCPs.

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... Signalling pathways (reported in 36 studies across eight disease models 48,54,56,60,61,63,65,66,69,71,82,84,112,119,121,123,125,126,131,135,[137][138][139]143,148,149,161,164,168,169,187,196,[198][199][200][201] 42,44,67,95,97,128,178 ). Improved clearance and levels of protein transporters for neurotransmitters was reported to improve synaptic transmission. ...
... Altered hippocampal mRNA expression of genes related to lipid and energy metabolism [77] Increase in brain PGC1β mRNA (bioenergetic function) and decreased TNF-α mRNA (inflammation) [125] Redox balance Reduced hippocampal oxidative stress markers that correlated with reduced PARP-1 requirement [31]. Acute production of H2O2 and 4-HNE activating Nrf2 and improving mitochondrial redox state [90] and lowered Oligomycin-induced ROS production [137]. ...
... No evidence of negative morphologic or histochemical alterations in the brain [116] Variable neuroanatomical differences with prenatal exposure to ketogenic diet with altered neurobehavior in adulthood [138]. Mitochondrial (Decreased mitochondrial DNA levels) without a reduction in mass [125] and increased maximum mitochondrial respiration rates in the hippocampus [137]. Neuroplasticity ...
Article
Objectives Ketogenic diets have reported efficacy for neurological dysfunctions however there are limited published human clinical trials elucidating the mechanisms by which nutritional ketosis produces therapeutic effects. The purpose of this present study was to investigate animal models that report variations in nervous system function by changing from a standard animal diet to a ketogenic diet, synthesise these into broad themes, and compare these with mechanisms reported as targets in pain neuroscience to inform human chronic pain trials. Methods An electronic search of seven databases was conducted in July 2020. Two independent reviewers screened studies for eligibility, and descriptive outcomes relating to nervous system function were extracted for a thematic analysis then synthesised into broad themes. Results One hundred and seventy studies from 18 different disease models were identified and grouped into 14 broad themes including: alterations in cellular energetics and metabolism, biochemical, cortical excitability, epigenetic regulation, mitochondrial function, neuroinflammation, neuroplasticity, neuroprotection, neurotransmitter function, nociception, redox balance, signalling pathways, synaptic transmission and vascular supply. Discussion The mechanisms presented centred around the reduction of inflammation and oxidative stress as well as a reduction in nervous system excitability. Given the multiple potential mechanisms presented, it is likely that many of these are involved synergistically and undergo adaptive processes within the human body, and controlled animal models that limit the investigation to a particular pathway in isolation may reach differing conclusions. Attention is required when translating this information to human chronic pain populations due to the limitation outlined from the animal research.
... Although the molecular mechanisms of action of the ketogenic diet are unclear, growing research suggests that KD can be an important element in adjunctive therapy in the treatment of central nervous system (CNS) diseases. More recently, it has been shown that KD can affect the course of diseases by modulating inflammation [5][6][7][8][9][10], controlling the balance between pro-and antioxidant processes [11][12][13][14] and/or altering the composition of the gut microbiome [15]. ...
... It appears to play a pivotal role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease [79,80]. Many in vitro and animal studies confirm the beneficial effects of a ketogenic diet and ketone bodies, by enhancing free radical scavenging and improving activity of antioxidant systems [11][12][13][14]. ...
... Reduced cell death was also observed. Sullivan et al. [13] observed that oligomycin (ATP-synthase inhibitor) induced ROS production was lower in KD-fed mice compared to mice fed a standard diet. At the same time, uncoupling protein 2, 4 and 5 (UCP 2, UCP4 and UCP5) levels were higher in KD-fed mice, resulting in increased maximum mitochondrial respiration rates. ...
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The ketogenic diet (KD) is a high-fat, low-carbohydrate and adequate-protein diet that has gained popularity in recent years in the context of neurological diseases (NDs). The complexity of the pathogenesis of these diseases means that effective forms of treatment are still lacking. Conventional therapy is often associated with increasing tolerance and/or drug resistance. Consequently, more effective therapeutic strategies are being sought to increase the effectiveness of available forms of therapy and improve the quality of life of patients. For the moment, it seems that KD can provide therapeutic benefits in patients with neurological problems by effectively controlling the balance between pro- and antioxidant processes and pro-excitatory and inhibitory neurotransmitters, and modulating inflammation or changing the composition of the gut microbiome. In this review we evaluated the potential therapeutic efficacy of KD in epilepsy, depression, migraine, Alzheimer’s disease and Parkinson’s disease. In our opinion, KD should be considered as an adjuvant therapeutic option for some neurological diseases.
... Its expression is associated with a decrease in ROS through the expression of peroxisome proliferatoractivated receptor (PPAR) and forkhead box (FOX). Sullivan et al., 2004. and electrographic seizures in vivo. Besides, Bad ablation reduces the hippocampal-entorhinal circuit activity in picrotoxin-induced epileptiform neurons, partial inhibitors of GABA A -receptors (GABA A -Rs), conferring a protective effect against seizures dependent on the K ATP channels activity. ...
... The KD is also thought to decrease ROS production through the expression of uncoupling proteins (UCPs) due to fatty acid metabolism by peroxisome proliferator-activated receptor (PPAR) and forkhead box (FOX) enhancement (Azzu and Brand, 2010). Moreover, experimental models have shown increased levels of UCP2, UCP4, and UCP5 in the hippocampus associated with higher seizure-induced resistance (Sullivan et al., 2003(Sullivan et al., , 2004. ...
... It has been shown how fenofibrate, a PPARα ligand, in adult rats can have an anticonvulsant effect (Porta et al., 2009). PUFAs also induce the expression of uncoupling proteins (UCPs) in the mitochondria by decreasing ROS production (Sullivan et al., 2004;Bough and Rho, 2007). A variant of the KD is the medium-chain triglyceride diet, which aims to increase medium straight-chain fatty acids. ...
Article
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.
... 76 Ketones control the acetylation of proteins and increase histone deacetylation of the SIRT1 gene in neurons 77 (Figure 3A 78 ). The activation of the SIRT1 gene caused by ketone bodies in the brain leads to the activation of uncoupling protein (UCP)2, UCP4, and UCP5 expression in the hippocampus 79,80 (Figure 3A 78 ). Ultimately, the induced expression of UCPs by ketone bodies is linked to the activation of SIRT1 in the brain. ...
... 132 Given that improvement of brain insulin resistance enhances memory function in the diabetic brain, 133 the modulation of ketone bodies may a good option for the treatment of diabetes-induced dementia by increasing brain insulin sensitivity. In addition, results of some studies suggested a KD reduces the generation of ROS 79,134 against oxidative stress and attenuates DNA methylation 135 involving antioxidant responses. Ketone bodies cross the blood-brain barrier by binding monocarboxylic acid transporters and enter neurons to reduce oxidative stress. ...
... UCPs regulate the production of ROS and mitochondrial membrane potential in mitochondria, and some isoforms have a neuroprotective effect in CNS diseases. 181,182 The KD could increase the level of UCPs and ultimately attenuate secretion of ROS in hippocampal neurons 79 (Figure 3A 78 ). ...
Article
Patients with type 2 diabetes can have several neuropathologies, such as memory deficits. Recent studies have focused on the association between metabolic imbalance and neuropathological problems, and the associated molecular pathology. Diabetes triggers neuroinflammation, impaired synaptic plasticity, mitochondrial dysfunction, and insulin resistance in the brain. Glucose is a main energy substrate for neurons, but under certain conditions, such as fasting and starvation, ketone bodies can be used as an energy fuel for these cells. Recent evidence has shed new light on the role of ketone bodies in regulating several anti-inflammation cellular pathways and improving glucose metabolism, insulin action, and synaptic plasticity, thereby being neuroprotective. However, very high amount of ketone bodies can be toxic for the brain, such as in ketoacidosis, a dangerous complication that may occur in type 1 diabetes mellitus or alcoholism. Recent findings regarding the relationship between ketone bodies and neuropathogenesis in dementia are reviewed in this article. They suggest that the adequately low amount of ketone bodies can be a potential energy source for the treatment of diabetes-induced dementia neuropathology, considering the multifaceted effects of the ketone bodies in the central nervous system. This review can provide useful information for establishing the therapeutic guidelines of a ketogenic diet for diabetes-induced dementia.
... Experimental studies in rodents have demonstrated that animals fed both a ketogenic diet or a ketone ester upregulate UCP4 and 5 in the brain [82,83]. Neuronal UCPs are important for the regulation of ROS production by reducing the mitochondrial membrane potential, thus normally leading to lower ATP generation [84]. ...
... Mitochondrial efficiency can be enhanced by ketone bodies, probably through the expression of uncoupling proteins (UCP) [79]. Experimental studies in rodents have demonstrated that animals fed both a ketogenic diet or a ketone ester upregulate UCP4 and 5 in the brain [82,83]. Neuronal UCPs are important for the regulation of ROS production by reducing the mitochondrial membrane potential, thus normally leading to lower ATP generation [84]. ...
Article
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Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.
... It is hypothesized that a ketogenic diet may reduce inflammation [59]. Compared with glucose metabolism, the metabolism of ketone bodies produces fewer ROS, which contribute to inflammation. ...
... Compared with glucose metabolism, the metabolism of ketone bodies produces fewer ROS, which contribute to inflammation. Ketolytic metabolism produces fewer free radicals and ROS, affecting the mitochondrial Q coenzyme pair and the cytoplasmic glutathione couple [59,60]. ...
Article
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Anxiety disorders comprise persistent, disabling conditions that are distributed across the globe, and are associated with the high medical and socioeconomic burden of the disease. Within the array of biopsychosocial treatment modalities—including monoaminergic antidepressants, benzodiazepines, and CBT—there is an unmet need for the effective treatment of anxiety disorders resulting in full remission and recovery. Nutritional intervention may be hypothesized as a promising treatment strategy; in particular, it facilitates relapse prevention. Low-carbohydrate high-fat diets (LCHF) may provide a rewarding outcome for some anxiety disorders; more research is needed before this regimen can be recommended to patients on a daily basis, but the evidence mentioned in this paper should encourage researchers and clinicians to consider LCHF as a piece of advice somewhere between psychotherapy and pharmacology, or as an add-on to those two.
... Mitochondrial respiration was assessed using a Clark-type oxygen electrode (Hansatech Instruments), in a sealed, thermostatically controlled (37°C), and continuously stirred chamber as described previously (Sullivan et al., 2003;Sullivan et al., 2004). Mitochondria were added to the chamber to yield a final protein concentration of 50 µg in 250 µl. ...
... State III respiration was initiated by the addition of 120 nmol ADP followed by the addition of oligomycin (1 µM) to induce state IV respiration. UCP-mediated proton conductance was measured as increased free fatty acid (60 µM linoleic acid) induced respiration (Sullivan et al., 2003;Sullivan et al., 2004), followed by recoupling of the mitochondria by sequestration of FFA with the addition of BSA to a final concentration of 3%. Finally, mitochondria were treated with FCCP (1 µM) to allow for quantification of complex I driven, maximal electron transport. ...
Article
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Mechanisms that enhance energy expenditure are attractive therapeutic targets for obesity. Previously we have demonstrated that mice lacking cd47 are leaner, exhibit increased energy expenditure, and are protected against diet-induced obesity. In this study, we further defined the physiological role of cd47 deficiency in regulating mitochondrial function and energy expenditure in both white and brown adipose tissue. We observed that cd47 deficient mice (under normal chow diet) had comparable amount of white fat mass but reduced white adipocyte size as compared to wild-type mice. Subsequent ex vivo and in vitro studies suggest enhanced lipolysis, and not impaired lipogenesis or energy utilization, contributes to this phenotype. In contrast to white adipose tissue, there were no obvious morphological differences in brown adipose tissue between wild-type and knockout mice. However, mitochondria isolated from brown fat of cd47 deficient mice had significantly higher rates of free fatty acid-mediated uncoupling. This suggests that enhanced fuel availability via white adipose tissue lipolysis may perpetuate elevated brown adipose tissue energy expenditure and contributes to the lean phenotype observed in cd47 deficient mice.
... KDs reduce seizure frequency in persons with epilepsy (Kossoff et al. 2009), which suggests manipulating brain energy metabolism in some settings confers neurologic benefits. Different mechanisms may contribute as this intervention can support bioenergetics, enhance ROS scavenging, modulate neurotransmitters, induce post-translational protein modifications, increase neurotrophin signaling, and activate signaling receptors (Erecinska et al. 1996;Kimura et al. 2011;Marosi et al. 2016;Rahman et al. 2014;Rardin et al. 2013;Shimazu et al. 2013;Sullivan et al. 2004;Xie et al. 2016). ...
Article
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Ketogenic diets (KDs) alter brain metabolism. Multiple mechanisms may account for their effects, and different brain regions may variably respond. Here, we considered how a KD affects brain neuron and astrocyte transcription. We placed male C57Bl6/N mice on either a 3-month KD or chow diet, generated enriched neuron and astrocyte fractions, and used RNA-Seq to assess transcription. Neurons from KD-treated mice generally showed transcriptional pathway activation while their astrocytes showed a mix of transcriptional pathway suppression and activation. The KD especially affected pathways implicated in mitochondrial and endoplasmic reticulum function, insulin signaling, and inflammation. An unbiased analysis of KD-associated expression changes strongly implicated transcriptional pathways altered in AD, which prompted us to explore in more detail the potential molecular relevance of a KD to AD. Our results indicate a KD differently affects neurons and astrocytes, and provide unbiased evidence that KD-induced brain effects are potentially relevant to neurodegenerative diseases such as AD.
... Animal studies have investigated the neuroprotective effects of KD. Mice fed for 10-12 days on KD showed an increase in mitochondrial uncoupling protein activity and a decrease in ROS (Sullivan et al., 2004). Two types of ketones-β-hydroxybutyrate and acetoacetate-were found to reduce ROS levels in isolated neocortical mitochondria . ...
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Background: Bipolar disorder is a neurodevelopmental illness characterized by severe biphasic changes in mood, energy, or thought. Key underlying metabolic pathologies thought to play a role include dysfunction in energy metabolism. The purpose of this article is to review the findings to date of the effects of a low carbohydrate ketogenic diet (KD) on mood symptoms in preclinical and clinical models of bipolar illness. The review highlights the underlying metabolic pathologies of bipolar disorder (BD) and potential therapeutic effects of the KD on these pathologies. The article also explores the potential effects of a KD on metabolic health in BD, including proposed mechanisms of action. Summary: Recent findings support the idea that bipolar disorder, along with other psychiatric disease, may have roots of metabolic dysfunction: cerebral glucose hypometabolism, oxidative stress, as well as mitochondrial and neurotransmitter dysfunction which has downstream effects on synapse connections. A KD provides alternative fuel to the brain aside from glucose and is believed to contain beneficial neuroprotective effects, including stabilization of brain networks, reduction of inflammation and oxidative stress. Several beneficial metabolic effects on insulin resistance, weight, and lipids have been shown. Based on its effectiveness in treating epilepsy, the KD has garnered recent interest in its application for mood disorders as it may imitate the pharmacological effects of mood stabilizers, commonly prescribed agents in the treatment of both BD and epilepsy. Additionally, it may improve metabolic dysfunction often seen in BD and repair deficits in energy metabolism. Limited case studies on KD treatment in BD have been reported; however, studies addressing the potential therapeutic effects of KD on metabolic abnormalities in mental illness are promising. Literature of plausible mechanisms and reports of improvements in psychosis, cognition and mood symptoms have been increasing. Conclusions: Preliminary findings support further testing of a low carbohydrate KD as a potential therapeutic tool in repairing energy metabolism in bipolar illness. Further research and clinical trials are needed to evaluate the efficacy of a KD as a supplemental or co-treatment of bipolar illness and the first open-label trial testing the diet in bipolar illness is currently underway at Stanford.
... The majority of AcAc and BHB are produced in the liver mitochondria, transport across the BBB, and enter mitochondria of the brain CNS where they undergo ketolysis for ATP production in the TCA cycle and electron transport chain (Taylor et al., 2019b). In the brain, evidence suggests that ketone bodies uncouple mitochondrial respiration (Sullivan et al., 2004;Liu et al., 2006;Kashiwaya et al., 2010), enhance multiple complexes of the mitochondrial respiratory chain (Ho et al., 2006;Chu et al., 2009;Wei et al., 2009;Kwok et al., 2010;Ramsden et al., 2012), and increase ATP production . The KD has also been shown to modify expression of genes associated with neurodegenerative disease, including counteracting impairments in oxidative phosphorylation (Koppel et al., 2021) and improving expression of metabolism-related genes in the hippocampus (Ling et al., 2019), a region susceptible to Aβ accumulation in AD pathology (Oh et al., 2016). ...
Article
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Alzheimer’s disease (AD) is a progressive neurodegenerative condition characterized by clinical decline in memory and other cognitive functions. A classic AD neuropathological hallmark includes the accumulation of amyloid-β (Aβ) plaques, which may precede onset of clinical symptoms by over a decade. Efforts to prevent or treat AD frequently emphasize decreasing Aβ through various mechanisms, but such approaches have yet to establish compelling interventions. It is still not understood exactly why Aβ accumulates in AD, but it is hypothesized that Aβ and other downstream pathological events are a result of impaired bioenergetics, which can also manifest prior to cognitive decline. Evidence suggests that individuals with AD and at high risk for AD have functional brain ketone metabolism and ketotherapies (KTs), dietary approaches that produce ketone bodies for energy metabolism, may affect AD pathology by targeting impaired brain bioenergetics. Cognitively normal individuals with elevated brain Aβ, deemed “preclinical AD,” and older adults with peripheral metabolic impairments are ideal candidates to test whether KTs modulate AD biology as they have impaired mitochondrial function, perturbed brain glucose metabolism, and elevated risk for rapid Aβ accumulation and symptomatic AD. Here, we discuss the link between brain bioenergetics and Aβ, as well as the potential for KTs to influence AD risk and progression.
... Moderate ketosis has been reported to result in multiple beneficial effects to brain function. A ketogenic diet is neuroprotective through reduction of ROS levels, by increasing mitochondrial uncoupling protein levels and activity [436], as well as by increasing oxidation of NADH and enhancing mitochondrial respiration [437]. This diet results in increased SIRT1 levels in mice hippocampal neurons [438]. ...
Article
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Sirtuins are a family of highly conserved NAD+-dependent proteins and this dependency links Sirtuins directly to metabolism. Sirtuins’ activity has been shown to extend the lifespan of several organisms and mainly through the post-translational modification of their many target proteins, with deacetylation being the most common modification. The seven mammalian Sirtuins, SIRT1 through SIRT7, have been implicated in regulating physiological responses to metabolism and stress by acting as nutrient sensors, linking environmental and nutrient signals to mammalian metabolic homeostasis. Furthermore, mammalian Sirtuins have been implicated in playing major roles in mammalian pathophysiological conditions such as inflammation, obesity and cancer. Mammalian Sirtuins are expressed heterogeneously among different organs and tissues, and the same holds true for their substrates. Thus, the function of mammalian Sirtuins together with their substrates is expected to vary among tissues. Any therapy depending on Sirtuins could therefore have different local as well as systemic effects. Here, an introduction to processes relevant for the actions of Sirtuins, such as metabolism and cell cycle, will be followed by reasoning on the system-level function of Sirtuins and their substrates in different mammalian tissues. Their involvement in the healthy metabolism and metabolic disorders will be reviewed and critically discussed.
... This is being pursued on the assumption that ketone bodies themselves, rather than the lower levels of blood glucose and insulin associated with low CHO, ketogenic diets, play a critical role in the reduction in tumors seen with ketogenic diets (28,87). Of the three ketone bodies, β-HB, has been reported to be uniquely anti-inflammatory (88), in part because it suppresses IL-1β expression in bone marrow derived macrophages (89), and promotes uncoupling protein 2 expression in mitochondria (90). The latter observation might account for its reported ability to lower oxidative stress (91). ...
Article
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Ketogenic diets are low carbohydrate (CHO), high fat diets that are currently very popular for weight loss. Since cancer cells typically consume far more glucose than normal cells, low CHO diets are currently being considered as possible therapeutic regimens to manage cancer. However, our understanding of the safety and efficacy of such CHO-restricted diets in the prevention and treatment of cancer is still in its infancy. In this perspective we provide an overview of the current state of knowledge regarding the use of low CHO diets in the prevention and treatment of cancer. We also highlight the gaps in our knowledge regarding the potential usefulness of low CHO diets in cancer. While pre-clinical rodent studies have provided convincing evidence that CHO restriction may be effective in reducing cancer growth, there has not been sufficient attention given to the effect of these low CHO diets, that are often high in fats and low in soluble fiber, on inflammation. This is important, given that different fats have distinct effects on inflammation. As well, we demonstrate that short chain fatty acids, which are produced via the fermentation of fiber by our gut microbiome, have more anti-inflammatory properties than β-hydroxybutyrate, a ketone body produced during nutritional ketosis that is touted to have anti-inflammatory activity. Since chronic inflammation is strongly associated with cancer formation, defining the type of fats in low CHO diets may contribute to our understanding of whether these diets may work simply by reducing glucose bioavailability, or via modulation of inflammatory responses.
... Sullivan et al. (Sullivan et al. 2004) found that rats fed KD for 10-12 days showed increased hippocampal uncoupling proteins, suggesting a decreased ROS produced by mitochondria. In addition, mitochondrial biogenesis increased in rats maintained on KD for 4-6 weeks (Bough and Rho 2007; Bough et al. 2006). ...
Preprint
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This work aims to investigate the possible inhibitory action of β-hydroxybutyrate (βOHB) against hematological alterations and hepatic injury associated with oxidative stress caused by D-galactose or γ-irradiation in rats. Six groups of male rats were used as the control, irradiated group (5 Gy), D-galactose (150 mg/kg b.wt), β-hydroxybutyrate (72.8 mg/kg b.wt), γ-irradiation plus βOHB, and D-galactose plus βOHB. Complete blood count and glucose-6-phosphate-dehydrogenase (G6PD) activity were determined in whole-blood samples. In addition, the hepatic malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels and the superoxide dismutase (SOD) activity were evaluated. Moreover, certain elements were measured in liver tissue (iron (Fe), copper (Cu), and zinc (Zn)). The G6PD activity significantly diminished post exposure to D-galactose or γ-irradiation. In the βOHB, D-galactose, or γ-irradiation groups, liver MDA levels and SOD activity were significantly increased. Meanwhile, NO and GSH levels were significantly increased relative to normal control levels in the γ-irradiation group. The findings showed that βOHB alleviated hematological alterations, enhanced the altered biochemical indices, and modulated the change in Cu, Fe, and Zn elements in D-galactose or γ-irradiation group. These results highlight the role of βOHB as a powerful protective agent against hematological alterations and liver impairment by reducing G6PD-mediated oxidative stress and controlling the measured elements.
... In addition, there is the intracellular modulation of the NADþ/ NADH ratio, which protects against ROS and plays a vital role in redox reactions, mitochondrial biogenesis and cellular respiration (Yang and Sauve 2016). Ketogenic diets also play other significant oxidation regulating mechanisms including the increased efficiency of the expression of uncoupling proteins (Sullivan et al. 2004) that reduces the production of ROS and reactive oxygen nitrogen species through reduction the mitochondrial membrane potential (Harper et al. 2004). ...
Article
Psoriasis is a chronic skin immune-mediated disease with systemic pro-inflammatory activation; both genetic and lifestyles factors contribute to its pathogenesis and severity. In this context, nutrition plays a significant role, per se, in psoriasis' pathogenesis. Obesity is another important risk factor for psoriasis, and weight reduction may improve psoriasis' clinical severity. The excess body weight, particularly visceral fat mass, can affect both drug's pharmacokinetics and pharmacodynamics. Therefore, psoriasis and obesity share a certain degree of synergy, and the chronic inflammatory state represents the basis of this vicious cycle. Evidence reported that nutrition has different impact on the clinical severity of psoriasis, though some specific diets have been more investigated in clinical studies compared to others. Diets with systemic anti-inflammatory properties seem to have a higher effect on improving the clinical severity of psoriasis. Of interest, very-low-calorie ketogenic diet (VLCKD), through the production of ketone bodies, has been associated with both a significant reduction of body weight and inflammatory state. VLCKD leading to both weight loss and reduction of systemic inflammation may decrease the exacerbation of the clinical manifestations or even it may block the trigger of psoriatic disease. This dietary pattern could represent a potential first-line treatment in psoriatic patients with obesity. The review aims to summarize the current evidence regarding VLCKD and psoriasis with specific reference to antioxidant and anti-inflammatory effects of this dietary pattern.
... The KD should reduce inflammation as it enhances various antioxidant mechanisms 14-26 . Indeed, KD treatment reduces reactive oxygen species 17,18,[27][28][29][30][31][32] limits oxidative damage to DNA 17,20,33 , lipids 29,[34][35][36][37] and proteins 16,20,23,35 , and modulates immune cell function 28,38 . Most of these studies did not use a calorie-restricted KD. ...
Article
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Ketogenic diets are very low carbohydrate, high fat, moderate protein diets used to treat medication-resistant epilepsy. Growing evidence suggests that one of the ketogenic diet’s main mechanisms of action is reducing inflammation. Here, we examined the diet’s effects on experimental inflammatory pain in rodent models. Young adult rats and mice were placed on the ketogenic diet or maintained on control diet. After 3–4 weeks on their respective diets, complete Freund’s adjuvant (CFA) was injected in one hindpaw to induce inflammation; the contralateral paw was used as the control. Tactile sensitivity (von Frey) and indicators of spontaneous pain were quantified before and after CFA injection. Ketogenic diet treatment significantly reduced tactile allodynia in both rats and mice, though with a species-specific time course. There was a strong trend to reduced spontaneous pain in rats but not mice. These data suggest that ketogenic diets or other ketogenic treatments might be useful treatments for conditions involving inflammatory pain.
... Endogenous uncoupling is activated by ROS [33], alkylsulfonate [34], adrenaline and noradrenaline [35], leptin [36], thyroid hormone [37], and peroxisome proliferator-activated receptor a (PPAR-a) agonist [38] and inhibited by purine nucleotides such as guanosine diphosphate (UDP), guanosine triphosphate (GTP), and ATP [39]. UCPs and ANTs can also be induced by oxidised lipid products (for example, 4-hydroxy-2-nonenal (HNE)) [40] and upregulated by high-fat diets [41], ketogenic diets [42,43], or fasting [44,45] as a potential mechanism to combat oxidative stress. ...
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Background: Mitochondrial uncouplers are well-known for their ability to treat a myriad of metabolic diseases, including obesity and fatty liver diseases. However, for many years now, mitochondrial uncouplers have also been evaluated in diverse models of cancer in vitro and in vivo. Furthermore, some mitochondrial uncouplers are now in clinical trials for cancer, although none have yet been approved for the treatment of cancer. Scope of review: In this review we summarise published studies in which mitochondrial uncouplers have been investigated as an anti-cancer therapy in preclinical models. In many cases, mitochondrial uncouplers show strong anti-cancer effects both as single agents, and in combination therapies, and some are more toxic to cancer cells than normal cells. Furthermore, the mitochondrial uncoupling mechanism of action in cancer cells has been described in detail, with consistencies and inconsistencies between different structural classes of uncouplers. For example, many mitochondrial uncouplers decrease ATP levels and disrupt key metabolic signalling pathways such as AMPK/mTOR but have different effects on reactive oxygen species (ROS) production. Many of these effects oppose aberrant phenotypes common in cancer cells that ultimately result in cell death. We also highlight several gaps in knowledge that need to be addressed before we have a clear direction and strategy for applying mitochondrial uncouplers as anti-cancer agents. Major conclusions: There is a large body of evidence supporting the therapeutic use of mitochondrial uncouplers to treat cancer. However, the long-term safety of some uncouplers remains in question and it will be critical to identify which patients and cancer types would benefit most from these agents.
... Furthermore, since ketone bodies produce fewer ROS than glucose, they can participate in a decrease in the oxidative stress in AD [59,125]. This decrease in ROS production could be induced by stimulating the expression of uncoupling proteins (UCP), as shown previously [126,127]. Another possible mechanism is that reducing glutamate transport and improving GABA activity decreases the excitability of neurons and thus ROS production (see Section 3.1). In addition, KD was shown to upregulate antioxidant proteins (MnSOD, Glutathione, and Nrf2) [58]. ...
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Although diet interventions are mostly related to metabolic disorders, nowadays they are used in wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, through cancer or neurological disorders and stroke, nutritional recommendations applied to almost all diseases. Among those disorders, metabolic disturbances and brain function and/or diseases have recently been shown to be linked. Indeed, numerous neurological functions are often associated with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in various neurological conditions such as epilepsy, stroke, or seizure recovery. In addition, Alzheimer’s disease or Autism Spectrum Disorders are also considered as putatively improved by diet intervention. Glycemic index diets are a novel developed indicator expected to anticipate the changes in blood glucose induced by specific foods, and how they can affect various physiological function. Several results provide indications of efficiency of low glycemic index diets in weight management, insulin sensitivity, but also cognitive function, epilepsy treatment, stroke, or neurodegenerative diseases. Overall, studies involving glycemic index could provide new insight in the relationship between energy homeostasis regulation and brain function or related disorders. Therefore, in this review we will summarize main evidences on glycemic index involvement in brain mechanisms of energy homeostasis regulation.
... One dietary model that has been proposed to reverse mitochondrial dysfunction, especially the shift from aerobic to glycolytic energy generation in depression, is the ketogenic diet, although clinical trials assessing this hypothesis in humans are still awaited [145]. A ketogenic diet increases both the activity and levels of mitochondrial uncoupling proteins [146]. The extent to which alteration in mitochondrial biogenesis mediates the beneficial effects of a healthy Mediterranean type diet in depression is yet to be determined. ...
Article
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The field of nutritional psychiatry has generated observational and efficacy data supporting a role for healthy dietary patterns in depression onset and symptom management. To guide future clinical trials and targeted dietary therapies, this review provides an overview of what is currently known regarding underlying mechanisms of action by which diet may influence mental and brain health. The mechanisms of action associating diet with health outcomes are complex, multifaceted, interacting, and not restricted to any one biological pathway. Numerous pathways were identified through which diet could plausibly affect mental health. These include modulation of pathways involved in inflammation, oxidative stress, epigenetics, mitochondrial dysfunction, the gut microbiota, tryptophan–kynurenine metabolism, the HPA axis, neurogenesis and BDNF, epigenetics, and obesity. However, the nascent nature of the nutritional psychiatry field to date means that the existing literature identified in this review is largely comprised of preclinical animal studies. To fully identify and elucidate complex mechanisms of action, intervention studies that assess markers related to these pathways within clinically diagnosed human populations are needed.
... The concept of uncoupling to reduce cancer risk seems logical and attractive but human evidence in this sense is lacking. Identified uncoupling agents are: 2,4 dinitrophenol 207 and ketogenic diet 208 . Weak uncouplers are aspirin, valproate, fibrates (clofibrate, ciprofibrate 209 , fenofibrate 210 , 211 ), and chloramphenycol 212 . ...
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Reactive oxygen species (ROS) are considered by many authors as by-products of mitochondrial oxidative metabolism in normal and cancer cells. However, this is not the case when ROS is generated by NADPH oxidase. ROS are not really by-products, but signaling molecules. In any case, they might be both: metabolic by-products in some cases and signaling molecules in others. The main problem of research is the difficulty to distinguish between both situations and their possible different mechanisms of action. The difference between normal and malignant cells is that in cancer there is a significantly higher ROS production. The increased level of ROS produces oxidative stress by oxidizing lipids and proteins that may eventually induce apoptosis. Cancer cells "learn" to live under oxidative stress and even they use this condition for their advantage in proliferation, migration, invasion and metastasis. At the same time, they over-express antioxidant mechanisms, in order to avoid excessive oxidative stress. Uncoupling oxidative phosphorylation is one of the natural mechanisms used by normal and cancer cells to reduce oxidative stress. Increasing pharmacologically oxidative stress is one of the possible treatments against cancer that has been suggested by many authors. Drugs that uncouple oxidative phosphorylation have also been tested against cancer, and active research is going on with metformin, one of the best known oxidative uncouplers. A second ROS source is the enzymatic complex NADPH oxidase. In cancer, this source can surpass mitochondrial ROS in order of importance. While the main objective of the mitochondrial electron transfer chain is energy generation being ROS production a collateral effect, NADPH oxidase has only one central goal: the production of ROS. In the first case, ROS can be viewed as a by-product. In the second case it is a "desired" molecule by the cancer cell. Finally, the activity and medical indications of antioxidants in cancer are discussed. The controversies on these compounds are still unsolved. Our knowledge of ROS metabolism and its consequences on the cancer process has many gaps that need to be filled in order to have a clear and integrated view which is still lacking.
... Furthermore, since ketone bodies produce fewer ROS than glucose, they can participate in a decrease in the oxidative stress in AD [59,125]. This decrease in ROS production could be induced by stimulating the expression of uncoupling proteins (UCP), as shown previously [126,127]. Another possible mechanism is that reducing glutamate transport and improving GABA activity decreases the excitability of neurons and thus ROS production (see Section 3.1). In addition, KD was shown to upregulate antioxidant proteins (MnSOD, Glutathione, and Nrf2) [58]. ...
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Although diet interventions are mostly related to metabolic disorders, nowadays they are used in a wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, to cancer or neurological disorders and stroke, nutritional recommendations are applied to almost all diseases. Among such disorders, metabolic disturbances and brain function and/or diseases have recently been shown to be linked. Indeed, numerous neurological functions are often associated with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in various neurological conditions, such as epilepsy, stroke, or seizure recovery. In addition, Alzheimer's disease and Autism Spectrum Disorders are also considered to be putatively improved by diet interventions. Glycemic index diets are a novel developed indicator expected to anticipate the changes in blood glucose induced by specific foods and how they can affect various physiological functions. Several results have provided indications of the efficiency of low-glycemic index diets in weight management and insulin sensitivity, but also cognitive function, epilepsy treatment, stroke, and neurodegenerative diseases. Overall, studies involving the glycemic index can provide new insights into the relationship between energy homeostasis regulation and brain function or related disorders. Therefore, in this review, we will summarize the main evidence on glycemic index involvement in brain mechanisms of energy homeostasis regulation.
... Ketogenic therapy decreased the formation of reactive oxygen radicals and reversed gene expression patterns of several genes that control ROS and oxidative stress in animal and cellular models (Maalouf et al., 2007;Stafford et al., 2010;Sullivan et al., 2004). Modification of cellular oxidative stress and ROS generation is important, since increased PARP1 activation and mitochondrial oxidative stress levels were shown to play a crucial role in epilepsy-associated neuronal death and contribute to epileptogenesis (Waldbaum and Patel, 2010;Wang et al., 2013). ...
Article
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.
... Animal studies have investigated the neuroprotective effects of KD. Mice fed for 10-12 days on KD showed an increase in mitochondrial uncoupling protein activity and a decrease in ROS (Sullivan et al., 2004). Two types of ketones-β-hydroxybutyrate and acetoacetate-were found to reduce ROS levels in isolated neocortical mitochondria . ...
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Background: Bipolar disorder is a neurodevelopmental illness characterized by severe biphasic changes in mood, energy, or thought. Key underlying metabolic pathologies thought to play a role include dysfunction in energy metabolism. The purpose of this article is to review the findings to date of the effects of a low carbohydrate ketogenic diet (KD) on mood symptoms in preclinical and clinical models of bipolar illness. The review highlights the underlying metabolic pathologies of bipolar disorder (BD) and potential therapeutic effects of the KD on these pathologies. The article also explores the potential effects of a KD on metabolic health in BD, including proposed mechanisms of action. Summary: Recent findings support the idea that bipolar disorder, along with other psychiatric disease, may have roots of metabolic dysfunction: cerebral glucose hypometabolism, oxidative stress, as well as mitochondrial and neurotransmitter dysfunction which has downstream effects on synapse connections. A KD provides alternative fuel to the brain aside from glucose and is believed to contain beneficial neuroprotective effects, including stabilization of brain networks, reduction of inflammation and oxidative stress. Several beneficial metabolic effects on insulin resistance, weight, and lipids have been shown. Based on its effectiveness in treating epilepsy, the KD has garnered recent interest in its application for mood disorders as it may imitate the pharmacological effects of mood stabilizers, commonly prescribed agents in the treatment of both BD and epilepsy. Additionally, it may improve metabolic dysfunction often seen in BD and repair deficits in energy metabolism. Limited case studies on KD treatment in BD have been reported; however, studies addressing the potential therapeutic effects of KD on metabolic abnormalities in mental illness are promising. Literature of plausible mechanisms and reports of improvements in psychosis, cognition and mood symptoms have been increasing. Conclusions: Preliminary findings support further testing of a low carbohydrate KD as a potential therapeutic tool in repairing energy metabolism in bipolar illness. Further research and clinical trials are needed to evaluate the efficacy of a KD as a supplemental or co-treatment of bipolar illness and the first open-label trial testing the diet in bipolar illness is currently underway at Stanford.
... In particular, the ketone body beta-hydroxybutyrate reduces mitochondrial ROS production and inhibits histone deacetylases, upregulating the transcription of some genes that are protective against oxidative stress [282]. Moreover, ketone bodies contribute to the reduction of ROS production through the expression of mitochondrial uncoupling protein (UCP), thereby decreasing mitochondrial membrane potential [283]. ...
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Aging is inevitable and it is one of the major contributors to cognitive decline. However, the mechanisms underlying age-related cognitive decline are still the object of extensive research. At the biological level, it is unknown how the aging brain is subjected to progressive oxidative stress and neuroinflammation which determine, among others, mitochondrial dysfunction. The link between mitochondrial dysfunction and cognitive impairment is becoming ever more clear by the presence of significant neurological disturbances in human mitochondrial diseases. Possibly, the most important lifestyle factor determining mitochondrial functioning is nutrition. Therefore, with the present work, we review the latest findings disclosing a link between nutrition, mitochondrial functioning and cognition, and pave new ways to counteract cognitive decline in late adulthood through diet.
... 5 In animal models, wild-type mice fed with a KD showed increased mitochondrial respiration, a decrease in reactive oxygen species, and induction of mitochondrial uncoupling proteins. 6 Moreover, a KD in a transgenic mouse model for progressive mitochondrial myopathy resulted in decreased cytochrome c oxidase negative muscle fibers, improved mitochondrial ultrastructure, and increased mitochondrial biogenesis. 7 In humans, there are case reports of possible beneficial effects of a KD in patients with MELAS 8 and with epilepsy. ...
Article
KARS encodes lysyl-tRNA synthetase, which is essential for protein translation. KARS mutations sometimes cause impairment of cytoplasmic and mitochondrial protein synthesis, and sometimes lead to progressive leukodystrophies with mitochondrial signature and psychomotor regression, and follow a rapid regressive course to premature death. There has been no disease-modifying therapy beyond supportive treatment. We present a 5-year-old male patient with an asymmetrical leukodystrophy who showed overt evidence of mitochondrial dysfunction, including elevation of lactate on brain MR spectroscopy and low oxygen consumption rate in fibroblasts. We diagnosed this patient's condition as KARS-related leukodystrophy with cerebral calcification, congenital deafness, and evidence of mitochondrial dysfunction. We employed a ketogenic diet as well as multiple vitamin supplementation with the intention to alleviate mitochondrial dysfunction. The patient showed alleviation of his psychomotor regression and even partial restoration of his abilities within 4 months. This is an early report of a potential disease-modifying therapy for KARS-related progressive leukodystrophy without appreciable adverse effects.
... 43 However, in contrary, Sullivan et al. reported that ketosis, induced by KD, significantly decreased ROS production in the hippocampus, presumably by increasing the expression of mitochondrial uncoupling protein activity. 44 Finally, electron microscope pictures of the cells showed us that cells incubated with a normal medium appear healthy and their axons were extended ( Figures 5A and B), while 16 h later, there were noticeable drawbacks in the axons of the cells incubated with reduced glucose medium (CR and PF; Figures 5C and D). In the cells that were incubated under the same conditions plus added ketone (CRK and PFK) media, axon withdrawals were seen to be less ( Figures 5E and F). ...
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Background Calorie restriction (CR) during daily nutrition has been shown to affect the prognosis of many chronic diseases such as metabolic syndrome, diabetes, and aging. As an alternative nutrition model, prolonged intermittent fasting (PF) in humans is defined by the absence of food for more than 12 h. In our previous human studies, CR and PF models were compared and it was concluded that the two models might have differences in signal transduction mechanisms. We have investigated the effects of these models on neurons at the molecular level in this study. Methods Neurons (SH-SY5Y) were incubated with normal medium (N), calorie-restricted medium (CR), fasting medium (PF), and glucose-free medium (G0) for 16 h. Simultaneously, ketone (beta-hydroxybutyrate; bOHB) was added to other experiment flasks containing the same media. Concentrations of lactate, lactate dehydrogenase (LDH), bOHB, and glucose were measured to demonstrate the changes in the energy metabolism together with the mitochondrial functions of cells. Citrate synthase activity and flow cytometric mitochondrial functions were investigated. Results At the end of incubations, lactate and LDH levels were decreased and mitochondrial activity was increased in all ketone-added groups (P < .01) regardless of the glucose concentration in the environment. In the fasting model, these differences were more prominent. Conclusion Our results demonstrated that neurons use ketones regardless of the amount of glucose, and bOHB-treated cells had positive changes in mitochondrial function. We conclude that the presence of bOHB might reverse neuron damage and that exogenous ketone treatment may be beneficial in the treatment of neurological diseases in the future.
... Finally, a similar involvement of ROS level regulation can be found in AD (Prins, 2008;Achanta and Rae, 2017). Several reports suggest that ROS production could be inhibited by an increased expression level of uncoupling proteins (U) as previously shown independently of the diet (Sullivan et al., 2004;Klaus and Ost, 2020). Therefore, the expression level of UCPs needs to be determined in healthy diets fed individuals to evaluate whether it could be another player involved in the beneficial effect of such diets. ...
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Aging in modern societies is often associated with various diseases including metabolic and neurodegenerative disorders. In recent years, researchers have shown that both dysfunctions are related to each other. Although the relationship is not fully understood, recent evidence indicate that metabolic control plays a determinant role in neural defects onset. Indeed, energy balance dysregulation affects neuroenergetics by altering energy supply and thus neuronal activity. Consistently, different diets to help control body weight, blood glucose or insulin sensitivity are also effective in improving neurodegenerative disorders, dampening symptoms, or decreasing the risk of disease onset. Moreover, adapted nutritional recommendations improve learning, memory, and mood in healthy subjects as well. Interestingly, adjusted carbohydrate content of meals is the most efficient for both brain function and metabolic regulation improvement. Notably, documented neurological disorders impacted by specific diets suggest that the processes involved are inflammation, mitochondrial function and redox balance as well as ATP production. Interestingly, processes involving inflammation, mitochondrial function and redox balance as well as ATP production are also described in brain regulation of energy homeostasis. Therefore, it is likely that changes in brain function induced by diets can affect brain control of energy homeostasis and other brain functions such as memory, anxiety, social behavior, or motor skills. Moreover, a defect in energy supply could participate to the development of neurodegenerative disorders. Among the possible processes involved, the role of ketone bodies metabolism, neurogenesis and synaptic plasticity, oxidative stress and inflammation or epigenetic regulations as well as gut-brain axis and SCFA have been proposed in the literature. Therefore, the goal of this review is to provide hints about how nutritional studies could help to better understand the tight relationship between metabolic balance, brain activity and aging. Altogether, diets that help maintaining a metabolic balance could be key to both maintain energy homeostasis and prevent neurological disorders, thus contributing to promote healthy aging.
... Preclinical evidence showed promising results for the neuroprotective properties of KD (Paoli et al., 2014) ( Table 1). For instance, KD in mice improved mitochondrial function, decreased oxidative stress, and increased ATP cerebral concentrations (Sullivan et al., 2004). In several transgenic mouse models of AD, KD was found to improve glycolysis, mitochondrial function and cognition, while reducing oxidative stress and amyloid deposition (Van der Auwera et al., 2005;Beckett et al., 2013;Kashiwaya et al., 2013;Zhang et al., 2013;Pawlosky et al., 2017). ...
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Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.
... Several molecular mechanisms that contribute to KDmediated reduction of oxidative stress have been described ( Figure 3). Mice fed the KD had higher mitochondrial respiration rates and increased expression of mitochondrial uncoupling proteins (UCP) than mice on a control diet (57). Increased UCP activity reduces mitochondrial membrane potential and lowers production of ROS and reactive oxygen nitrogen species. ...
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The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has been used for decades as a non-pharmacologic approach to treat metabolic disorders and refractory pediatric epilepsy. In recent years, enthusiasm for the KD has increased in the scientific community due to evidence that the diet reduces pathology and improves various outcome measures in animal models of neurodegenerative disorders, including multiple sclerosis, stroke, glaucoma, spinal cord injury, retinal degenerations, Parkinson's disease and Alzheimer's disease. Clinical trials also suggest that the KD improved quality of life in patients with multiple sclerosis and Alzheimer's disease. Furthermore, the major ketone bodies BHB and ACA have potential neuroprotective properties and are now known to have direct effects on specific inflammatory proteins, transcription factors, reactive oxygen species, mitochondria, epigenetic modifications and the composition of the gut microbiome. Neuroprotective benefits of the KD are likely due to a combination of these cellular processes and other potential mechanisms that are yet to be confirmed experimentally. This review provides a comprehensive summary of current evidence for the effectiveness of the KD in humans and preclinical models of various neurological disorders, describes molecular mechanisms that may contribute to its beneficial effects, and highlights key controversies and current gaps in knowledge.
... This was similarly concluded in the adult study by Sabapathy et al mentioned above (Sabapathy et al., 2006). Although several studies in older animals have shown that the KD improves mitochondrial respiration in the hippocampus (Sullivan et al., 2004), we did not observe an effect of the KD on mitochondrial respiration in the liver and frontal cortex between the groups. The reason for these differences is unknown but the effects of the KD on mitochondrial respiration may have differential regional and possibly age-specific effects. ...
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Infantile Spasms syndrome is a catastrophic, epileptic encephalopathy of infancy that is often refractory to current antiepileptic therapies. The ketogenic diet has emerged as an alternative treatment for patients with medically intractable epilepsy, though the prospective validity and mechanism of action for Infantile Spasms remains largely unexplored. We investigated the ketogenic diet’s efficacy as well as its mechanism of action in a rodent model of intractable Infantile Spasms. The spasms were induced using the triple-hit paradigm and the animals were then artificially reared and put on either the ketogenic diet (4:1 fats: carbohydrate + protein) or a control-milk diet (CM; 1.7:1). 31Phosphorus magnetic resonance spectroscopy (MRS) and head-out plethysmography were examined in conjunction with continuous video-EEG behavioural recordings in lesioned animals and sham-operated controls. The ketogenic diet resulted in a peripheral ketosis observed both in the blood and urine. The ketogenic diet led to a robust reduction in the frequency of spasms observed, with approximately a 1.5-fold increase in the rate of survival. Intriguingly, the ketogenic diet resulted in an intracerebral acidosis as measured with 31Phosphorus magnetic resonance spectroscopy. In addition, the respiratory profile of the lesioned rats on the ketogenic diet was significantly altered with slower, deeper, and longer breathing, resulting in decreased levels of expired CO2. Sodium bicarbonate supplementation, acting as a pH buffer, partially reversed the ketogenic diet’s protective effects on spasm frequency. There were no differences in the mitochondrial respiratory profiles in the liver and brain frontal cortex measured between the groups, supporting the notion that the effects of the ketogenic diet on breathing are not entirely due to changes in intermediary metabolism. Together, our results indicate that the ketogenic diet produces its anticonvulsant effects through changes in respiration leading to intracerebral acidosis. These findings provide a novel understanding of the mechanisms underlying the anti-seizure effects of the ketogenic diet in Infantile Spasms. Further research is required to determine whether the effects of the ketogenic diet on breathing and intracerebral acid-base balance are seen in other pediatric models of epilepsy.
... One dietary model that has been proposed to reverse mitochondrial dysfunction, especially the shift from aerobic to glycolytic energy generation in depression, is the ketogenic diet, although clinical trials assessing this hypothesis in humans are still awaited [145]. A ketogenic diet increases both the activity and levels of mitochondrial uncoupling proteins [146]. The extent to which alteration in mitochondrial biogenesis mediates the beneficial effects of a healthy Mediterranean type diet in depression is yet to be determined. ...
... This type of diet aims to shift metabolism toward betaoxidation and ketone body production, to increase transcription of OXPHOS, TCA cycle, and glycolysis genes (Bough et al., 2006). In mouse models following a ketogenic diet, a decrease in mitochondrial ROS, and an increase in mitochondrial uncoupling protein and glutathione levels were reported (Sullivan et al., 2004;Jarrett et al., 2008), suggesting that ketogenic diets might act to reduce mitochondrial-mediated oxidative stress. However, there is still a lot of controversy regarding the safety and efficacy of this dietary option (Garone and Viscomi, 2018;Kuszak et al., 2018). ...
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Leigh syndrome is a rare, complex, and incurable early onset (typically infant or early childhood) mitochondrial disorder with both phenotypic and genetic heterogeneity. The heterogeneous nature of this disorder, based in part on the complexity of mitochondrial genetics, and the significant interactions between the nuclear and mitochondrial genomes has made it particularly challenging to research and develop therapies. This review article discusses some of the advances that have been made in the field to date. While the prognosis is poor with no current substantial treatment options, multiple studies are underway to understand the etiology, pathogenesis, and pathophysiology of Leigh syndrome. With advances in available research tools leading to a better understanding of the mitochondria in health and disease, there is hope for novel treatment options in the future.
... Alternatively, KD-fed mice displayed lower ROS levels in brain relative to standard diet-fed controls. Mechanistically, it is suggested that KD may diminish ROS production by increasing the expression and activity of mitochondrial uncoupling proteins (UCPs; Sullivan et al., 2004). In a mouse model of ischemic stroke, combined ACA/BHB injection increased the NAD + /NADH ratio relative to vehicle-treated control animals (Yin et al., 2015). ...
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Classical mitochondrial disease (MD) represents a group of complex metabolic syndromes primarily linked to dysfunction of the mitochondrial ATP-generating oxidative phosphorylation (OXPHOS) system. To date, effective therapies for these diseases are lacking. Here we discuss the ketogenic diet (KD), being a high-fat, moderate protein, and low carbohydrate diet, as a potential intervention strategy. We concisely review the impact of the KD on bioenergetics, ROS/redox metabolism, mitochondrial dynamics and mitophagy. Next, the consequences of the KD in (models of) MD, as well as KD adverse effects, are described. It is concluded that the current experimental evidence suggests that the KD can positively impact on mitochondrial bioenergetics, mitochondrial ROS/redox metabolism and mitochondrial dynamics. However, more information is required on the bioenergetic consequences and mechanistic mode-of-action aspects of the KD at the cellular level and in MD patients.
... There are also studies suggesting a potential beneficial effect of KD in MD, besides reducing seizures [14,18]. However, this was mainly studied in patient derived fibroblasts and animal models [8,14,[19][20][21][22][23]. Of note, while it was previously assumed that the liver provides ketone bodies to the brain, astrocytes itself have shown to be ketogenic cells. ...
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Background No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative stress, increase antioxidants and scavenge free radicals, putting ketogenic diets (KDs) on the list of management options for MD. Furthermore, KDs are well-known, safe and effective treatments for epilepsy, a frequent symptom of MD. This systematic review evaluates efficacy and safety of KD for MD. Methods We searched Pubmed, Cochrane, Embase and Cinahl (November 2020) with search terms linked to MD and KD. From the identified records, we excluded studies on Pyruvate Dehydrogenase Complex deficiency. From these eligible reports, cases without a genetically confirmed diagnosis and cases without sufficient data on KD and clinical course were excluded. The remaining studies were included in the qualitative analysis. Results Only 20 cases (14 pediatric) from the 694 papers identified met the inclusion criteria (one controlled trial (n = 5), 15 case reports). KD led to seizure control in 7 out of 8 cases and improved muscular symptoms in 3 of 10 individuals. In 4 of 20 cases KD reversed the clinical phenotype (e.g. cardiomyopathy, movement disorder). In 5 adults with mitochondrial DNA deletion(s) related myopathy rhabdomyolysis led to cessation of KD. Three individuals with POLG mutations died while being on KD, however, their survival was not different compared to individuals with POLG mutations without KD. Conclusion Data on efficacy and safety of KD for MD is too scarce for general recommendations. KD should be considered in individuals with MD and therapy refractory epilepsy, while KD is contraindicated in mitochondrial DNA deletion(s) related myopathy. When considering KD for MD the high rate of adverse effects should be taken into account, but also spectacular improvements in individual cases. KD is a highly individual management option in this fragile patient group and requires an experienced team. To increase knowledge on this—individually—promising management option more (prospective) studies using adequate outcome measures are crucial.
... KD management has also been shown to reduce activated microglial expression (17). While mechanism of KD in neuroprotection is unknown, past reports found that KD increases glutathione level(18) and Uncoupling protein (UCP) (19) in cells after brain injuries, decreasing Reactive Oxygen Species (ROS). ...
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Background: Traumatic brain injury (TBI) is a brain dysfunction without present treatment. Previous studies have shown that animals fed a ketogenic diet (KD) perform better in learning tasks than those fed a standard diet (SD) following brain injury. The goal of this study was to examine whether KD is neuroprotective in a TBI mouse model. Methods: We utilized a closed head injury model to induce mild TBI (mTBI) in mice. Mice were fed KD or SD starting immediately following the trauma and throughout the following 30 days. Tail blood ketone bodies levels were checked at 0, 3, 7 and 30 days post injury. Behavioral tests took place at 7 and 30 days post injury, visual and spatial memory impairments were assessed using the Novel object recognition (NOR) paradigm and the Y-maze test, respectively, and anxiety-like behavior was assessed using the elevated plus maze test. Primary mouse SIRT1 levels antibodies were used to detect changes in protein levels following TBI induction and treatments 7 and 30 days post injury and Immunohistochemical sections were stained with, NeuN (for mature neurons), Iba-1 (for microglia) and GFAP (for astrocyte). Results: Elevated levels of ketone bodies were confirmed in the blood following KD. Cognitive and behavioral performance was assessed post injury and molecular and cellular changes were assessed within the temporal cortex and hippocampus. Y‑maze and NOR tasks indicated that mTBI mice maintained on KD displayed better cognitive abilities than mTBI mice maintained on SD. Mice maintained on SD post-injury demonstrated SIRT1 reduction when compared with uninjured and KD groups. In addition, KD management attenuated mTBI-induced microglia activation and astrocyte reactivity in the dentate gyrus and decreased degeneration of neurons in the dentate gyrus and in the cortex. Conclusion: These results support accumulating evidence that KD may be an effective approach to increase the brain’s resistance to damage and suggest a potential new therapeutic strategy for treating mTBI.
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Traumatic brain injury (TBI) is a brain dysfunction without present treatment. Previous studies have shown that animals fed ketogenic diet (KD) perform better in learning tasks than those fed standard diet (SD) following brain injury. The goal of this study was to examine whether KD is a neuroprotective in TBI mouse model. We utilized a closed head injury model to induce TBI in mice, followed by up to 30 days of KD/SD. Elevated levels of ketone bodies were confirmed in the blood following KD. Cognitive and behavioral performance was assessed post injury and molecular and cellular changes were assessed within the temporal cortex and hippocampus. Y-maze and Novel Object Recognition tasks indicated that mTBI mice maintained on KD displayed better cognitive abilities than mTBI mice maintained on SD. Mice maintained on SD post-injury demonstrated SIRT1 reduction when compared with uninjured and KD groups. In addition, KD management attenuated mTBI-induced astrocyte reactivity in the dentate gyrus and decreased degeneration of neurons in the dentate gyrus and in the cortex. These results support accumulating evidence that KD may be an effective approach to increase the brain’s resistance to damage and suggest a potential new therapeutic strategy for treating TBI.
Article
Obesity is an emerging non-communicable disease associated with chronic low-grade inflammation and oxidative stress, compounded by the development of many obesity-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, and a range of cancers. Originally developed for the treatment of epilepsy in drug non-responder children, the ketogenic diet (KD) is being increasingly used in the treatment of many diseases, including obesity and obesity-related conditions. The KD is a dietary pattern characterized by high fat intake, moderate to low protein consumption, and very low carbohydrate intake (<50 g) that has proved to be an effective and weight-loss tool. In addition, it also appears to be a dietary intervention capable of improving the inflammatory state and oxidative stress in individuals with obesity by means of several mechanisms. The main activity of the KD has been linked to improving mitochondrial function and decreasing oxidative stress. β-hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species, improving mitochondrial respiration. In addition, KDs exert anti-inflammatory activity through several mechanisms, e.g., by inhibiting activation of the nuclear factor kappa-light-chain-enhancer of activated B cells, and the inflammatory nucleotide-binding, leucine-rich-containing family, pyrin domain-containing-3, and inhibiting histone deacetylases. Given the rising interest in the topic, this review looks at the underlying anti-inflammatory and antioxidant mechanisms of KDs and their possible recruitment in the treatment of obesity and obesity-related disorders.
Article
Background: Traumatic brain injury (TBI) is one of the most prevalent causes of permanent physical and cognitive disabilities. TBI pathology results from primary insults and a multi-mechanistic biochemical process, termed as secondary brain injury. Currently, there are no pharmacological agents for definitive treatment of patients with TBI. Objectives: This article is presented with the purpose of reviewing molecular mechanisms of TBI pathology, as well as potential strategies and agents against pathological pathways. Methods: In this review article, materials were obtained by searching PubMed, Scopus, Elsevier, Web of Science, and Google Scholar. This search was considered without time limitation. Results: Evidence indicates that oxidative stress and mitochondrial dysfunction are two key mediators of the secondary injury cascade in TBI pathology. TBI-induced oxidative damage results in the structural and functional impairments of cellular and subcellular components, such as mitochondria. Impairments of mitochondrial electron transfer chain and mitochondrial membrane potential result in a vicious cycle of free radical formation and cell apoptosis. The results of some preclinical and clinical studies, evaluating mitochondria-targeted therapies, such as mitochondria-targeted antioxidants and compounds with pleiotropic effects after TBI, are promising. Conclusions: As a proposed strategy in recent years, mitochondria-targeted multi-potential therapy is a new hope, waiting to be confirmed. Moreover, based on the available findings, biologics, such as stem cell-based therapy and transplantation of mitochondria are novel potential strategies for the treatment of TBI; however, more studies are needed to clearly confirm the safety and efficacy of these strategies.
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Epilepsy is a neurological disorder in which, in many cases, there is poor pharmacological control of seizures. Nevertheless, it may respond beneficially to alternative treatments such as dietary therapy, like the ketogenic diet or caloric restriction. One of the mechanisms of these diets is to produce a hyperpolarization mediated by the adenosine triphosphate (ATP)-sensitive potassium (KATP) channels (KATP channels). An extracellular increase of K+ prevents the release of Ca2+ by inhibiting the signaling of the Wnt pathway and the translocation of β-catenin to the cell nucleus. Wnt ligands hyperpolarize the cells by activating K+ current by Ca2+. Each of the diets described in this paper has in common a lower use of carbohydrates, which leads to biochemical, genetic processes presumed to be involved in the reduction of epileptic seizures. Currently, there is not much information about the genetic processes implicated as well as the possible beneficial effects of diet therapy on epilepsy. In this review, we aim to describe some of the possible genes involved in Wnt pathways, their regulation through the KATP channels which are implicated in each one of the diets, and how they can reduce epileptic seizures at the molecular level.
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Purpose: Treatments that delay retinal cell death regardless of genetic causation are needed for inherited retinal degeneration (IRD) patients. The ketogenic diet is a high-fat, low-carbohydrate diet, used to treat epilepsy, and has beneficial effects for neurodegenerative diseases. This study aimed to determine whether the ketogenic diet could slow retinal degeneration. Methods: Early weaned, rd10 and wild-type (WT) mice were placed on either standard chow, a ketogenic diet, or a ketogenic & low-protein diet. From postnatal day (PD) 23 to PD50, weight and blood β-hydroxybutyrate levels were recorded. Retinal thickness, retinal function, and visual performance were measured via optical coherence tomography, electroretinography (ERG), and optokinetic tracking (OKT). At PD40, serum albumin, rhodopsin protein, and phototransduction gene expression were measured. Results: Both ketogenic diets elicited a systemic induction of ketosis. However, rd10 mice on the ketogenic & low-protein diet had significant increases in photoreceptor thickness, ERG amplitudes, and OKT thresholds, whereas rd10 mice on the ketogenic diet showed no photoreceptor preservation. In both rd10 and WT mice, the ketogenic & low-protein diet was associated with abnormal weight gain and decreases in serum albumin levels, 27% and 56%, respectively. In WT mice, the ketogenic & low-protein diet was also associated with an ∼20% to 30% reduction in ERG amplitudes. Conclusions: The ketogenic & low-protein diet slowed retinal degeneration in a clinically relevant IRD model. In WT mice, the ketogenic & low-protein diet was associated with a decrease in phototransduction and serum albumin, which could serve as a protective mechanism in the rd10 model. Although ketosis was associated with protection, its role remains unclear. Translational relevance: Neuroprotective mechanisms associated with the ketogenic & low-protein diet have potential to slow retinal degeneration.
Article
There is growing evidence for the disease‐modifying potential of metabolic therapies, including the ketogenic diet (KD), which is used to treat medically intractable epilepsy. However, it remains unclear whether the KD exerts direct effects on histopathological changes in epileptic brain, or whether the changes are a consequence of diet‐induced reduction in seizure activity. Here, we used unbiased stereological techniques to quantify the seizure‐induced reduction in cell number in the CA1 region of the hippocampus of epileptic Kcna1‐null mice and compared the effects of the KD with that of phenobarbital (PB), a widely employed anti‐seizure drug. Our data suggest that the anti‐seizure activity of the KD or PB was similar. However, CA1 cell numbers of KD‐treated hippocampi were not significantly different from those seen in wild‐type (WT) mice, whereas CA1 cell counts in standard diet and PB‐treated Kcna1‐null mice were 23% and 31% lower than WT animals, respectively. These results support the notion that structural protection of cells may involve more than seizure attenuation, and that the KD engages mechanisms that also promote or restore hippocampal morphological integrity.
Article
Pharmacoresistant epilepsy causes serious deleterious effects on the patient’s health and quality of life. For this condition, a ketogenic diet (KD) is a treatment option. The KD is a general term for a set of diets that contain high amounts of fat and low content of carbohydrates. The most prominent KD treatments are classical KD (4:1 ratio of fat to carbohydrate), modified Atkins diet (2:1 to 1:1 ratio), medium-chain triglycerides KD (with medium-chain triglyceride as a part of the fat content), and low glycemic index KD (using low glycemic carbohydrates). KD has been widely prescribed for children with epilepsy but not for adult patients. One of the main concerns about adult use of KD is its cardiovascular risk associated with high-fat and cholesterol intake. Therefore, this narrative review provides comprehensive information of the current literature on the effects of KD on lipid profile, glycemic-control biomarkers, and other cardiometabolic risk factors in adult patients with pharmacoresistant epilepsy.
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Background Mitochondrial diseases (MDs) are heterogeneous group of disorders caused by inborn defects in the mitochondrial respiratory chain (MRC) and malfunctions of cellular oxidative phosphorylation (OXPHOS). MDs are caused by mutations both in mitochondrial and nuclear DNA. Leigh syndrome (LS) is a neurodegenerative MD with specific clinical and neuroradiological features. There is a broad clinical spectrum of MDs, including organ-specific and multiorgan presentations with symptoms occurring at any age. High energy requiring organs are most frequently involved and cardiac involvement is common. At present there is no specific treatment for MD. Ketogenic diet (KD) has been proposed as a treatment option for patients with MD with seizures or myopathy. It is suggested that KD itself may trigger cardiological complications after long-term therapy, but according to an animal model study, KD could be considered as a therapeutic option for some mitochondrial cardiomyopathies.Method Here we present a retrospective case report on a male infant diagnosed with LS (m.12706T > C in MTND5) with severe progressive hypertrophic cardiomyopathy, with significant cardiological improvement after KD implementation .ResultsThe ketogenic diet was introduced in a male infant with clinical, biochemical and radiological features of Leigh syndrome, confirmed by next-generation sequencing (NGS) (known pathogenic variant in mtDNA), suffering from severe progressive hypertrophic cardiomyopathy and heart failure with no significant improvement on cardiological treatment, mitochondrial cocktail therapy and mechanical ventilation. The follow-up after KD initiation have shown significant clinical improvement in cardiovascular efficiency and echocardiographic parameters with no adverse effect observed so far.Conclusion Screening for cardiomyopathy is a standard of care (SoC) in the management of patients with mitochondrial disease. Although there are reports suggesting the efficacy and safety of KD in patients with mitochondrial disease, more studies are needed to understand the pathophysiology of mitochondrial diseases and to determine which patients are likely to benefit from this therapy.
Article
Spinal cord injury (SCI) is one of the leading causes of neurological disability and death. So far, there is no satisfactory treatment for SCI, because of its complex and ill-defined pathophysiology. Recently, autophagy has been implicated as protective in acute SCI rat models. Here, we investigated the therapeutic value of a dietary intervention, namely, intermittent fasting (IF), on neuronal survival after acute SCI in rats, and its underlying mechanism related to autophagy regulation. We found remarkable improvement in both behavioral performance and neuronal survival at the injured segment of the spinal cord of animals previously subjected to IF. Western blotting revealed a marked decrease in apoptosis-related markers such as cleaved caspase 3 levels and the bax/bcl-2 ratio in the IF group, which suggested an inhibition of the intrinsic apoptosis pathway. In addition, the expression of the autophagy markers LC3-II and beclin 1 was also increased in the IF group compared with ad libitum fed animals. In parallel, IF decreased the levels of the substrate protein of autophagy, p62, indicative of an upregulation of the autophagic processes. Treatment with 3-methyladenine (3-MA), a selective inhibitor of autophagy, reversed the downregulated apoptosis-related markers by IF. Finally, IF could activate the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway and enhance lysosome function by upregulating transcription factor (TF)EB expression. Altogether, the present findings suggest that IF exerts a neuroprotective effect after acute SCI via the upregulation of autophagy, and further points to dietary interventions as a promising combinatorial treatment for SCI.
Article
The use of hyperbaric oxygen (HBO2) in hyperbaric and undersea medicine is limited by the risk of seizures (i.e., CNS oxygen toxicity, CNS-OT) resulting from increased production of reactive oxygen species (ROS) in the CNS. Importantly, ketone supplementation has been shown to delay onset of CNS-OT in rats by ~600% in comparison to control groups (D'Agostino et al., 2013). We have tested the hypothesis that ketone body supplementation inhibits ROS production during exposure to hyperoxygenation in rat brainstem cells. We measured the rate of cellular superoxide (.O2‑) production in the caudal Solitary Complex (cSC) in rat brain slices using a fluorogenic dye, dihydroethidium (DHE), during exposure to control O2 (0.4 ATA) followed by 1-2 hr of normobaric oxygen (NBO2) (0.95 ATA) and HBO2 (1.95, and 4.95 ATA) hyperoxia, with and without a 50:50 mixture of ketone salts (KS) DL-b-hydroxybutyrate (BHB + acetoacetate (AcAc)). All levels of hyperoxia tested stimulated .O2- production similarly in cSC cells, and co-exposure to 5 mM KS during hyperoxia significantly blunted the rate of increase in DHE fluorescence intensity during exposure to hyperoxia. Not all cells tested produced .O2- at the same rate during exposure to control O2 and hyperoxygenation; cells that increased .O2‑ production by >25% during hyperoxia in comparison to baseline were inhibited by KS, whereas cells that did not reach that threshold during hyperoxia were unaffected by KS. These findings support the hypothesis that ketone supplementation decreases the steady state concentrations of superoxide produced during exposure to NBO2 and HBO2 hyperoxia.
Article
Ketogenic diet therapies are high-fat, low-carbohydrate diets designed to mimic a fasting state. Although initially developed nearly one century ago for seizure management, most clinical trials for the management of drug-resistant epilepsy in children as well as adults have been conducted over the last 3 decades. Moreover, ketogenic diets offer promising new adjunctive strategies in the critical care setting for the resolution of acute status epilepticus when traditional antiseizure drugs and anesthetic agents fail. Here, we review the history of ketogenic diet development, the clinical evidence supporting its use for the treatment of drug-resistant epilepsy in children and adults, and the early evidence supporting ketogenic diet feasibility, safety, and potential efficacy in the management of status epilepticus.
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Brustkrebs ist die häufigste maligne Erkrankung der Frau. Die Therapie setzt sich in der Regel individuell aus den Bausteinen der chirurgischen Tumorexzision, der Bestrahlung und der systemischen Therapie zusammen. Daneben gewinnt die ketogene Diät als supportiver Therapieansatz immer mehr an Aufmerksamkeit und Forschungsinteresse. Diese Ernährungsform imitiert durch starke Restriktion der Kohlenhydratzufuhr den Fastenstoffwechsel, da Blutzucker- und konsekutiv auch Insulinspitzen im Blut vermieden werden. Eine tragende Rolle kommt dabei der Bildung von Ketonkörpern, allen voran Betahydroxybutyrat, zu, die sowohl in den Tumorstoffwechsel als auch in immunologische Prozesse eingreifen können. In dieser Arbeit wurde ausgewählten Brustkrebszellen 3 mM Betahydroxybutyrat zugesetzt und ihr Wachstumsverhalten, ihre Chemo- und Radiosensitivität im Vergleich zu Kontrollzellen erfasst. Die Kontrollzellen wurden identisch behandelt, jedoch wurde Ihnen kein Betahydroxybutyrat zugefügt. Es zeigte sich dabei kein statistisch signifikanter Unterschied zwischen den beiden Zellgruppen.
Article
Кетогенная диета (КД) - это низкоуглеводная диета с высоким содержанием жиров и умеренным содержанием белков с включением витаминных комплексов, микро-, макроэлементов, особенно, кальция в сочетании с витамином D. У здорового человека при традиционном взвешенном питании углеводы, поступающие с пищей, перерабатываются в глюкозу, которая обеспечивает энергетическое питание и функционирование ЦНС. Посредством КД в рационе присутствует малое количество углеводов, поэтому печень компенсаторно, стремясь обеспечить организм энергетическим питанием, начинает интенсивно преобразовывать жир в жирные кислоты, затем в кетоновые тела - ацетоацетат, b-оксибутират, ацетон (кетогенез) в качестве альтернативы глюкозе. В результате, формируется состояние кетоза - повышенного уровня кетоновых тел в крови - и затем их утилизация в митохондриях периферических тканей и ЦНС (кетолизис). Одновременно происходит глубокое перепрограммирование метаболических процессов с терапевтическими (при эпилепсии и многих нейродегенеративных заболеваниях), или негативными последствиями при дефектах метаболизма жиров, функции печени и почек. КД изначально применялась (часто, с высоким терапевтическим эффектом) для лечения эпилептиформных состояний, вызванных дефектами энергетического метаболизма, у детей; затем у взрослых - ее облегченные модификации посредством умеренного повышения в рационе углеводов, белков, среднецепочечных жирных кислот. КД предусматривает (в соответствии с ростом и возрастом) достаточное количество калорий для поддержания нормальной массы тела, необходимое количество белков и минимальное количество углеводов для роста, регенерации организма. КД-терапия успешно используется при дефекте транспорта глюкозы (транспортера GLUT-1) в ЦНС, дефиците пируватдегидрогеназы; оказывает положительное действие при ожирении, диабете 2-го типа, болезнях Паркинсона и Альцгеймера, боковом амиотрофическом склерозе, рассеянном склерозе, инсультах, травмах и злокачествеенных опухолях головного мозга. Классическая КД противопоказана при нарушениях кетогенеза и кетолизиса, нарушениях функции печени и почек, недостаточности карнитин-пальмитоилтрансферазы I (транспортера жирных кислот в митохондрии), но ее модификации эффективны при некоторых дефектах обмена жиров. Ketogenic diet (KD) is a low carbohydrate diet that contains high amounts of fats and moderate amounts of proteins and includes vitamins, micro- and macroelements (particularly, calcium in combination with vitamin D). In a healthy human on traditional balanced diet, carbohydrates from food are being converted to glucose that provides energy for the central nervous system (CNS). KD contains little carbohydrates, therefore liver, to provide organism with energy, compensatory converts fat into fatty acids and then into ketone bodies acetoacetate, b-hydroxybutyrate, acetone as an alternative to glucose (ketogenesis). This results in ketosis - increased levels of ketone bodies in blood followed by their utilization in mitochondria of peripheral tissues and CNS (ketolysis). Simultaneously, a deep reprogramming of metabolic processes occurs resulting in therapeutic (in epilepsy and many neurodegenerative diseases) or negative (when fat metabolism defects or liver and kidney insufficiency are present) consequences. KD was initially used (frequently with therapeutic benefit) for the treatment of epileptiform conditions caused by defects in energy metabolism in children and later in adults (using lightened modifications with modestly increased levels of carbohydrates, proteins and medium-chain fatty acids). KD provides sufficient number of calories (matching patient’s height and age) to maintain normal body weight, necessary amount of protein and minimal amount of carbohydrates for organism growth and regeneration. KD is used successfully in patients with CNS glucose transport defects (GLUT-1), pyruvate dehydrogenase deficit, it provides benefits in obesity, type 2 diabetes, Parkinson’s and Alzheimer’s disease, lateral amyotrophic sclerosis, multiple sclerosis, stroke, traumas and brain malignancies, Classic KD is contraindicated in ketogenesis and ketolysis defects, liver insufficiency, kidney insufficiency, carnitine palmitoyltransferase I (mitochondrial fatty acid transporter) deficiency but its modifications are effective in some fat metabolism defects.
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A better understanding of the secondary injury mechanisms that occur after traumatic spinal cord injury (SCI) is essential for the development of novel neuroprotective strategies linked to the restoration of metabolic deficits. We and others have shown that Ketogenic diet (KD), a high fat, moderate in proteins and low in carbohydrates is neuroprotective and improves behavioural outcomes in rats with acute SCI. Ketones are alternative fuels for mitochondrial ATP generation, and can modulate signaling pathways via targeting specific receptors. Here, we demonstrate that ad libitum administration of KD for 7 days after SCI rescued mitochondrial respiratory capacity, increased parameters of mitochondrial biogenesis, affected the regulation of mitochondrial-related genes, and activated the NRF2-dependent antioxidant pathway. This study demonstrates that KD improves post-SCI metabolism by rescuing mitochondrial function and supports the potential of KD for treatment of acute SCI in humans.
Article
Dietary modification would be the most translatable, cost-efficient, and, likely, the safest approach available that can reduce the reliance on pharmaceutical treatments for treating acute or chronic neurological disorders. A wide variety of evidence suggests that the ketogenic diet (KD) could have beneficial effects in acute traumatic events, such as spinal cord injury and traumatic brain injury. Review of existing human and animal studies revealed that KD can improve motor neuro-recovery, gray matter sparing, pain thresholds, and neuroinflammation and decrease depression. Although the exact mechanism by which the KD provides neuroprotection is not fully understood, its effects on cellular energetics, mitochondria function and inflammation are likely to have a role.
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Uncoupling protein 1 (UCP1) diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose tissue by catalysing a regulated leak of protons across the inner membrane. The functions of its homologues, UCP2 and UCP3, in other tissues are debated. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage. Here we show that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2 and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. It correlates with the tissue expression of UCPs, appears in mitochondria from yeast expressing UCP1, and is absent in skeletal muscle mitochondria from UCP3 knockout mice. Our findings indicate that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of reactive oxygen species inside mitochondria.
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Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing human UCP-2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurological recovery was enhanced. In cultured cortical neurons, UCP-2 reduced cell death and inhibited caspase-3 activation induced by oxygen and glucose deprivation. Mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) reduced neuronal death, and UCP-2 activity was enhanced by palmitic acid in isolated mitochondria. Also in isolated mitochondria, UCP-2 shifted the release of reactive oxygen species from the mitochondrial matrix to the extramitochondrial space. We propose that UCP-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.
Article
To determine the efficacy of the ketogenic diet in multiple centers. A prospective study of the change in frequency of seizures in 51 children with intractable seizures who were treated with the ketogenic diet. Patients were enrolled from the clinical practices of 7 sites. The diet was initiated in-hospital and the patients were followed up for at least 6 months. Fifty-one children, aged 1 to 8 years, with more than 10 seizures per week, whose electroencephalogram showed generalized epileptiform abnormalities or multifocal spikes, and who had failed results when taking at least 2 appropriate anti-epileptic drugs. The children were hospitalized, fasted, and a 4:1 ketogenic diet was initiated and maintained. Frequency of seizures was documented from parental calendars and efficacy was compared with prediet baseline after 3, 6, and 12 months. The children were categorized as free of seizures, greater than 90% reduction, 50% to 90% reduction, or lower than 50% reduction in frequency of seizures. Eighty-eight percent of all children initiating the diet remained on it at 3 months, 69% remained on it at 6 months, and 47% remained on it at 1 year. Three months after initiating the diet, frequency of seizures was decreased to greater than 50% in 54%. At 6 months, 28 (55%) of the 51 initiating the diet had at least a 50% decrease from baseline, and at 1 year, 40% of those starting the diet had a greater than 50% decrease in seizures. Five patients (10%) were free of seizures at 1 year. Age, sex, principal seizure type, and electroencephalogram were not statistically related to outcome. The ketogenic diet is effective in substantially decreasing difficult-to-control seizures and can successfully be administered in a wide variety of settings.
Article
The present study was conducted to investigate the brain distribution of the recently cloned uncoupling protein 2 (UCP2). Northern blot analyses were first carried out to confirm the presence of UCP2 in the brain. These analyses revealed the brain presence of UCP2 mRNA and the absence of the mRNAs encoding uncoupling protein 1 and uncoupling protein 3. They also demonstrate that UCP2 mRNA expression was abundant in the hypothalamus and not affected by cold acclimation. In situ hybridization histochemistry was used to determine the brain distribution of the mRNA encoding UCP2. A markedly intense hybridization signal was found in the hypothalamus, the ventral septal region, the caudal hindbrain (medulla), the ventricular region, and the cerebellum. A very highly intense hybridization signal was apparent in the suprachiasmatic nucleus, the medial parvicellular part of the paraventricular hypothalamic nucleus, the arcuate nucleus, the dorsal motor nucleus of the vagus nerve, and the choroid plexus. The specifically localized expression of UCP2 mRNA suggests that this mRNA has a neuronal localization. Neuronal expression was particularly manifest in the nucleus of the horizontal limb of the diagonal band, the submedius thalamic nucleus and the dorsal motor nucleus of the vagus nerve, where agglomerations of the silver grains delineated individual cells. The role played by UCP2 in the brain has yet to be fully described, but the pattern of distribution of the transcript suggests that this mitochondrial protein is part of neuronal circuitries controlling neuroendocrine functions, autonomic responses, and the general arousal of the brain. Given the involvement of the proteins from the uncoupling protein's family in the uncoupling of cellular respiration, it can be argued that UCP2 contributes to the metabolic rate and thermoregulation of these circuitries. In addition, by promoting oxygen consumption in the brain, UCP2 could control the production of reactive oxygen species and thereby influence the process of neural degeneration. J. Comp. Neurol. 397:549–560, 1998. © 1998 Wiley-Liss, Inc.
Article
The electrical stimulus necessary to produce a minimal convulsion in adult rats started rising 10 days after they were placed on a high-fat diet, reaching a maximum at about 20 days. The convulsive threshold did not change in animals on a high-carbohydrate diet. When the diet was changed from high-fat to high-carbohydrate, the electroconvulsive threshold reverted rapidly to prestudy levels. Biochemical studies revealed the high-fat diet to be ketogenic as the blood concentrations of D-β-hydroxybutyrate and acetoacetate were elevated. Serum chloride, triglycerides, esterified fatty acids, and total lipids were also elevated, but the serum cholesterol was lowered. In brain, the only changes were elevations of D-β-hydroxybutyrate and sodium and lowering of the acetoacetyl Co A transferase activity. It is suggested that ketosis alters cerebral metabolism of glucose leading to an elevation in the electroconvulsive threshold.
Article
To proceed at a high rate, phosphorylating respiration requires ADP to be available. In the resting state, when the energy consumption is low, the ADP concentration decreases so that phosphorylating respiration ceases. This may result in an increase in the intracellular concentrations of O 2 as well as of one-electron O 2 reductants such as These two events should dramatically enhance non-enzymatic formation of reactive oxygen species, i.e. of , and OHׁ, and, hence, the probability of oxidative damage to cellular components. In this paper, a concept is put forward proposing that non-phosphorylating (uncoupled or non-coupled) respiration takes part in maintenance of low levels of both O 2 and the O 2 reductants when phosphorylating respiration fails to do this job due to lack of ADP. In particular, it is proposed that some increase in the H ⁺ leak of mitochondrial membrane in State 4 lowers , stimulates O 2 consumption and decreases the level of which otherwise accumulates and serves as one-electron O 2 reductant. In this connection, the role of natural uncouplers (thyroid hormones), recouplers (male sex hormones and progesterone), non-specific pore in the inner mitochondrial membrane, and apoptosis, as well as of non-coupled electron transfer chains in plants and bacteria will be considered.
Article
The present study was conducted to investigate the brain distribution of the recently cloned uncoupling protein 2 (UCP2). Northern blot analyses were first carried out to confirm the presence of UCP2 in the brain. These analyses revealed the brain presence of UCP2 mRNA and the absence of the mRNAs encoding uncoupling protein 1 and uncoupling protein 3. They also demonstrate that UCP2 mRNA expression was abundant in the hypothalamus and not affected by cold acclimation. In situ hybridization histochemistry was used to determine the brain distribution of the mRNA encoding UCP2. A markedly intense hybridization signal was found in the hypothalamus, the ventral septal region, the caudal hindbrain (medulla), the ventricular region, and the cerebellum. A very highly intense hybridization signal was apparent in the suprachiasmatic nucleus, the medial parvicellular part of the paraventricular hypothalamic nucleus, the arcuate nucleus, the dorsal motor nucleus of the vagus nerve, and the choroid plexus. The specifically localized expression of UCP2 mRNA suggests that this mRNA has a neuronal localization. Neuronal expression was particularly manifest in the nucleus of the horizontal limb of the diagonal band, the submedius thalamic nucleus and the dorsal motor nucleus of the vagus nerve, where agglomerations of the silver grains delineated individual cells. The role played by UCP2 in the brain has yet to be fully described, but the pattern of distribution of the transcript suggests that this mitochondrial protein is part of neuronal circuitries controlling neuroendocrine functions, autonomic responses, and the general arousal of the brain. Given the involvement of the proteins from the uncoupling protein's family in the uncoupling of cellular respiration, it can be argued that UCP2 contributes to the metabolic rate and thermoregulation of these circuitries. In addition, by promoting oxygen consumption in the brain, UCP2 could control the production of reactive oxygen species and thereby influence the process of neural degeneration.
Article
The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet developed in the 1920s for the treatment of children with difficult to control seizures. Despite advances in both the pharmacotherapy and the surgery of epilepsy, many children continue to have difficult-to-control seizures. This prospective study sought to determine the ketogenic diet's effectiveness and tolerability in children refractory to today's medications. One hundred fifty consecutive children, ages 1 to 16 years, virtually all of whom continued to have more than two seizures per week despite adequate therapy with at least two anticonvulsant medications, were prospectively enrolled in this study, treated with the ketogenic diet, and followed for a minimum of 1 year. Seizure frequency was tabulated from patients' daily seizure calendars and seizure reduction calculated as percentage of baseline frequency. Adverse events and reasons for diet discontinuation were recorded. The children (mean age, 5.3 years), averaged 410 seizures per month before the diet, despite an exposure to a mean of 6.2 antiepileptic medications. Three months after diet initiation, 83% of those starting remained on the diet and 34% had >90% decrease in seizures. At 6 months, 71% still remained on the diet and 32% had a >90% decrease in seizures. At 1 year, 55% remained on the diet and 27% had a >90% decrease in seizure frequency. Most of those discontinuing the diet did so because it was either insufficiently effective or too restrictive. Seven percent stopped because of intercurrent illness. The ketogenic diet should be considered as alternative therapy for children with difficult-to-control seizures. It is more effective than many of the new anticonvulsant medications and is well tolerated by children and families when it is effective.
Article
To determine whether changes in the high-energy phosphates occur with use of the ketogenic diet in patients with intractable epilepsy. 31P magnetic resonance spectroscopic imaging studies were performed at 4.1 T in seven patients with intractable epilepsy (four Lennox-Gastaut syndrome, one absence, one primary generalized tonic-clonic, and one partial complex) before and after institution of the ketogenic diet. Coronal 1H anatomic imaging also was performed to provide correlation to the 31P data. Taking the patients as a group, the ratio of phosphocreatine (PC)/gamma-adenosine triphosphate (ATP) measured at baseline (regular diet) compared with that measured after the ketogenic diet showed a small but significant increase from 0.61+/-0.08 to 0.69+/-0.08 (p < 0.05). Comparing the ratio of PCr inorganic phosphorus (Pi) measured at baseline with the postketogenic diet, there was a significant increase from 2.45+/-0.27 to 2.99+/-0.44 (p < 0.05). As a group, improvement of energy metabolism occurs with use of the ketogenic diet. This is in agreement with the chronic ketosis studies performed earlier in rodents.
Article
Despite strong clinical data confirming the anticonvulsant efficacy of a ketogenic diet (KGD) in pediatric patients, corroborative experimental data in young animals are limited. In the present study, the effects of a KGD on flurothyl seizure susceptibility were examined in normal juvenile mice after a dietary duration of 3, 7, or 12 days, and in adult mice for 15 days. In all groups of KGD-treated mice, blood beta-hydroxybutyrate levels were significantly elevated over those measured in controls. The present KGD was anticonvulsant (i.e. delayed onset) against the first (clonic) flurothyl-induced seizure for juvenile mice treated for either 7 or 12 days, but not for juvenile mice and adult mice fed the diet for 3 and 15 days, respectively. While this KGD was not anticonvulsant against the second (tonic extension) seizure induced by flurothyl in any of the juvenile groups, it significantly delayed tonic extension in the adult group. In addition, juvenile mice fed a KGD exhibited a lower mortality rate following flurothyl-induced seizures compared to mice fed a standard diet. In our discussion of animal models of the KGD, we highlight the need to understand better the impact of important variables such as dietary composition, genetic background, and mode of seizure induction in the study of the KGD.
Article
The ketogenic diet (KD) is a high-fat, low-carbohydrate and -protein diet that has been used to treat refractory seizures in children for more than 75 years. However, little is known about how the KD inhibits seizures or its effects on epileptogenesis. Several animal models of epilepsy have responded favorably to KD treatment, but the KD has not been studied in animals with a genetic predisposition to seizures. Here we studied the antiepileptogenic effect of the KD in EL mice, an animal model for human idiopathic epilepsy. Young male EL mice (postnatal day 30) were randomly separated into two groups fed ad libitum with either the KD (treated, n = 21) or Agway chow (control, n = 19). The mice were weighed and tested for seizures once per week for a total of 10 weeks. The effects of the KD on plasma levels of ketone bodies and glucose were analyzed at several time points throughout the study. Associative learning was compared between treated and control animals using a water maze. KD treatment delayed seizure onset in young male EL mice by 1 month; however, seizure protection was transient, inasmuch as the treated and control mice experienced a similar number and intensity of seizures after 6 weeks on the diet. Plasma glucose levels and associative learning were similar in the treated and control groups, but the plasma beta-hydroxybutyrate levels were significantly higher in mice on the KD. The level of ketosis, however, was not predictive of seizure protection in EL mice. The KD delayed seizure onset in EL mice, suggesting a transient protection against epileptogenesis. The KD did not influence plasma glucose levels or associative learning. Therefore, the EL mouse may serve as a good model to study the antiepileptogenic mechanisms of the KD.
Article
Creatine, one of the most common food supplements used by individuals at almost every level of athleticism, promote gains in performance, strength, and fat-free mass. Recent experimental findings have demonstrated that creatine affords significant neuroprotection against ischemic and oxidative insults. The present experiments investigated the possible effect of creatine dietary supplementation on brain tissue damage after experimental traumatic brain injury. Results demonstrate that chronic administration of creatine ameliorated the extent of cortical damage by as much as 36% in mice and 50% in rats. Protection seems to be related to creatine-induced maintenance of mitochondrial bioenergetics. Mitochondrial membrane potential was significantly increased, intramitochondrial levels of reactive oxygen species and calcium were significantly decreased, and adenosine triphosphate levels were maintained. Induction of mitochondrial permeability transition was significantly inhibited in animals fed creatine. This food supplement may provide clues to the mechanisms responsible for neuronal loss after traumatic brain injury and may find use as a neuroprotective agent against acute and delayed neurodegenerative processes.
Article
The role of uncoupling protein-2 (UCP-2) in beta-cells is presently unclear. We have tested the notion that UCP-2 participates in beta-cell defense against oxidants. Expression of the UCP-2 gene in clonal beta-cells (INS-1) was decreased by 45% after 48 h of culture with vitamin E and selenite. When INS-1 cells were exposed to 200 microM H(2)O(2) for 5 min, the cell viability (MTT assay) decreased to 85 +/- 1, 61 +/- 1, 40 +/- 2, and 39 +/- 2% of control when measured respectively 30 min, 2 h, 6 h, and 16 h after H(2)O(2) exposure. At corresponding time points UCP-2 mRNA levels were 1.01 +/- 0.09, 1.53 +/- 0.15 (P < 0.05), 1.44 +/- 0.18 (P = 0.06), and 1.12 +/- 0.09 fold of control, i.e., transiently increased. We next tested whether overexpression of UCP-2 could enhance resistance of beta-cells toward H(2)O(2) toxicity. A cotransfection method using EGFP as a suitable marker and a human cDNA UCP-2 construct was used for transient overexpression of UCP-2. Transfected cells expressed the gene about 30-fold more than normal cells. After exposure to H(2)O(2) (200 micrometer, 5 min), the survival of UCP-2 overexpressing cells was measured 30-45 min later by flow cytometry. Survival was 13 +/- 0.05% higher than control (EGFP only) cells, P < 0.004 for difference. The results indicate that oxidative stress induces UCP-2 expression in beta-cells, and that UCP-2 serves a role in beta-cell defense against oxidative stress.
Article
Ketogenic diet (KD) is a high fat, low carbohydrate diet used to treat children with epilepsy that are refractory to conventional antiepileptic drugs (AEDs). The anticonvulsant mechanism of the KD is unknown. To determine if the noradrenergic system has a role in mediating the anticonvulsant action of the KD, dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack norepinephrine (NE) and Dbh +/- littermates that have normal NE content were fed either a standard rodent chow or the KD. When exposed to the convulsant flurothyl, Dbh +/- mice fed the KD had significantly longer latencies to myoclonic jerk (MJ) and generalized clonic-tonic (CT) seizures than Dbh +/- mice fed normal chow. In contrast, Dbh -/- mice fed the KD had seizure latencies to both MJ and CT comparable to Dbh -/- mice fed normal chow. These results suggest that an intact, functional noradrenergic nervous system is required for the KD to exert an anticonvulsant effect.
Article
Mitochondria are widely believed to be the source of reactive oxygen species (ROS) in a number of neurodegenerative disease states. However, conditions associated with neuronal injury are accompanied by other alterations in mitochondrial physiology, including profound changes in the mitochondrial membrane potential DeltaPsi(m). In this study we have investigated the effects of DeltaPsi(m) on ROS production by rat brain mitochondria using the fluorescent peroxidase substrates scopoletin and Amplex red. The highest rates of mitochondrial ROS generation were observed while mitochondria were respiring on the complex II substrate succinate. Under this condition, the majority of the ROS signal was derived from reverse electron transport to complex I, because it was inhibited by rotenone. This mode of ROS generation is very sensitive to depolarization of DeltaPsi(m), and even the depolarization associated with ATP generation was sufficient to inhibit ROS production. Mitochondria respiring on the complex I substrates, glutamate and malate, produce very little ROS until complex I is inhibited with rotenone, which is also consistent with complex I being the major site of ROS generation. This mode of oxidant production is insensitive to changes in DeltaPsi(m). With both substrates, ubiquinone-derived ROS can be detected, but they represent a more minor component of the overall oxidant signal. These studies demonstrate that rat brain mitochondria can be effective producers of ROS. However, the optimal conditions for ROS generation require either a hyperpolarized membrane potential or a substantial level of complex I inhibition.
Article
Outside the nervous system, members of the mitochondrial uncoupling protein (UCP) family have been proposed to contribute to control of body temperature and energy metabolism, and regulation of mitochondrial production of reactive oxygen species (ROS). However, the function of brain mitochondrial carrier protein 1 (BMCP1), which is highly expressed in brain, remains to be determined. To study BMCP1 expression and function in the nervous system, a high-affinity antibody to BMCP1 was generated and used to analyze tissue expression of BMCP1 protein in mouse. BMCP1 protein was highly expressed in heart and kidney, but not liver or lung. In the nervous system, BMCP1 was present in cortex, basal ganglia, substantia nigra, cerebellum, and spinal cord. Both BMCP1 mRNA and protein expression was almost exclusively neuronal. To study the effect of BMCP1 expression on mitochondrial function, neuronal (GT1-1) cell lines with stable overexpression of BMCP1 were generated. Transfected cells had higher State 4 respiration and lower mitochondrial membrane potential (psi(m)), consistent with greater mitochondrial uncoupling. BMCP1 expression also decreased mitochondrial production of ROS. These data suggest that BMCP1 can modify mitochondrial respiratory efficiency and mitochondrial oxidant production, and raise the possibility that BMCP1 might alter the vulnerability of brain to both acute injury and to neurodegenerative conditions.
Article
Experimental traumatic brain injury (TBI) results in a rapid and significant necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the primary damage resulting in significant neurological dysfunction. The identification of cell death pathways that mediate this secondary traumatic injury have not been elucidated, however recent studies have implicated a role for apoptosis in the neuropathology of traumatic brain injury. The present study utilized a controlled cortical impact model of brain injury to assess the involvement of apoptotic pathways: release of cytochrome c from mitochondria and the activation of caspase-1- and caspase-3-like proteases in the injured cortex at 6, 12 and 24 h post-injury. Collectively, these results demonstrate cytochrome c release from mitochondria and its redistribution into the cytosol occurs in a time-dependent manner following TBI. The release of cytochrome c is accompanied by a time-dependent increase in caspase-3-like protease activity with no apparent increase in caspase-1-like activity. However, pretreatment with a general caspase inhibitor had no significant effect on the amount of cortical damage observed at 7 days post-injury. Our data suggest that several pro-apoptotic events occur following TBI, however the translocation of cytochrome c itself and/or other events upstream of caspase activation/inhibition may be sufficient to induce neuronal cell death.
Article
This study was designed to evaluate the antiapoptotic effects of a ketogenic diet (KD) through histological (cresyl violet staining, TUNEL staining and immunohistochemistry) and behavioral studies using kainic acid (KA, 25mg/kg i.p.)-induced seizures in male ICR mice. KA-induced seizure in rodents is widely used as an experimental model for human temporal lobe epilepsy because of their behavioral and pathological similarities. A KA-induced seizure causes neuronal damage in hippocampal pyramidal neurons and involves a caspase-3-mediated apoptotic pathway. In this study, the seizure onset time of the KD-fed group was delayed compared to that of the group fed a normal diet (ND) after a systemic KA injection. Histological studies revealed that KA caused pyknosis in most of the hippocampal areas in the ND-fed group, however, well-preserved pyramidal neurons were detected in the hippocampus of mice that had been on KD for 1 month, which began on postnatal day 21. The number of TUNEL-positive cells and caspase-3-positive cells in the hippocampus of the KD-fed group was lower than that of the ND-fed group. These findings indicate that KD has an antiepileptic effect via a neuroprotective action that involves the inhibition of caspase-3-mediated apoptosis of hippocampal neurons.
Article
The function of the nervous system relies upon synaptic transmission, a process in which a neurotransmitter released from pre-synaptic terminals of one neuron (in response to membrane depolarization and calcium influx) activates post-synaptic receptors on dendrites of another neuron. Synapses are subjected to repeated bouts of oxidative and metabolic stress as the result of changing ion gradients and ATP usage. Mitochondria play central roles in meeting the demands of synapses for ATP and in regulating calcium homeostasis, and mitochondrial dysfunction can cause dysfunction and degeneration of synapses, and can trigger cell death. We have identified two types of mitochondrial proteins that serve the function of protecting synapses and neurons against dysfunction and death. Mitochondrial ATP-sensitive potassium (MitoKATP) channels modulate inner membrane potential and oxyradical production; mitochondrial potassium fluxes can affect cytochrome c release and caspase activation and may determine whether neurons live or die in experimental models of stroke and Alzheimer's disease. Uncoupling proteins (UCPs) are a family of mitochondrial membrane proteins that uncouple electron transport from ATP production by transporting protons across the inner membrane. Neurons express at least three UCPs including the widely expressed UCP-2 and the neuron-specific UCP-4 and UCP-5 (BMCP-1). We have found that UCP-4 protects neurons against apoptosis by a mechanism involving suppression of oxyradical production and stabilization of cellular calcium homeostasis. The expression of UCP-4 is itself regulated by changes in energy metabolism. In addition to their roles in neuronal cell survival and death, MitoKATP channels and UCPs may play roles in regulating neuronal differentiation during development and synaptic plasticity in the adult.
Article
Excitotoxic cell death is the fundamental process responsible for many human neurodegenerative disorders, yet the basic mechanisms involved are not fully understood. Here, we exploited the fact that the immature brain is remarkably resistant to seizure-induced excitotoxic cell death and examined the underlying protective mechanisms. We found that, unlike in the adult, seizures do not increase the formation of reactive oxygen species or result in mitochondrial dysfunction in neonatal brain, because of high levels of the mitochondrial uncoupling protein (UCP2). UCP2 expression and function were basally increased in neonatal brain by the fat-rich diet of maternal milk, and substituting a low-fat diet reduced UCP2, restored mitochondrial coupling, and permitted seizure-induced neuronal injury. Thus, modulation of UCP2 expression and function by dietary fat protects neonatal neurons from excitotoxicity by preventing mitochondrial dysfunction. This mechanism offers novel neuroprotective strategies for individuals, greater than 1% of the world's population, who are affected by seizures.
Article
Uncoupling proteins (UCPs) are localized in the inner membrane of the mitochondria in diverse tissues and decrease mitochondrial membrane potential. The first of these proteins, UCP1, was discovered in brown adipose tissue, where it has a well-described role in thermogenesis. The functional significance of other UCPs, including UCP2, is less well understood. Here we summarize the recent advancements on the role of UCP2 in the brain and portray this uncoupler as an important player in normal neuronal function as well as a key cell death-suppressing device. These previously unknown functions of UCPs offer new avenues not only for the better understanding of these proteins but also for the furthering of our knowledge on the central nervous system in healthy and disease states.
Mitochondrial un-coupling protein-2 protects the immature brain from excito-toxic neuronal death
  • Pg Sullivan
  • Dorenbos C K Dube
Sullivan PG, Dube C, Dorenbos K, et al. Mitochondrial un-coupling protein-2 protects the immature brain from excito-toxic neuronal death. Ann Neurol 2003;53:711–717.
An animal model for the ketogenic diet: electroconvulsive threshold and biochemical alterations consequent upon a high-fat diet
  • Appleton Db
  • Devivo
  • Dc
Appleton DB, DeVivo DC. An animal model for the ketogenic diet: electroconvulsive threshold and biochemical alterations consequent upon a high-fat diet. Epilepsia 1974;15:211–217.
Age-dependent differ-ences in flurothyl seizure sensitivity in mice treated with a ke-togenic diet
  • Rho Jm
  • Robbins Ca
Rho JM, Kim DW, Robbins CA, et al. Age-dependent differ-ences in flurothyl seizure sensitivity in mice treated with a ke-togenic diet. Epilepsy Res 1999;37:233–240.
Accepted for publication Current address for Dr McConville: Department of Neurology, Royal Victoria Hospitals Trust, Grosvenor Road
  • Detection
  • Neurology
  • General Southern
  • Hospital
  • Glasgow
  • Scotland
  • United
  • Kingdom
Detection and Neurology, Southern General Hospital, Glasgow, Scotland, United Kingdom. Received Sep 25, 2003, and in revised form Jan 13, 2004. Accepted for publication Jan 13, 2004. Current address for Dr McConville: Department of Neurology, Royal Victoria Hospitals Trust, Grosvenor Road, Belfast BT12, Northern Ireland, United Kindgom. Published online Mar 22, 2004, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.20061 Address correspondence to Dr Vincent, Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospi-tal, Oxford OX3 9DS, United Kingdom. E-mail: angela.vincent@imm.ox.ac.uk
  • Sullivan