Ketogenic Diet Prevents Seizures By Enhancing Brain Energy Production, Increasing Neuron Stability

przedruk z:
http://www.sciencedaily.com/releases/20 … 220938.htm

Date:      November 15, 2005

Science Daily — Although the high-fat, calorie-restricted ketogenic diet (KD) has long been used to prevent childhood epileptic seizures that are unresponsive to drugs, physicians have not really understood exactly why the diet works. New studies by a research team at Emory University School of Medicine show that the diet alters genes involved in energy metabolism in the brain, which in turn helps stabilize the function of neurons exposed to the challenges of epileptic seizures. This knowledge could help scientists identify specific molecular or genetic targets and lead to more effective drug treatments for epilepsy and brain damage.


The research will be presented at the annual meeting of the Society for Neuroscience in Washington, D.C. by Kristopher Bough, PhD, a postdoctoral student in the laboratory of Emory pharmacology professor Raymond Dingledine, PhD.

"These findings support our hypothesis that a dietary regimen can dramatically affect the expression of genes and the function of neurons within the brain, which enhances the ability of these neurons to withstand the metabolic challenges of epileptic seizures," Dr. Dingledine said.

The ketogenic diet causes molecules called ketone bodies to be produced as fat is broken down. Scientists have understood that these molecules somehow cause a change in metabolism leading to a potent anticonvulsant effect. According to some animal studies they also may limit the progression of epilepsy.

The Emory research team studied the link between diet and epileptic seizures on the behavioral, cellular and genetic level. They found, as had others, that in rats fed the KD the resistance to seizures develops slowly, over one to two weeks, in contrast to rats treated with conventional anticonvulsant drugs. On the cellular level, they found that the anticonvulsant effect of the ketogenic diet did not correlate with a rise in plasma ketone levels or with a decrease in plasma glucose. Because longer treatment with the KD was necessary to increase the resistance to seizures, they concluded that changes in gene expression might hold the key to the diet's anticonvulsant effects.

To identify which genes might be involved, the researchers used microarray "gene chips" to examine changes in gene expression for more than 7,000 rat genes simultaneously. They focused on the hippocampus, a region of the brain known to play an important role in many kinds of epilepsies. More than 500 of the genes they examined were correlated with treatment with the KD. The most striking finding was the coordinated up-regulation of genes involved in energy metabolism.

To explain this genetic effect, the scientists first eliminated the possibility that the KD diet might cause enhanced production of GABA, a chemical messenger in the brain that helps limit seizure activity. They found that GABA levels in the hippocampus were unchanged with the KD.

To test whether energy reserves in hippocampal neurons were enhanced with the KD, they counted the number of energy "factories," or mitochondria, within cells using electron microscopy. They found that KD treatment significantly increased the number of mitochondria per unit area in the hippocampus. This finding, along with the concerted increase in the expression of genes encoding energy metabolic enzymes, led them to conclude that KD treatment enhances energy production in the hippocampus and may lead to improved neuronal stability.

Finally, the researchers tested whether brain tissue affected by the KD would be more resistant to low levels of glucose (an effect of seizures) because of their enhanced energy reserves. They found that synaptic communication in KD-fed rats was more resistant to low glucose levels than in control animals fed a regular diet.

The researchers believe their new knowledge could lead to the development of more effective drug treatments for epilepsy and brain damage.

And because the diet enhances the brain's ability to withstand metabolic challenges, they also believe the ketogenic diet should be studied as a possible treatment for other neurodegenerative disorders such as Alzheimer's or Parkinson's diseases.

Note: This story has been adapted from material provided by Emory University Health Sciences Center.


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Ketogenesis, Ketogenic Diet, And Prostate Cancer Progression

przedruk z:
http://www.cancerportfolio.org/abstract … tID=116197

Principal Investigator:     Freedland, Stephen
Institution Receiving Award:     Duke University Medical Center
Location:     Durham, NC US

Award Code:     PC050785
Funding Organization:     U. S. Department of Defense, CDMRP
Award Funding Period:     11-15-05 to 12-14-07
Funding Mechanism:     New Investigator Award

Background: New prostate cancer (CaP) treatments are desperately needed. However, to better treat CaP, we need a better understudying of the cause of CaP. Epidemiological data suggests that obese men are at increased risk for CaP death. To understand the molecular mechanisms underlying this apparent increased risk of aggressive CaP among obese men, we compared gene expression profiles using cDNA microarrays of CaPs from obese versus normal weight men. We identified that mitochondrial 3-hydroxymethyl glutaryl coA synthase (HMGCS2), the rate limiting enzyme in ketogenesis, was the most differentially expressed gene (fourfold lower in CaPs from obese men). Subsequently, we also found that HMGCS2 was decreased in high-grade CaP, suggesting that HMGCS2 may be a marker of aggressive CaP. We hypothesized that down-regulation of HMGCS2 and ketogenesis may provide a selective growth advantage for CaP. Viewed alternatively, ketone bodies (KBs) may be directly toxic to CaP cells. To test this, we treated 4 CaP cell lines with varying doses of the KB, beta-hydroxybutyrate (BHB). Physiological doses of BHB reduced cell growth by 10%-25% in all cell lines. Transfection of CaP cell lines with wild-type HMGCS2 resulted in 40%-60% reduced growth relative to transfection with a mutated and inactive HMGCS2. These data suggest that methods that upregulation of HMGCS2 activity and ketogenesis may delay tumor growth. Fortunately, two dietary interventions, fasting and a ketogenic diet (KD, i.e. Atkins) are known to upregulate ketogenesis.

Hypothesis: We hypothesize that novel approaches to increase ketogenesis and HMGCS2 activity may slow CaP growth. Specifically, we hypothesize that a KD with or without intermittent fasting (both methods to increase ketogenesis) will upregulate HMGCS2 activity in the prostate and slow tumor growth. We propose to study this in a mouse xenograft model by feeding the mice various diets (low-fat, KD, etc.) and examining the effect on prostatic HMGCS2 activity and xenograft tumor growth.

Specific Aims: (1) To examine the effect of a KD and fasting on prostatic HMGCS2 activity. (2) To examine the therapeutic potential of dietary factors, specifically altering ketogenesis via KD and/or fasting, on CaP growth.

Study Design: The first step is to ascertain to what degree a KD and fasting can induce prostatic HMGCS2 activity. To accomplish this, we will randomize 18 severe combined immunodeficient (SCID) mice to either an ad-lib KD, hi-fat non-ketogenic diet (HF), or a low-fat diet (LF). After two weeks, one-half of the mice in each group will be sacrificed for measurement of HMGCS2 expression in the liver and prostate. The remaining 9 mice (3/group) will be fed in a modified pair-feeding protocol and two weeks thereafter. All remaining mice will be sacrificed for assays of liver and prostate HMGCS2 expression. Additionally, a time course will be carried out to assess how quickly prostatic HMGCS2 is upregulated upon fasting and to determine how quickly prostatic HMGCS2 is downregulated following refeeding after a 12, 24, and 36 hour fast. Following this, a similar experiment will be performed as described above comparing KD, KD plus fasting versus a standard mouse diet with fasting for its affect on prostatic HMGCS2 activity. The length of fasting will be determined from the earlier experiment on the time course and will be the shortest time possible that optimizes HMGCS2 induction, but will not exceed 36 hours once per week.

To assess whether a KD can delay tumor growth, SCID mice will be randomized to a KD, HF, or LF. Based upon power calculations for an expected 35% growth delay in the KD fed mice, we require 25 mice/diet. After 2 weeks, mice will be injected subcutaneously with human CaP cells (LAPC-4). Tumor growth will be monitored and the mice followed until sacrifice. Serum will be collected for BHB assays, prostate and liver harvested for HMGCS2 expression, and tumor harvested for cDNA microarray analysis. Three additional mice/diet will be sacrificed when tumor volumes are between 0.1 to 0.2 cc and tumors harvested for cDNA microarray analysis. Finally, we will compare a KD diet with or without fasting versus a standard mouse diet with fasting using a modified paired feeding protocol to determine whether this results in greater tumor delay than a KD alone. The protocol for monitoring the mice and tissue/serum collection and analysis will be identical to that outlined above for the other diets.

Relevance: The role of dietary fat in CaP has been actively investigated for many years. However, little is known about the role of KBs in CaP. Therefore, one major advance, which would stem from these studies, would be a better understanding of the role of KB and ketogenesis in CaP. Specifically, the gene expression data will allow us to determine which genes may be responsible for the growth inhibiting effects of a KD. If particular genes can be identified that are associated with the benefits of the KD then specific therapies can be targeted to these genes, which when combined with dietary changes, may delay progression more than either treatment alone. In addition, treatments which slow tumor growth, though not curative, may be sufficient to prevent many premature CaP related deaths given the long natural history of CaP and the fact that most men with CaP are older. Given that KDs are used routinely to treat epilepsy and have a long history of safety, we believe it is clinically feasible for a CaP patient to maintain a KD for many years. Therefore, if a benefit is seen in terms of delaying tumor growth in these preclinical studies, we foresee beginning Phase I clinical trials in the near future.

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Brain Cancer
Seyfried Laboratory

przedruk z:

http://www2.bc.edu/~seyfridt/braincancer.html

Alternative therapies are needed that can better manage brain tumors while permitting a decent quality of life. Surgical resection followed by radiation is the standard therapy for malignant gliomas today as it has been for over five decades. Chemotherapy has had little positive benefit on malignant glioma management and is often associated with adverse effects that diminish quality of life. It is also unlikely that therapeutic targeting of tumor-associated mutations will be effective in brain tumor management, as most tumor mutations arise as epiphenomena of tissue disorganization and their involvement with tumor initiation, promotion, or progression has not been conclusively established. We recently found that caloric restriction, a simple therapy that lowers glucose and elevates blood ketone levels, has powerful anti-angiogenic and pro-apoptotic effects on experimental mouse and human brain tumors. We are now defining the molecular mechanisms by which dietary caloric restriction can manage brain cancer. These studies will have direct translational benefit to the clinic.

Diet Therapy for Brain Cancer

We are studying the effect of dietary caloric restriction (DR) and the low carbohydrate, high fat, ketogenic diet on brain tumor growth, angiogenesis, and apoptosis. DR is produced from a total restriction of dietary nutrients and differs from starvation in that it reduces total caloric energy intake without causing anorexia or malnutrition. The KD, in addition to managing refractory pediatric epilepsy, is also the only known diet therapy effective against pediatric astrocytoma. It is recognized that the anti-tumor effects of DR result from caloric restriction per se and not from the restriction of any specific dietary component such as proteins, vitamins, minerals, fats, or carbohydrates. Besides inhibiting tumor growth, DR also produces a marked increase in general health. DR has documented beneficial effects on numerous diseases including cancer, but its mechanism of action is unknown.
Recently, we showed that DR has significant pro-apoptotic and anti-angiogenic effects on the inhibition of experimental brain tumor growth. Angiogenesis involves neovascularization or the formation of new capillaries from existing blood vessels and is associated with the processes of tissue inflammation, wound healing, and tumorigenesis. Apoptosis involves cell suicide in response to environmental stress. Both the ketogenic diet and DR may manage brain cancer by stressing the metabolic weakness of the tumor cells that are dependent almost exclusively on glucose for energy.

Gangliosides and Brain Cancer

We are also studying the role of gangliosides in brain tumor growth, angiogenesis, and metastasis. Gangliosides are complex glycolipids enriched on the outer surface of virtually all mammalian cells. Gangliosides may influence tumor growth and progression through modulation of adhesion, migration, and angiogenesis. We are interested in the effect of gene-linked alterations of ganglioside biosynthesis on brain tumor angiogenesis and invasion.


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The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer

Przedruk:
http://www.nutritionandmetabolism.com/content/4/1/5

Abstract
Background

Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal®, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG).
Methods

Adult mice were implanted orthotopically with the malignant brain tumors and KetoCal® was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal® on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet.
Results

KetoCal® administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal® diet reduced plasma glucose levels while elevating plasma ketone body (β-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal® groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, β-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy.
Conclusion

The results indicate that KetoCal® has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal® for brain cancer management was due largely to the reduction of total caloric content, which reduces circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet. Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal® is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.
pelny free art:
http://www.nutritionandmetabolism.com/content/4/1/5