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Dominic P. D’agostino - One of the best experts on this subject based on the ideXlab platform.

  • Metabolic Therapy with Deanna Protocol Supplementation Delays Disease Progression and Extends Survival in Amyotrophic Lateral Sclerosis (ALS) Mouse Model
    2016
    Co-Authors: Csilla Ari, Angela M. Poff, Heather E. Held, Craig R. Goldhagen, Nicholas Mavromates, Carol S. L, Dominic P. D’agostino
    Abstract:

    Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a Metabolic Therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a Metabolic Therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5

  • Metabolic Therapy: a new paradigm for managing malignant brain cancer.
    Cancer Letters, 2015
    Co-Authors: Thomas N. Seyfried, Roberto Flores, Angela M. Poff, Dominic P. D’agostino, Purna Mukherjee
    Abstract:

    Little progress has been made in the long-term management of glioblastoma multiforme (GBM), considered among the most lethal of brain cancers. Cytotoxic chemoTherapy, steroids, and high-dose radiation are generally used as the standard of care for GBM. These procedures can create a tumor microenvironment rich in glucose and glutamine. Glucose and glutamine are suggested to facilitate tumor progression. Recent evidence suggests that many GBMs are infected with cytomegalovirus, which could further enhance glucose and glutamine metabolism in the tumor cells. Emerging evidence also suggests that neoplastic macrophages/microglia, arising through possible fusion hybridization, can comprise an invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells, as well as for the more rapidly proliferating cancer stem cells. Therapies that increase inflammation and energy metabolites in the GBM microenvironment can enhance tumor progression. In contrast to current GBM therapies, Metabolic Therapy is designed to target the Metabolic malady common to all tumor cells (aerobic fermentation), while enhancing the health and vitality of normal brain cells and the entire body. The calorie restricted ketogenic diet (KD-R) is an anti-angiogenic, anti-inflammatory and pro-apoptotic Metabolic Therapy that also reduces fermentable fuels in the tumor microenvironment. Metabolic Therapy, as an alternative to the standard of care, has the potential to improve outcome for patients with GBM and other malignant brain cancers.

  • Metabolic Therapy with Deanna Protocol Supplementation Delays Disease Progression and Extends Survival in Amyotrophic Lateral Sclerosis (ALS) Mouse Model
    2014
    Co-Authors: Csilla Ari, Angela M. Poff, Heather E. Held, Carol S. Landon, Craig R. Goldhagen, Nicholas Mavromates, Dominic P. D’agostino
    Abstract:

    Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a Metabolic Therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a Metabolic Therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with Metabolic Therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients.

Adrienne C Scheck - One of the best experts on this subject based on the ideXlab platform.

  • abstract 1440 Metabolic Therapy reduces expression of pecam 1 cd31 and decreases peritumoral edema in a mouse model of malignant glioma
    Cancer Research, 2014
    Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C Scheck
    Abstract:

    Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemoTherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the Metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by Metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival and potentiates standard Therapy in mouse models of malignant gliomas, yet the anti-tumor mechanisms are not fully understood. It has been previously shown that caloric restriction, which induces ketosis, reduces microvessel density in mouse and human brain tumor models, suggesting an anti-angiogenic effect. We now report that in animals fed KetoCal® (KC) (4:1 fat:protein/carbohydrates) ad libitum, peritumoral edema is significantly reduced early in tumor progression when compared to those fed a standard rodent diet (SD). Western blot analysis showed a reduction of platelet endothelial cell adhesion molecule 1 (PECAM1/CD31) in tumors from animals maintained on KC. These results were supported by immunohistochemical staining for CD31 which also revealed abnormal vessel structure in the tumors from animals fed SD but not in those fed KC, suggesting a normalizing effect by the KC. Furthermore gene expression profiling demonstrated that KC decreases expression of a group of genes involved in angiogenesis and vessel structuring including the genes encoding vascular endothelial growth factor B (VEGFB) and angiopoetin 1 receptor (TEK), integrin beta 1 (ITGB1), urokinase-type plasminogen activator (PLAU) and tissue inhibitor of metalloproteases 1 (TIMP1). Taken together our data suggests that KC alters the angiogenic processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant Therapy will allow for a more rational approach to its clinical use. Citation Format: Eric C. Woolf, Julie A. Charlton, Qingwei Liu, Gregory Turner, Mark C. Preul, Adrienne C. Scheck. Metabolic Therapy reduces expression of PECAM-1/CD31 and decreases peritumoral edema in a mouse model of malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1440. doi:10.1158/1538-7445.AM2014-1440

  • Metabolic Therapy reduces expression of pecam cd31 and decreases peritumoral edema in a mouse model of malignant glioma
    2012
    Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C Scheck
    Abstract:

    Brain tumors remain one of the most deadly malignant tumors, claiming an estimated 13,000 lives in the US every year. Despite neurosurgical advances and improvements in chemoTherapy and radioTherapy, median survival remains at ~12 months. The occurrence and severity of the disease has prompted the investigation of novel therapies that can be utilized as an adjuvant to current standards of care. Alteration of tumor metabolism is one such Therapy. The ketogenic diet (KD) is a therapeutic high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. While it is generally accepted that the KD provides a neuroprotective effect, the mechanisms are not fully understood. Our laboratory [2] and others [3] have shown that the KD causes an elevation in blood ketones and extends life in mouse models of brain tumor. Initial gene expression data from these experiments show that the KD alters the expression of genes involved in not only metabolism but other crucial processes involved in tumor progression, including inflammation. We also explored KetoCal® (KC) (Nutricia North America, Gaithersburg, MD, USA), a 4:1 (fat to protein + carbohydrate ratio) formula, which is already approved for human use in other disease states such as refractory epilepsy. In our mouse model of malignant glioma, KC when given in combination with radiation treatment, apparently cured the implanted tumor in 9 out of 11 mice [5]. These exciting results warrant a closer look at the mechanisms underlying the KD. One hallmark of many cancers including brain tumors is increased angiogenesis. The deregulated formation of these tumor blood vessels often renders them highly permeable which can lead to increased peritumoral edema, which increases the overall tumor burden on the brain and reduces the quality of life for patients. The current treatment for edema relies on corticosteroids which results in harsh side effects. Therefore a less toxic alternative Therapy is needed to mitigate peritumoral edema in brain tumor patients (6). Our data suggests that KC reduces peritumoral edema, reduces tumor angiogenesis and normalizes blood vessel formation. This data taken together with our previous work suggests that the ketogenic diet may not only enhance radiation Therapy but also target tumor angiogenesis and inflammation simultaneously. Further exploration of the KD could provide valuable insight into the anti-tumor mechanisms underlying Metabolic Therapy. This in turn could lead to ways to enhance current treatment while improving quality of life for patients.

  • Metabolic Therapy reduces expression of PECAM/CD31 and decreases peritumoral edema in a mouse model of malignant glioma
    2012
    Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C Scheck
    Abstract:

    Brain tumors remain one of the most deadly malignant tumors, claiming an estimated 13,000 lives in the US every year. Despite neurosurgical advances and improvements in chemoTherapy and radioTherapy, median survival remains at ~12 months. The occurrence and severity of the disease has prompted the investigation of novel therapies that can be utilized as an adjuvant to current standards of care. Alteration of tumor metabolism is one such Therapy. The ketogenic diet (KD) is a therapeutic high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. While it is generally accepted that the KD provides a neuroprotective effect, the mechanisms are not fully understood. Our laboratory [2] and others [3] have shown that the KD causes an elevation in blood ketones and extends life in mouse models of brain tumor. Initial gene expression data from these experiments show that the KD alters the expression of genes involved in not only metabolism but other crucial processes involved in tumor progression, including inflammation. We also explored KetoCal® (KC) (Nutricia North America, Gaithersburg, MD, USA), a 4:1 (fat to protein + carbohydrate ratio) formula, which is already approved for human use in other disease states such as refractory epilepsy. In our mouse model of malignant glioma, KC when given in combination with radiation treatment, apparently cured the implanted tumor in 9 out of 11 mice [5]. These exciting results warrant a closer look at the mechanisms underlying the KD. One hallmark of many cancers including brain tumors is increased angiogenesis. The deregulated formation of these tumor blood vessels often renders them highly permeable which can lead to increased peritumoral edema, which increases the overall tumor burden on the brain and reduces the quality of life for patients. The current treatment for edema relies on corticosteroids which results in harsh side effects. Therefore a less toxic alternative Therapy is needed to mitigate peritumoral edema in brain tumor patients (6). Our data suggests that KC reduces peritumoral edema, reduces tumor angiogenesis and normalizes blood vessel formation. This data taken together with our previous work suggests that the ketogenic diet may not only enhance radiation Therapy but also target tumor angiogenesis and inflammation simultaneously. Further exploration of the KD could provide valuable insight into the anti-tumor mechanisms underlying Metabolic Therapy. This in turn could lead to ways to enhance current treatment while improving quality of life for patients.

William C. Stanley - One of the best experts on this subject based on the ideXlab platform.

  • Metabolic Therapy for Heart Disease: Impact of Trimetazidine
    Heart failure reviews, 2005
    Co-Authors: Hani N. Sabbah, William C. Stanley
    Abstract:

    Coronary artery disease remains the major contributor to the development of heart failure. Despite the massive efforts targeted toward preventative Therapy and life style changes, the incidence of coronary artery disease continues to be high, shows little or no signs of abatement, and remains the leading health economic burden in developed countries and, for that matter, worldwide. There is no doubt that the aggressive use of thrombolytic Therapy and primary coronary angioplasty has had a major impact on limiting the sequelae of acute myocardial infarction. There is also little doubt that routine coronary revascularization through coronary artery bypass surgery or coronary angioplasty with attendant coronary stent deployment has had a positive impact, albeit transient, on limiting symptoms of coronary artery disease. Despite all of these successes of the twentieth century, however, chronic stable angina pectoris remains a major clinical problem that must be dealt with by cardiologists, internists and primary care physicians alike as we move into the next millenium. Many of the patients that present with stable angina pectoris are not candidates for further revascularization, or, in this the age of rationed health care, even if eligible, must “stand in line” to have the procedure performed. Needless to say that most, if not all, of these patients are candidates for the development of congestive heart failure (CHF), truly the disease of the next millenium. The myocardium depends on oxygen to support high energy phosphate production by oxidative phosphorylation. The latter is the only Metabolic process that can generate sufficient chemical energy to fuel the continuous needs of the contractile machinery of the heart. Accordingly, when the amount of oxygen delivered to the myocardium is insufficient to meet the requirements for mitochondrial respiration, the production of high energy phosphates falls and lactate, the end product of anaerobic glycolysis, starts to accumulate. The interruption of oxygen supply to the myocardium or ischemia, regardless of etiology, leads to the clinical symptom of angina pectoris. Ischemia can be defined as an imbalance between the supply of oxygenated blood to the myocardium and the oxygen requirements of the myocardium. When the supply of oxygen cannot meet the demands, as is the case when coronary artery disease is present, contractile function diminishes along with clinical manifestation of anginal pain. The latter the result of stimulation of cardiac sensory afferent nerve fibers by “noxious stimuli” produced in the myocardium. The cardiac sensory afferents nerves are stimulated by a rise in interstitial adenosine and K+, both of which increase when oxygen delivery and aerobic ATP synthesis are reduced [1]. Electrocardiographically, ischemia is reflected through ST-segment elevation or depression on the electrocardiogram with the latter believed to reflect delayed repolarization in the ischemic zone, and has recently been attributed to KATP channels [2], which presumably open in response to the fall in ATP. Taken together, both angina and ST-segment changes during ischemia are arguably the result of a failure to regenerate ATP, and as such, are of Metabolic origin.

  • Metabolic Therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine.
    Fundamental & clinical pharmacology, 2003
    Co-Authors: William C. Stanley, Mario Marzilli
    Abstract:

    The primary result of myocardial ischaemia is reduced oxygen consumption and adenosine triphosphate (ATP) formation in the mitochondria, and accelerated anaerobic glycolysis, lactate accumulation and cell acidosis. Classic pharmacoTherapy for demand-induced ischaemia is aimed at restoring the balance between ATP synthesis and breakdown by increasing the oxygen delivery (i.e. with long acting nitrates or Ca2+ channel antagonist) or by decreasing cardiac power by reducing blood pressure and heart rate (i.e. with beta-blocker or Ca2+ channel antagonist). Animal studies show that fatty acids are the primary mitochondrial substrate during moderate severity myocardial ischaemia, and that they inhibit the oxidation of carbohydrate and drive the conversion of pyruvate to lactate. Drugs that partially inhibit myocardial fatty acid oxidation increase carbohydrate oxidation, which results in reduced lactate production and a higher cell pH during ischaemia. Trimetazidine (1-[2,3,4-trimethoxibenzyl]-piperazine) is the first and only registered drug in this class, and is available in over 90 countries world-wide. Trimetazidine selectively inhibits the fatty acid beta-oxidation enzyme 3-keto-acyl-CoA dehydrogenase (3-KAT), and is devoid of any direct haemodynamic effects. In double-blind placebo-controlled trials trimetazidine significantly improved symptom-limited exercise performance in stable angina patients when used either as monoTherapy or in combination with beta-blockers or Ca2+ channel antagonists. Given available evidence, trimetazidine is an excellent alternative to classic haemodynamic agents, and is unique in its ability to reduce symptoms of angina when used in patients resistant to a haemodynamic treatment as vasodilators, beta-blockers or Ca2+ channel antagonists.

Thomas N. Seyfried - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Ketogenic Metabolic Therapy on patients with breast cancer: A randomized controlled clinical trial
    Clinical nutrition (Edinburgh Scotland), 2020
    Co-Authors: Adeleh Khodabakhshi, Thomas N. Seyfried, Miriam Kalamian, Mohammad Esmaeil Akbari, Hamid Reza Mirzaei, Sayed Hossein Davoodi
    Abstract:

    Summary Background Ketogenic Metabolic Therapy (KMT) using ketogenic diets (KD) is emerging as viable alternative or complementary strategy for managing cancer; however, few clinical trials have been reported. The present study aimed to evaluate the effects of a KD in patients with locally advanced and metastatic breast cancer receiving chemoTherapy. Methods A total of 80 patients undergoing treatment with chemoTherapy were randomly assigned to KD or control group for 12 weeks. Concurrent with the admission, midway point, and at 12 weeks, fasting blood samples were collected for evaluation of insulin, IGF-1, CEA, CA15-3, ESR, CRP, IL-10, and TNF-α. Sonography for patients with locally advanced disease and CT or MRI scans for patients with metastatic disease were done on admission and at 12 weeks. At the completion of the chemoTherapy, patients with locally advanced disease underwent surgery and stage was recalculated. Also patients with metastases were evaluated for response rate. Results TNF-α decreased significantly after 12 weeks of treatment (MD: 0.64 [CI 95%: −3.7, 5] P  Conclusions KMT in breast cancer patients might exert beneficial effects through decreasing TNF-α and insulin and increasing IL-10. KD may result in a better response through reductions in tumor size and downstaging in patients with locally advanced disease; however, more studies are needed to elucidate the potential beneficial effects of KD in patients with metastases. Trial registration This trial has been registered on Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT20171105037259N2. https://www.irct.ir/trial/30755 .

  • Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer.
    Frontiers in nutrition, 2020
    Co-Authors: Thomas N. Seyfried, Purna Mukherjee, Miriam Kalamian, Mehmet Salih Iyikesici, Abdul Kadir Slocum, Jean-pierre Spinosa, Christos Chinopoulos
    Abstract:

    Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial Metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie Therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic Metabolic Therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable Metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.

  • Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?
    Neurochemical research, 2019
    Co-Authors: Thomas N. Seyfried, Joseph C. Maroon, Laura M. Shelton, Gabriel Arismendi-morillo, Miriam Kalamian, Ahmed M A Elsakka, Purna Mukherjee
    Abstract:

    No major advances have been made in improving overall survival for glioblastoma (GBM) in almost 100 years. The current standard of care (SOC) for GBM involves immediate surgical resection followed by radioTherapy with concomitant temozolomide chemoTherapy. Corticosteroid (dexamethasone) is often prescribed to GBM patients to reduce tumor edema and inflammation. The SOC disrupts the glutamate–glutamine cycle thus increasing availability of glucose and glutamine in the tumor microenvironment. Glucose and glutamine are the prime fermentable fuels that underlie Therapy resistance and drive GBM growth through substrate level phosphorylation in the cytoplasm and the mitochondria, respectively. Emerging evidence indicates that ketogenic Metabolic Therapy (KMT) can reduce glucose availability while elevating ketone bodies that are neuroprotective and non-fermentable. Information is presented from preclinical and case report studies showing how KMT could target tumor cells without causing neurochemical damage thus improving progression free and overall survival for patients with GBM.

  • Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up
    Frontiers in nutrition, 2018
    Co-Authors: Ahmed M A Elsakka, Purna Mukherjee, Miriam Kalamian, Mohamed Abdel Bary, Eman Abdelzaher, Mostafa Elnaggar, Thomas N. Seyfried
    Abstract:

    Abstract Few advances have been made in overall survival for glioblastoma multiforme (GBM) in more than 40 years. Here we report the case of a 38-year-old man who presented with chronic headache, nausea, and vomiting accompanied by left partial motor seizures and upper left limb weakness. Enhanced brain MRI revealed a solid cystic lesion in the right partial space suggesting GBM. Serum testing revealed vitamin D deficiency, and elevated levels of insulin and triglycerides. Prior to sub-total tumor resection and standard of care (SOC), the patient conducted a 72-hr water-only fast. Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day. In addition to radioTherapy, temozolomide chemoTherapy, and the KD (increased to 1500 kcal/day at day 22), the patient received metformin (1000 mg/day), methylfolate (1000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (EGCG, 400 mg/day), and hyperbaric oxygen Therapy (HBOT) (60 min/session, 5 sessions/wk at 2.5 ATA). The patient also received levetiracetam (1500 mg/day). No steroid medication was given at any time. Post-surgical histology confirmed the diagnosis of GBM. Reduced invasion of tumor cells and thick-walled hyalinized blood vessels were also seen suggesting a therapeutic benefit of pre-surgical Metabolic Therapy. After nine months treatment with the modified SOC and complimentary ketogenic Metabolic Therapy (KMT), the patient’s body weight was reduced by about 19%. Seizures and left limb weakness resolved. Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced Metabolic activity (choline/NAA ratio) and normalized levels of insulin, triglycerides, and vitamin D. This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted Metabolic therapies. As rapid regression of GBM is rare following sub-total resection and SOC alone, it is possible that the response observed in this case resulted in part from the modified SOC and other novel treatments. Additional studies are needed to validate the efficacy of KMT administered with alternative approaches that selectively increase oxidative stress in tumor cells while restricting their access to glucose and glutamine. The patient remains in excellent health (Karnofsky Score,

  • The role of Metabolic Therapy in treating glioblastoma multiforme
    Surgical neurology international, 2015
    Co-Authors: Joseph C. Maroon, Thomas N. Seyfried, Joseph P. Donohue, Jeffrey Bost
    Abstract:

    Glioblastoma multiforme (GBM) is an aggressive and nearly uniformly fatal malignancy of the central nervous system. Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter its lethal prognosis. The current standard of care (SOC) includes maximal surgical resection, radiation Therapy and chemoTherapy and temozolomide (TMZ), including the selective use of glucocorticoids for symptom control. These same treatments, however, have the potential to create an environment that may actually facilitate tumor growth and survival. Research investigating the unique Metabolic needs of tumor cells has led to the proposal of a new Metabolic treatment for various cancers including GBMs that may enhance the effectiveness of the SOC. The goal of Metabolic cancer Therapy is to restrict GBM cells of glucose, their main energy substrate. By recognizing the underlying energy production requirements of cancer cells, newly proposed Metabolic Therapy is being used as an adjunct to standard GBM therapies. This review will discuss the calorie restricted ketogenic diet (CR-KD) as a promising potential adjunctive Metabolic Therapy for patients with GBMs. The effectiveness of the CR-KD is based on the “Warburg Effect” of cancer metabolism and the microenvironment of GBM tumors. We will review recent case reports, clinical studies, review articles, and animal model research using the CR-KD and explain the principles of the Warburg Effect as it relates to CR-KD and GBMs.

Susan A. Masino - One of the best experts on this subject based on the ideXlab platform.

  • Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?
    Frontiers in molecular neuroscience, 2017
    Co-Authors: Marwa Elamin, David N. Ruskin, Susan A. Masino, Paola Sacchetti
    Abstract:

    The ketogenic diet’s anticonvulsant effects have been well-documented for nearly a century, including in randomized controlled trials. Some patients become seizure-free and some remain so after diet cessation. Many recent studies have explored its expanded therapeutic potential in diverse neurological disorders, yet no mechanism(s) of action have been established. The diet’s high fat, low carbohydrate composition promotes ketone bodies as an energy source and improves mitochondrial function and biogenesis. Cellular energy production depends on the Metabolic coenzyme nicotinamide adenine dinucleotide (NAD), a marker for mitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes) associated with major benefits such as longevity and reduced inflammation; thus, increasing NAD is a coveted therapeutic endpoint. Based on differential NAD+ utilization during glucose- versus ketone body-based acetyl-CoA generation for entry into the tricarboxylic cycle, we propose that a ketogenic diet will increase the NAD+/NADH ratio. When rats were fed ad libitum ketogenic diet significant increases in hippocampal NAD+/NADH ratio and blood ketone bodies were detected already at two days and remained elevated at three weeks, indicating an early and persistent Metabolic shift. Based on diverse published literature and these initial data we suggest that increased NAD during ketolytic metabolism may be a primary mechanism behind the beneficial effects of this Metabolic Therapy in a variety of brain disorders and in promoting health and longevity.

  • Metabolic Therapy for temporal lobe epilepsy in a dish: investigating mechanisms of ketogenic diet using electrophysiological recordings in hippocampal slices
    Frontiers Media S.A., 2016
    Co-Authors: Masahito Kawamura, David Ruskin, Susan A. Masino
    Abstract:

    The hippocampus is prone to epileptic seizures and is a key brain region and experimental platform for investigating mechanisms associated with the abnormal neuronal excitability that characterizes a seizure. Accordingly, the hippocampal slice is a common in vitro model to study treatments that may prevent or reduce seizure activity. The ketogenic diet is a Metabolic Therapy used to treat epilepsy in adults and children for nearly 100 years; it can reduce or eliminate even severe or refractory seizures. New insights into its underlying mechanisms have been revealed by diverse types of electrophysiological recordings in hippocampal slices. Here we review these reports and their relevant mechanistic findings. We acknowledge that a major difficulty in using hippocampal slices is the inability to reproduce precisely the in vivo condition of ketogenic diet feeding in any in vitro preparation, and progress has been made in this in vivo/in vitro transition. Thus far at least three different approaches are reported to reproduce relevant diet effects in the hippocampal slices: (1) direct application of ketone bodies, (2) mimicking the ketogenic diet condition during a whole-cell patch-clamp technique, and (3) reduced glucose incubation of hippocampal slices from ketogenic diet–fed animals. Significant results have been found with each of these methods and provide options for further study into short- and long-term mechanisms including ATP-sensitive potassium channels, vesicular glutamate transporter, pannexin channels and adenosine receptors underlying ketogenic diet and other forms of Metabolic Therapy

  • Metabolic Therapy for Autism Spectrum Disorder and Comorbidities
    Oxford Medicine Online, 2016
    Co-Authors: Ning Cheng, Susan A. Masino, Jong M. Rho
    Abstract:

    Autism spectrum disorder (ASD) is a heretogenous developmental disorder characterized by deficits in sociability and communication and by repetitive and/or restrictive behaviors. Currently, only comorbid manifestations can be alleviated (such as seizures and sleep disturbance) not core behavioral symptoms. Recent studies have increasingly implicated mitochondrial dysfunction as a cause of ASD. Mitochondria play an integral role in many cellular functions and are susceptible to many pathophysiological insults. Derangements in mitochondrial structure and function provide a scientific rationale for experimental therapeutics. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD) has been shown to enhance mitochondrial function through a multiplicity of mechanisms. Reviewed herein is clinical and basic laboratory evidence for the use of metabolism-based therapies such as the KD in the treatment of ASD, as well as emerging comorbid models of epilepsy and autism. Future research directions aimed at validating such therapeutic approaches and identifying novel mechanistic targets are discussed.

  • Purines and neuronal excitability: Links to the ketogenic diet
    Epilepsy Research, 2011
    Co-Authors: Susan A. Masino, Masahito Kawamura, David N. Ruskin, Jonathan D Geiger, Detlev Boison
    Abstract:

    ATP and adenosine are purines that play dual roles in cell metabolism and neuronal signaling. Acting at the A1 receptor (A1R) subtype, adenosine acts directly on neurons to inhibit excitability and is a powerful endogenous neuroprotective and anticonvulsant molecule. Previous research showed an increase in ATP and other cell energy parameters when an animal is administered a ketogenic diet, an established Metabolic Therapy to reduce epileptic seizures, but the relationship among purines, neuronal excitability and the ketogenic diet was unclear. Recent work in vivo and in vitro tested the specific hypothesis that adenosine acting at A1Rs is a key mechanism underlying the success of ketogenic diet Therapy and yielded direct evidence linking A1Rs to the antiepileptic effects of a ketogenic diet. Specifically, an in vitro mimic of a ketogenic diet revealed an A1R-dependent Metabolic autocrine hyperpolarization of hippocampal neurons. In parallel, applying the ketogenic diet in vivo to transgenic mouse models with spontaneous electrographic seizures revealed that intact A1Rs are necessary for the seizure-suppressing effects of the diet. This is the first direct in vivo evidence linking A1Rs to the antiepileptic effects of a ketogenic diet. Other predictions of the relationship between purines and the ketogenic diet are discussed. Taken together, recent research on the role of purines may offer new opportunities for Metabolic Therapy and insight into its underlying mechanisms.