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      The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders

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          Abstract

          Dietary and metabolic therapies have been attempted in a wide variety of neurological diseases, including epilepsy, headache, neurotrauma, Alzheimer disease, Parkinson disease, sleep disorders, brain cancer, autism, pain, and multiple sclerosis. The impetus for using various diets to treat – or at least ameliorate symptoms of – these disorders stems from both a lack of effectiveness of pharmacological therapies, and also the intrinsic appeal of implementing a more “natural” treatment. The enormous spectrum of pathophysiological mechanisms underlying the aforementioned diseases would suggest a degree of complexity that cannot be impacted universally by any single dietary treatment. Yet, it is conceivable that alterations in certain dietary constituents could affect the course and impact the outcome of these brain disorders. Further, it is possible that a final common neurometabolic pathway might be influenced by a variety of dietary interventions. The most notable example of a dietary treatment with proven efficacy against a neurological condition is the high-fat, low-carbohydrate ketogenic diet (KD) used in patients with medically intractable epilepsy. While the mechanisms through which the KD works remain unclear, there is now compelling evidence that its efficacy is likely related to the normalization of aberrant energy metabolism. The concept that many neurological conditions are linked pathophysiologically to energy dysregulation could well provide a common research and experimental therapeutics platform, from which the course of several neurological diseases could be favorably influenced by dietary means. Here we provide an overview of studies using the KD in a wide panoply of neurologic disorders in which neuroprotection is an essential component.

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          Most cited references72

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          Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease.

          Alzheimer's disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn. We showed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded whole-cell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit.
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            Mitochondrial energetics and therapeutics.

            Mitochondrial dysfunction has been linked to a wide range of degenerative and metabolic diseases, cancer, and aging. All these clinical manifestations arise from the central role of bioenergetics in cell biology. Although genetic therapies are maturing as the rules of bioenergetic genetics are clarified, metabolic therapies have been ineffectual. This failure results from our limited appreciation of the role of bioenergetics as the interface between the environment and the cell. A systems approach, which, ironically, was first successfully applied over 80 years ago with the introduction of the ketogenic diet, is required. Analysis of the many ways that a shift from carbohydrate glycolytic metabolism to fatty acid and ketone oxidative metabolism may modulate metabolism, signal transduction pathways, and the epigenome gives us an appreciation of the ketogenic diet and the potential for bioenergetic therapeutics.
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              Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease.

              Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimer's disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Research Foundation
                1663-9812
                25 January 2012
                09 April 2012
                2012
                : 3
                : 59
                Affiliations
                [1] 1simpleDepartment of Neurology, University of Wisconsin Madison, WI, USA
                [2] 2simpleDepartment of Pediatrics, University of Wisconsin Madison, WI, USA
                [3] 3simpleDepartment of Pediatrics, University of Calgary Faculty of Medicine Calgary, AB, Canada
                [4] 4simpleDepartment of Clinical Neurosciences, University of Calgary Faculty of Medicine Calgary, AB, Canada
                Author notes

                Edited by: Yuri Zilberter, INSERM U751, Faculté de Médecine Timone, France

                Reviewed by: Yuri Zilberter, INSERM U751, Faculté de Médecine Timone, France; Marta Balietti, Istituto Nazionale di Ricovero e Cura per Anziani, Italy

                *Correspondence: Jong M. Rho, Alberta Children’s Hospital, University of Calgary, 2888 Shaganappi Trail Northwest, Calgary, AB, Canada T3B 6A8. e-mail: jmrho@ 123456ucalgary.ca

                This article was submitted to Frontiers in Neuropharmacology, a specialty of Frontiers in Pharmacology.

                Article
                10.3389/fphar.2012.00059
                3321471
                22509165
                ceca1258-abf4-4e9a-9fbd-5698c0761960
                Copyright © 2012 Stafstrom and Rho.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 17 January 2012
                : 21 March 2012
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 95, Pages: 8, Words: 8047
                Categories
                Pharmacology
                Review Article

                Pharmacology & Pharmaceutical medicine
                neuroplasticity,epilepsy,neurological disorders,ketogenic diet

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