A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis

Neuroinflammation Research Laboratories, Department of Psychiatry, USA.
BMC Neuroscience (Impact Factor: 2.67). 02/2006; 7(1):29. DOI: 10.1186/1471-2202-7-29
Source: PubMed


The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization.
SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-beta-3 hydroxybutyrate (DBH), has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047). In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH.
This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain.

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    • "The treatment restored normal body mass and adiposity, delayed disease onset and motor neuron degeneration, and life expectancy was extended by 20% (Dupuis et al., 2004). The beneficial effects of high fat diet, or ketogenic diet, for SOD1 mice were confirmed by other groups (Table 2, Mattson et al., 2007; Zhao et al., 2006, 2012). In 2008, we aimed to study the link between lipids and disease progression, by quantifying circulating lipids in ALS patients. "
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    ABSTRACT: Motor neuron diseases (MNDs) are characterized by selective death of motor neurons and include mainly adult-onset amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Neurodegeneration is not the single pathogenic event occurring during disease progression. There are multiple lines of evidence for the existence of defects in lipid metabolism at peripheral level. For instance, hypermetabolism is well characterized in ALS, and dyslipidemia correlates with better prognosis in patients. Lipid metabolism plays also a role in other MNDs. In SMA, misuse of lipids as energetic nutrients is described in patients and in related animal models. The composition of structural lipids in the central nervous system is modified, with repercussion on membrane fluidity and on cell signaling mediated by bioactive lipids. Here, we review the main epidemiologic and mechanistic findings that link alterations of lipid metabolism and motor neuron degeneration, and we discuss the rationale of targeting these modifications for therapeutic management of MNDs.
    Frontiers in Cellular Neuroscience 02/2014; 8:25. DOI:10.3389/fncel.2014.00025 · 4.29 Impact Factor
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    • "The improved metabolic efficiency observed suggests that, besides its anticonvulsant properties, KDs may be useful for treating several other neurological disorders. Current models of neurodegenerative diseases showed positive outcomes induced by ketogenic diet such as increased motor neuron number in ALS transgenic models [17,18], reduced lesion volume after traumatic brain injury [19], increased cell survival and decreased seizure frequency in kainate-induced seizure models [20] and suppressed inflammatory cytokines and chemokines in an experimental model of multiple sclerosis [21]. "
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    ABSTRACT: Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer's disease (AD) patients present an energy imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs), widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition) and Tg4510 (a model of tau deposition) mice were offered either a ketogenic or a control (NIH-31) diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition.
    PLoS ONE 09/2013; 8(9):e75713. DOI:10.1371/journal.pone.0075713 · 3.23 Impact Factor
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    • "As noted previously, children with autism and refractory epilepsy suffer poor outcomes [6], and a KD could offer dual benefits in this difficult clinical population. Consistent with a growing interest in metabolic underpinnings of neurological disorders, there has been increased basic research activity involving KDs and a dramatic increase in the number of clinical centers worldwide that administer the KD and its variants [45]–[47]. In conclusion, the present research identifies ASD as another potential major therapeutic target for metabolic strategies like the KD. "
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    ABSTRACT: AUTISM SPECTRUM DISORDERS SHARE THREE CORE SYMPTOMS: impaired sociability, repetitive behaviors and communication deficits. Incidence is rising, and current treatments are inadequate. Seizures are a common comorbidity, and since the 1920's a high-fat, low-carbohydrate ketogenic diet has been used to treat epilepsy. Evidence suggests the ketogenic diet and analogous metabolic approaches may benefit diverse neurological disorders. Here we show that a ketogenic diet improves autistic behaviors in the BTBR mouse. Juvenile BTBR mice were fed standard or ketogenic diet for three weeks and tested for sociability, self-directed repetitive behavior, and communication. In separate experiments, spontaneous intrahippocampal EEGs and tests of seizure susceptibility (6 Hz corneal stimulation, flurothyl, SKF83822, pentylenetetrazole) were compared between BTBR and control (C57Bl/6) mice. Ketogenic diet-fed BTBR mice showed increased sociability in a three-chamber test, decreased self-directed repetitive behavior, and improved social communication of a food preference. Although seizures are a common comorbidity with autism, BTBR mice fed a standard diet exhibit neither spontaneous seizures nor abnormal EEG, and have increased seizure susceptibility in just one of four tests. Thus, behavioral improvements are dissociable from any antiseizure effect. Our results suggest that a ketogenic diet improves multiple autistic behaviors in the BTBR mouse model. Therefore, ketogenic diets or analogous metabolic strategies may offer novel opportunities to improve core behavioral symptoms of autism spectrum disorders.
    PLoS ONE 06/2013; 8(6):e65021. DOI:10.1371/journal.pone.0065021 · 3.23 Impact Factor
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