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

Neuroinflammation Research Laboratories, Department of Psychiatry, USA.
BMC Neuroscience (Impact Factor: 2.85). 02/2006; 7:29. DOI: 10.1186/1471-2202-7-29
Source: PubMed

ABSTRACT 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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    • "Increasing mitochondrial antioxidant activities by elevating mitochondrial reducing power is considered as an important mechanism of neuroprotection by several naturally occurring compounds, including ketone bodies, pyruvate, and acyl-carnitines (Ryu et al, 2004; Zanelli et al, 2005; Gasior et al, 2006; Zhao et al, 2006b; Jarrett et al, 2008; Rosca et al, 2009; Alves et al, 2009; Jones et al, 2010; Zhang et al, 2010). This mechanism of action might be particularly important during reperfusion after cerebral ischemia, when the mitochondrial redox state is hyperoxidized, ROS production is elevated, and there are increased markers of oxidative molecular modification (Perez-Pinzon et al, 1999; Fiskum et al, 2004). "
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    • "Downstream of the Krebs cycle, b-hydroxybutyrate improved redox activity and decreased cell death in dopaminergic SH-SY5Y cells after exposure to the complex I toxin rotenone (Imamura et al. 2006). b-Hydroxybutyrate appears to require an intact complex II to confer its beneficial effects in two different models of neurodegeneration, including a complex II toxin (3-nitropropionic acid) model and the SOD1-G93A mouse model of amyotrophic lateral sclerosis (Lou Gehrig's disease) (Tieu et al. 2003; Zhao et al. 2006). More recently, Kim do et al. (2010) showed in hippocampal slices that a cocktail of b-hydroxybutyrate and acetoacetate preserved synaptic activity after exposure to rotenone or 3-nitropropionic acid, although there were some regional disparities (i.e., different responses even within the same slice) noted during ketone exposure to the latter. "
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    • "n seems to be present in the early stages of disease both in the mutant SOD1 mouse model ( Dupuis et al . , 2004 ; Ferraiuolo et al . , 2007 ) and in human ALS ( Desport et al . , 2000 , 2005 ) . Dietary inter - ventions with the potential to ameliorate the motoneuron energy deficit have already been shown to be of benefit in mouse models of ALS ( Zhao et al . , 2006 ; Patel et al . , 2010 ) and are being considered as a potential therapeutic approach in the human disease . This study supports the hypothesis that motoneuron degener - ation in SOD1 - related ALS is a ' non - cell - autonomous ' process . However , motoneurons themselves stimulate the pathophysio - logical properties in neighbouring a"
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