Open Access Highly Accessed Research article

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

Zhong Zhao1, Dale J Lange2, Andrei Voustianiouk2, Donal MacGrogan1, Lap Ho1, Jason Suh1, Nelson Humala1, Meenakshisundaram Thiyagarajan1, Jun Wang1 and Giulio M Pasinetti13*

Author affiliations

1 Neuroinflammation Research Laboratories, Department of Psychiatry, USA

2 Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1668, New York, New York 10029, USA

3 Bronx Veterans Affairs Medical Center, 130 W Kingsbridge Road, Bronx, NY 10468, USA

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Citation and License

BMC Neuroscience 2006, 7:29  doi:10.1186/1471-2202-7-29

Published: 3 April 2006

Abstract

Background

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.

Results

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-β-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.

Conclusion

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.