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


CONCLUSIONS
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.
Zhao
Zhong
Z
Neuroinflammation Research Laboratories, Department of Psychiatry, USA. rudy.zhao@mssm.edu
Lange
Dale J
DJ
Voustianiouk
Andrei
A
MacGrogan
Donal
D
Ho
Lap
L
Suh
Jason
J
Humala
Nelson
N
Thiyagarajan
Meenakshisundaram
M
Wang
Jun
J
Pasinetti
Giulio M
GM
D000690:Amyotrophic Lateral Sclerosis / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004032:Diet; D018450:Disease Progression; D006884:Hydroxybutyrate Dehydrogenase / Q000494:pharmacology; D007657:Ketone Bodies / Q000096:biosynthesis* / Q000097:blood; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics
D007657:Ketone Bodies; D006884:Hydroxybutyrate Dehydrogenase; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase