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BMC Neuroscience

, 7:29

First Online: 03 April 2006Received: 03 November 2005Accepted: 03 April 2006


BackgroundThe 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.

ResultsSOD1-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.

ConclusionThis 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.

AbbreviationsALSamyotrophic lateral sclerosis

KDketogenic diet

DBHD-β-3 hydroxybutyrate

SODCu-Zn superoxide dismutase

RLUrelative luminescence units

LDHlactate dehydrogenase

ROSreactive oxygen species

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2202-7-29 contains supplementary material, which is available to authorized users.

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Autor: Zhong Zhao - Dale J Lange - Andrei Voustianiouk - Donal MacGrogan - Lap Ho - Jason Suh - Nelson Humala - Meenakshisundaram

Fuente: https://link.springer.com/

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