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Neuroprotection in diet-induced ketotic rat brain after focal ischemia.

ABSTRACT: Neuroprotective properties of ketosis may be related to the upregulation of hypoxia inducible factor (HIF)-1alpha, a primary constituent associated with hypoxic angiogenesis and a regulator of neuroprotective responses. The rationale that the utilization of ketones by the brain results in elevation of intracellular succinate, a known inhibitor of prolyl hydroxylase (the enzyme responsible for the degradation of HIF-1alpha) was deemed as a potential mechanism of ketosis on the upregulation of HIF-1alpha. The neuroprotective effect of diet-induced ketosis (3 weeks of feeding a ketogenic diet), as pretreatment, on infarct volume, after reversible middle cerebral artery occlusion (MCAO), and the upregulation of HIF-1alpha were investigated. The effect of beta-hydroxybutyrate (BHB), as a pretreatment, via intraventricular infusion (4 days of infusion before stroke) was also investigated following MCAO. Levels of HIF-1alpha and Bcl-2 (anti-apoptotic protein) proteins and succinate content were measured. A 55% or 70% reduction in infarct volume was observed with BHB infusion or diet-induced ketosis, respectively. The levels of HIF-1alpha and Bcl-2 proteins increased threefold with diet-induced ketosis; BHB infusions also resulted in increases in these proteins. As hypothesized, succinate content increased by 55% with diet-induced ketosis and fourfold with BHB infusion. In conclusion, the biochemical link between ketosis and the stabilization of HIF-1alpha is through the elevation of succinate, and both HIF-1alpha stabilization and Bcl-2 upregulation play a role in ketone-induced neuroprotection in the brain.

SUBMITTER: Puchowicz MA

PROVIDER: S-EPMC3621146 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Neuroprotection in diet-induced ketotic rat brain after focal ischemia.

Puchowicz Michelle A MA Zechel Jennifer L JL Valerio Jose J Emancipator Douglas S DS Xu Kui K Pundik Svetlana S LaManna Joseph C JC Lust W David WD

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20080723 12

Neuroprotective properties of ketosis may be related to the upregulation of hypoxia inducible factor (HIF)-1alpha, a primary constituent associated with hypoxic angiogenesis and a regulator of neuroprotective responses. The rationale that the utilization of ketones by the brain results in elevation of intracellular succinate, a known inhibitor of prolyl hydroxylase (the enzyme responsible for the degradation of HIF-1alpha) was deemed as a potential mechanism of ketosis on the upregulation of HIF ...[more]

PMID: 18648382

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Dataset Information

Neuroprotection in diet-induced ketotic rat brain after focal ischemia.

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Neuroprotection in diet-induced ketotic rat brain after focal ischemia.

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