Neuroprotection in diet-induced ketotic rat brain after focal ischemia

Michelle Puchowicz, Jennifer L. Zechel, Jose Valerio, Douglas S. Emancipator, Kui Xu, Svetlana Pundik, Joseph C. Lamanna, W. David Lust

Research output: Contribution to journalArticle

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Abstract

Neuroprotective properties of ketosis may be related to the upregulation of hypoxia inducible factor (HIF)-1α, 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-1α) was deemed as a potential mechanism of ketosis on the upregulation of HIF-1α. 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-1α were investigated. The effect of Β-hydroxybutyrate (BHB), as a pretreatment, via intraventricular infusion (4 days of infusion before stroke) was also investigated following MCAO. Levels of HIF-1α 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-1α 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-1α is through the elevation of succinate, and both HIF-1α stabilization and Bcl-2 upregulation play a role in ketone-induced neuroprotection in the brain.

Original languageEnglish (US)
Pages (from-to)1907-1916
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume28
Issue number12
DOIs
StatePublished - Dec 1 2008

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Hypoxia-Inducible Factor 1
Ketosis
Ischemia
Diet
Brain
Succinic Acid
Up-Regulation
Middle Cerebral Artery Infarction
Ketones
Prolyl-Hydroxylase Inhibitors
Ketogenic Diet
Hydroxybutyrates
Intraventricular Infusions
Apoptosis Regulatory Proteins
Proteins
Neuroprotection
Neuroprotective Agents
Stroke
Enzymes

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Puchowicz, M., Zechel, J. L., Valerio, J., Emancipator, D. S., Xu, K., Pundik, S., ... Lust, W. D. (2008). Neuroprotection in diet-induced ketotic rat brain after focal ischemia. Journal of Cerebral Blood Flow and Metabolism, 28(12), 1907-1916. https://doi.org/10.1038/jcbfm.2008.79

Neuroprotection in diet-induced ketotic rat brain after focal ischemia. / Puchowicz, Michelle; Zechel, Jennifer L.; Valerio, Jose; Emancipator, Douglas S.; Xu, Kui; Pundik, Svetlana; Lamanna, Joseph C.; Lust, W. David.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 28, No. 12, 01.12.2008, p. 1907-1916.

Research output: Contribution to journalArticle

Puchowicz, M, Zechel, JL, Valerio, J, Emancipator, DS, Xu, K, Pundik, S, Lamanna, JC & Lust, WD 2008, 'Neuroprotection in diet-induced ketotic rat brain after focal ischemia', Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 12, pp. 1907-1916. https://doi.org/10.1038/jcbfm.2008.79
Puchowicz, Michelle ; Zechel, Jennifer L. ; Valerio, Jose ; Emancipator, Douglas S. ; Xu, Kui ; Pundik, Svetlana ; Lamanna, Joseph C. ; Lust, W. David. / Neuroprotection in diet-induced ketotic rat brain after focal ischemia. In: Journal of Cerebral Blood Flow and Metabolism. 2008 ; Vol. 28, No. 12. pp. 1907-1916.
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