Neuroprotection in diet-induced ketotic rat brain after focal ischemia.
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.
Puchowicz
Michelle A
MA
Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4930, USA. map10@case.edu
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
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D001929:Brain Edema / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D020520:Brain Infarction / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D002545:Brain Ischemia / Q000178:diet therapy* / Q000201:enzymology / Q000378:metabolism; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007657:Ketone Bodies / Q000096:biosynthesis*; D007662:Ketosis / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019802:Succinic Acid / Q000378:metabolism
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007657:Ketone Bodies; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D019802:Succinic Acid; D011393:Procollagen-Proline Dioxygenase