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Review
. 2008 Jan;28(1):1-16.
doi: 10.1038/sj.jcbfm.9600543. Epub 2007 Aug 8.

Cerebral metabolic adaptation and ketone metabolism after brain injury

Mayumi L Prins  1
Affiliations
Review

Cerebral metabolic adaptation and ketone metabolism after brain injury

Mayumi L Prins. J Cereb Blood Flow Metab. 2008 Jan.

Abstract

The developing central nervous system has the capacity to metabolize ketone bodies. It was once accepted that on weaning, the 'post-weaned/adult' brain was limited solely to glucose metabolism. However, increasing evidence from conditions of inadequate glucose availability or increased energy demands has shown that the adult brain is not static in its fuel options. The objective of this review is to summarize the body of literature specifically regarding cerebral ketone metabolism at different ages, under conditions of starvation and after various pathologic conditions. The evidence presented supports the following findings: (1) there is an inverse relationship between age and the brain's capacity for ketone metabolism that continues well after weaning; (2) neuroprotective potentials of ketone administration have been shown for neurodegenerative conditions, epilepsy, hypoxia/ischemia, and traumatic brain injury; and (3) there is an age-related therapeutic potential for ketone as an alternative substrate. The concept of cerebral metabolic adaptation under various physiologic and pathologic conditions is not new, but it has taken the contribution of numerous studies over many years to break the previously accepted dogma of cerebral metabolism. Our emerging understanding of cerebral metabolism is far more complex than could have been imagined. It is clear that in addition to glucose, other substrates must be considered along with fuel interactions, metabolic challenges, and cerebral maturation.

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Figures

Figure 1
Figure 1
The chemical structures of the three ketone bodies: acetone, acetoacetate, and β-OHB. There are three enzymatic steps involved in processing β-OHB to TCA cycle entry as acetyl-CoA. D-3-Hydroxybutyrate dehydrogenase (HBDH) converts β-OHB into acetoacetate, which can spontaneously be converted into acetone. 3-Ketoacyl-CoA transferase converts acetoacetate into acetoacetyl-CoA. Acetoacetyl-CoA thiolase is the enzyme that converts acetoacetyl-CoA into acetyl-CoA, which can then enter the TCA cycle.
Figure 2
Figure 2
Changes in arterial concentrations, cerebral enzyme activities, and cerebral transporters for (A) glucose and (B) ketone metabolism with postnatal age. The shaded area of each graph represents the suckling period. Changes in arterial concentrations (solid lines) are indicated by the mmol/L values on the y axis (right). Enzymatic activities (broken lines) and transporter density changes (bars) are expressed as percentage of adult (Leong and Clark, 1984; Lockwood and Bailey, 1971; Nehlig et al, 1987, 1991; Page et al, 1971; Shambaugh et al, 1977; Vannucci, 1994; Vannucci and Simpson, 2003).
Figure 3
Figure 3
Summary of the properties of ketone metabolism that potentially contribute to neuroprotection. The numbers in black diamonds denote each mechanism. Ketones (1) require only three enzymatic steps to enter the TCA cycle; (2) reduce the NAD couple; (3) decrease free radical formation; (4) increase production of ATP; (5) increase mitochondrial uncoupling; (6) increase glutathione peroxidase activity; and (7) inhibit pyruvate entry into the TCA cycle. Abbreviation: UCP, uncoupling protein.
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