Review
Ketone body synthesis in the brain: possible neuroprotective effects

https://doi.org/10.1016/j.plefa.2003.05.001Get rights and content

Abstract

Ketone bodies make an important contribution to brain energy production and biosynthetic processes when glucose becomes scarce. Although it is generally assumed that the liver supplies the brain with ketone bodies, recent evidence shows that cultured astrocytes are also ketogenic cells. Moreover, astrocyte ketogenesis might participate in the control of the survival/death decision of neural cells in at least two manners: first, by scavenging non-esterified fatty acids the ketogenic pathway would prevent the detrimental actions of these compounds and their derivatives (e.g. ceramide) on brain structure and function. Second, ketone bodies may exert pro-survival actions per se by acting as cellular substrates, thereby preserving neuronal synaptic function and structural stability. These findings support the notion that ketone bodies produced by astrocytes may be used in situ as substrates for neuronal metabolism, and raise the possibility that astrocyte ketogenesis is a neuroprotective pathway.

Introduction

The bulk of the mature brain metabolic substrate is consumed in energy metabolism, mostly for ion transport and the maintenance of ion gradients [1]. In fact, pathological conditions that diminish or arrest brain energy production, such as hypoglycemia or hypoxia/ischemia, lead to a rapid breakdown of transmembrane ion gradients and ultimately to neuron degeneration and death [1]. Although glucose is the primary fuel for the brain, ketone bodies and other glucose-replacing substances turn important when glucose becomes scarce [2], [3]. Here, we summarize the current knowledge on how the brain produces ketone bodies, and speculate on the possible neuroprotective action of this pathway.

Section snippets

Astrocytes as brain ketogenic cells

Astrocytes, the major class of glial cells in the mammalian brain, play a pivotal role in the regulation of brain energy metabolism. Owing to their strategic location surrounding intraparenchymal blood capillaries, astrocytes form the first cellular barrier encountered by nutrients and other substances entering the brain tissue. For example, evidence accumulated during the past decade supports the notion that astrocytes constitute a prevalent site of brain glucose uptake, allowing the

Astrocyte ketogenesis during synaptic activity

Astrocytes are associated intimately with neurons and also surround synapses. Owing to their close proximity to synaptic clefts, astrocytes are in a prime location to receive synaptic information from released neurotransmitters [24]. In fact, astrocytes express a wide range of neurotransmitter receptors and transporters [24], [25]. In general, it is assumed that the supply of lactate from astrocytes for neuronal oxidative metabolism is enhanced in situations of high synaptic activity [4], [5],

Pro-survival action of astrocyte ketogenesis

An enhanced breakdown of cellular glycerolipids and a concomitant accumulation of non-esterified fatty acids occurs in several models of brain trauma and ischemia [34], [35]. Phospholipid degradation leads to the irreversible damage of membranes, and seems to be the result of Ca2+-induced stimulation of phospholipases and impaired phospholipid resynthesis resulting from energy depletion [36]. The released non-esterified fatty acids exert per se various detrimental effects on brain structure and

Neuroprotection by ketone bodies in vivo

It is important to keep in mind that the aforementioned findings on astrocyte ketogenesis come from cell culture experiments. Nevertheless, an in vivo microdialysis study in which [14C]palmitate was perfused into the rat brain parenchyma has shown that 5-aminoimidazole-4-carbozamide ribonucleoside, a cell-permeable pro-drug that activates AMPK, induces a remarkable stimulation of [14C]ketone body recovery in the perfusate [31]. Although the extent to which ketone body formation by astrocytes

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