**1. Introduction**

330 Neuroscience – Dealing with Frontiers

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Living cells require energy to perform work, to maintain their organized structures, to synthesize cellular components, to generate electric currents and many other processes. Energy metabolism is a highly coordinated cellular activity in which enzymes are organized into discrete metabolic pathways that cooperate in degrading energy-rich nutrients from the environment. Glucose is the principal metabolic substrate for living cells including brain cells. It is rich in potential energy and is also a versatile precursor, giving rise to metabolic intermediaries for biosynthetic reactions. Glycogen is a polymer of glucose and is the form in which glucose is stored. The mammalian brain contains glycogen, which is located predominantly in astrocytes (Brown & Ransom, 2007). In particular situations, substrates other than glucose can be utilized by the brain. -hydroxybutyrate, acetoacetate and acetone are ketone bodies produced in the liver from Acetyl-CoA. Ketone bodies are an important source of brain energy in breast-fed neonates and during starvation when carbohydrates are scarce. However, it has been proposed that part of brain energy comes from the conversion of glucose to lactate at one location (within one cell) and part comes from the oxidation of lactate to pyruvate at another location (within the same cell or in a different cell).

The brain makes up 2% of a person's weight. Despite this, even at rest, the brain consumes 25% of the body's energy. Most of the energy consumed in the brain is attributable to restoration of the membrane gradient following neuronal depolarization. Neurotransmitter recycling, intracellular signaling and dendritic and axonal transport also require energy (Attwell & Laughlin, 2001). Even though neurons are responsible for massive energy consumption, the brain is made up of many cells*,* including neurons, glial and ependymal cells. Every brain cell has a specific function and thus every brain cell has different metabolic needs. Many of these specific functions are concerned with maintainance of neuronal transmission. For example, astrocytes play a central role in supporting neurons metabolically by producing lactate, through glycolysis and activation of glycogen catabolism (Brown & Ransom, 2007). Another critical factor for maintenance of neuronal

<sup>\*</sup> Corresponding Author

Brain Energy Metabolism in Health and Disease 333

glucose-6-phosphate is degraded to pyruvate. But glucose-6-phosphate can be used to generate glucose-1-phosphate, which in turn is used to synthesize glycogen (see below) or to generate NADPH and ribose-5-phosphate through PPP (see below). Myo-inositol is also synthesized from glucose-6-phosphate and serves as a precursor for phosphatidylinositide signaling molecules. The first step in glycolysis and the next nine enzymatic reactions occur

Fig. 1. Glycolysis. The first step in glycolysis is phosphorylation of glucose to glucose-6 phosphate by hexokinase, an enzyme inhibited by the same glucose-6-phosphate. Glucose must be phosphorylated to glucose-6-phosphate for it to enter glycolysis. The most

phosphofructokinase (PFK). PFK is inhibited by compounds that accumulate when energy status is high (ATP, citrate) and it is activated by products of functional metabolic activity (AMP, ADP). PFK1 in neurons is not activated by fructose 2,6-bisphosphate (Fructose-2,6-P2)

Major sites for the control of glycolytic flux are hexokinase (EC 2.7.1.1), phosphofructokinase 1 (PFK1, EC 2.7.1.11) and pyruvate kinase (EC 2.7.1.40; Lowry & Passoneau, 1964). Hexokinase catalyzes the transfer of a phosphate group from one

important step in the control of glycolytic flux is a reaction catalyzed by

because the enzyme that catalyzes F2,6BP production is constantly degraded.

in all brain cells (Lowry & Passonneau, 1964).

transmission is an adequate supply of nutrients and oxygen from blood. Neurotransmitters stimulate neurovascular messenger production in astrocytes and neurons. These molecules induce the local constriction and dilation of smooth muscle around the neighboring arterioles (Attwell et al., 2010).

There have been several reports of metabolic impairment in a variety of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease, among others (Mosconi et al., 2005, Leenders et al., 1986, Kuwert et al., 1993, Hattingen et al., 2009). Because brain is an expensive organ in energetic terms, disruptions in energy production may affect neuronal transmission and thus, neuronal survival. Moreover, deregulation of energy metabolism could be implicated in an increased production of oxidative species. Indeed, oxidative damage has been proposed in such disorders (Mazziotta et al., 1987, Navarro et al., 2009).
