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Abstract
There is mounting evidence that oxidative glucose metabolism is impaired in epilepsy and recent work has further characterized the metabolic mechanisms involved. In healthy people eating a traditional diet, including carbohydrates, fats and protein, the major energy substrate in brain is glucose. Cytosolic glucose metabolism generates small amounts of energy, but oxidative glucose metabolism in the mitochondria generates most ATP, in addition to biosynthetic precursors in cells. Energy is crucial for the brain to signal “normally,” while loss of energy can contribute to seizure generation by destabilizing membrane potentials and signaling in the chronic epileptic brain. Here we summarize the known biochemical mechanisms that contribute to the disturbance in oxidative glucose metabolism in epilepsy, including decreases in glucose transport, reduced activity of particular steps in the oxidative metabolism of glucose such as pyruvate dehydrogenase activity, and increased anaplerotic need. This knowledge justifies the use of alternative brain fuels as sources of energy, such as ketones, TCA cycle intermediates and precursors as well as even medium chain fatty acids and triheptanoin.
Highlights
INTRODUCTIONGlucose metabolism is highly regulated due to the necessity to supply cells with energy critical for cell survival as well as specific cellular functions such as signaling
Importance of Glucose Metabolism for Healthy Brain FunctionGlucose metabolism is highly regulated due to the necessity to supply cells with energy critical for cell survival as well as specific cellular functions such as signaling
In an attempt to understand the role of octanoic and decanoic acids as fuels in the brain, we investigated their effects [at 200 μM, a level that has been reported in the plasma of children who had received oral medium chain triglycerides (Sills et al, 1986)] in cultures of neonatal astrocytes
Summary
Glucose metabolism is highly regulated due to the necessity to supply cells with energy critical for cell survival as well as specific cellular functions such as signaling. The loss of PDH activity was coupled with a reduction of 13C-glucose entry into the TCA cycle after a five min flurothyl-generated seizure (McDonald and Borges, 2017) and in the chronic “epileptic” stage of the pilocarpine mouse model (Smeland et al, 2013; McDonald et al, 2017) and was previously described in the rat kainate model (Melo et al, 2005). This coincided with increased activities of succinate dehydrogenase staining in CA3 neurons, which may indicate an attempt by the cells to increase energy production by feeding more substrate into complex II to compensate for the complex I deficiency These studies support the theory that oxidative stress may contribute to the reduction of activities of TCA cycle enzymes, as many of them are sensitive to oxidation due to their structure. These (transient) impairments are most likely caused by oxidative stress, as we found transiently increased hippocampal levels of malondialdehyde one day after SE, which were restored 2 days after SE in our model (Carrasco-Pozo et al, 2015)
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