Brain energy deprivation in epilepsy

Epilepsy is a serious neurological disorder that affects approximately 1 % of the general population, making it one of the most common disorders of the central nervous system. Furthermore, up to 40 % of all patients with epilepsy cannot control their seizures with current medications. More efficacious treatments for medication refractory epilepsy are therefore needed. A better understanding of the mechanisms that cause this disorder is likely to facilitate the discovery of such treatments. Impairment in cerebral energy metabolism has been proposed as a possible causative factor in the pathogenesis of temporal lobe epilepsy (TLE), which is one of the most common types of medication-refractory epilepsies in adults. Emphasis has been placed on the role of energy substrates (lactate and ketone bodies) and their transporter molecules, particularly monocarboxylate transporters 1 and 2 (MCT1 and MCT2). We recently reported that the cellular distribution of MCT1 and MCT2 is perturbed in the hippocampus in patients with TLE. The changes may be an adaptive response aimed at keeping high levels of lactate in the epileptic tissue, which may serve to counteract epileptic activity by downregulating cAMP levels through the lactate receptor GPR81, newly discovered in hippocampus by us. We propose that the perturbation of MCTs may be further involved in the pathophysiology of TLE by influencing brain energy homeostasis, mitochondrial function, GABA-ergic and glutamatergic neurotransmission, and flux of lactate through the brain.

An impaired brain energy metabolism has been implicated in the pathogenesis of drug-resistant mesial temporal lobe epilepsy (MTLE); however, the molecular mechanism of this impairment is not fully understood. We propose that a reduced uptake of circulatin g monocarboxylate fuels especially ketone bodies to the brain, may contribute to the energetic failure and seizures in MTLE. A high-fat, low - carbohydrate - ketogenic - diet improves the brain energy stores in epilepsy and dramatically reduces the frequ ency of recurrent seizures in several types of epilepsy. The use of ketogenic diet as a treatment in drug-resistant epilepsy has existed for more than 80 years. It was devised to mimic the effects of starvation originally determined to be beneficial for e pileptic seizures. By making fat the main dietary energy source, a comparable ketosis was produced. The antiepileptic mechanism of the ketogenic diet is still not understood, but entry of ketone bodies from the blood into the brain is probably required fo r its efficacy. A group of transmembrane monocarboxylate transporter molecules (MCTs) present on endothelial cells, astrocytes and neurons, facilitate the transport of blood-derived ketone bodies as well as lactate, pyruvate to the various compartments o f the brain. Of relevance to this project is that MCT1, which is present on the plasma membrane of endothelial cells, is a key transporter of blood-derived monocarboxylates to the brain and that MCT2, which is present on neuronal plasma membranes is impor tant for transport of monocarboxylates into neurons. 1)Is MCT1 altered on microvessels in the epileptogenic hippocampus in human MTLE? 2)Is MCT2 altered on neurons in the hc in human MTLE? 3) Are MCT1 and MCT2 altered in a rat model mimicking MTLE? 4,5 ) In the rat MTLE model, does the ketogenic diet result in reversal of of MCT1 and MCT2 alterations, and are alterations in MCT1 and MCT2 expression related to alterations in the number of seizures.