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The fact that brain consumes ~20% of the body’s energy bespeaks the high energy-demanding nature of neural activity. The energy consumption is even higher when massive brain activity (such as seizures) occurs under pathological conditions. Thus manipulating energy metabolism may be helpful to control neural ...

The fact that brain consumes ~20% of the body’s energy bespeaks the high energy-demanding nature of neural activity. The energy consumption is even higher when massive brain activity (such as seizures) occurs under pathological conditions. Thus manipulating energy metabolism may be helpful to control neural excitability and seizures. Indeed, nearly a century ago (in 1920s), fasting was used as an anti-seizure therapy, which later evolved to the low-carbohydrate and high-fat ketogenic diet (KD). While KD is successful in controlling seizures, it waned shortly after the advent of the first generation of antiepileptic drugs. However, given with the availability of more than 20 antiepileptic drugs, as many as 1/3 of patients with epilepsy are drug-resistant. Thus, KD was re-introduced to the clinic in the 1990s and has proven to be highly effective in controlling many types of drug-refractory seizures. More recently, another approach has been proposed to alter energy metabolism by inhibiting glycolysis with a non-metabolizable glucose analogue, 2-deoxy-glucose (2-DG). Inhibition of glycolysis with 2-DG effectively blocks seizure activity in brain slices and in several animal models of seizures and epileptogenesis. In addition, modifying other metabolic pathways such as the pentose phosphate pathway (PPP) with fructose-1,6-bisphosphate (F1,6BP) has been shown to suppress seizures in several animals models. These clinical and laboratory studies demonstrate that manipulation of energy metabolism can profoundly alter brain excitability and seizure activity.

The question remain is, how the KD, glycolytic inhibition and other metabolic manipulations affect seizure activity? The fundamental basis of seizure generation is an increased neural excitability involving a host of cellular mechanisms such as ion channels, membrane properties, receptors, transporters, synaptic transmission and neural networks. Most likely, the anticonvulsive action of metabolic regulation is multifaceted, e.g., the KD may involve KATP channels, ketone bodies, and other mechanisms which lead to reduced neuronal excitability. The anticonvulsive activity by glycolytic inhibition may involve suppression of intrinsic neuronal firing and augmentation of GABAergic synaptic transmission, but the detailed mechanisms are yet to be elucidated. The anticonvulsant action of F1,6BP on animal models are remarkable yet the mechanisms of action are largely unknown. Moreover, metabolic manipulation may alter the process of epileptogenesis and produce antiepileptic effect through a variety of mechanisms. In addition to neuronal metabolism, glial cell metabolism may be also important for seizure generation (via “astrocyte-neuron lactate shuttle”). Elucidation of the action and mechanisms of metabolic manipulation would not only lead to new knowledge and better understanding regarding metabolic state and neuronal excitability and seizure control, but also hold the promise as a novel treatment of drug-resistant seizures and epilepsy prevention.

In summary, the field of cell metabolism on neural excitability and epilepsy is relatively new and under-explored, yet the emerging research in this field has begun to provide novel and exciting results on regulating neural excitability and controlling seizures from a unique perspective, which is both scientifically interesting and clinically important.

Keywords: Energy metabolism, Glycolysis, Neural excitability, Seizure, Electrophysiology


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