Thematic Issue: Epilepsy and Its Therapy

What is it about?

Several mechanisms of different type of epilepsies have been disclosed. Different neurotransmitters (glutamate/aspartate, GABA, biogenic amines, opioid peptides, purines etc.) and their receptors may play a role in the pathogenesis of epilepsy. Recently, a great number of studies demonstrated that epilepsy may be in relationship with depression, sleep and different types of brain insults such as stroke and infection. However, further studies are needed to get insight into the underlying etiology. For instance, brain injuries trigger brain inflammation, leakage of blood-brain barrier, cell damage and neuronal hyperexcitability, which result in lower seizure threshold and trigger epilepsy. In addition, it was demonstrated that peripherally and centrally evoked inflammation by lipopolysaccharide (LPS) may also aggravate epileptic activity. However, the etiology of epileptogenesis after brain insults is poorly understood so far. Synchronization of neuronal activity is crucial part of normal brain function. However, pathological synchronization is also the major characteristic of epilepsy. Therefore, in this issue, first the mechanisms of abnormal epileptic synchronizations are addressed in both temporal lobe epilepsy patients and in various animal models by Massimo Avoli. The available knowledge is summarized on interictal spikes, high frequency oscillations, and ictal discharges and their usefulness for developing seizure prediction tools. The comprehensive approach of description suggests that specific seizure onsets are directly preceded by distinctive patterns of interictal spiking and high frequency oscillations based on findings in some animal models. Temporal lobe epilepsy (TLE) is also often accompanied by hippocampal sclerosis. The specific loss of principal neurons and some interneuron types as well as adaptive reactions such as sprouting, among others, could be underlying reasons why excessive synchronization occurs. Another functional alteration that can take place associated with epilepsy is the disruption of the blood-brain barrier in the hippocampus and cerebral cortex. These events and potential pharmacological tools that counteract them and may lead to preventive approaches are the subject of the paper by Curia et al. with a major focus on ghrelin and its analogues. Because of the relatively high ratio of drug-resistant epilepsies, there is a need for new therapies interfering with epileptogenesis and preventing development of drug-resistance instead of merely suppressing seizures. In addition, predictive biomarkers of susceptibility to pharmacoresistant seizures are also required for better individual medication. In their review paper, Kovács and Heinemann discuss theories of drug resistance, present novel experimental models for its investigation and describe some current and potential future unconventional therapies addressing epileptogenesis. Absence epileptic mechanisms, that are considerably different from the development of partial epileptic disorders including TLE, are addressed in the paper of Luijtelaar and Zobeiri. In particular, the WAG/Rij rat model with spontaneous spike-wave discharges is characterized. The role of GABA, glutamate and ion channels in the genesis of spike-wave discharges in the thalamus and the cerebral cortex is described. Recent advances in the field including the role of environmental factors, glial cells and cytokines in the genesis of spike-wave discharges are also discussed. Finally, research for novel, often non-invasive treatment options such as transcranial direct current stimulation and transcranial magnetic stimulation in absence epilepsy is summarized. The major approach to treat epileptic patients is still anti-epileptic drugs of which new compounds are required to treat previously drug resistant patients. Development in this area is described by Mittapalli and Roberts. Their review focuses on antiepileptic compounds that are distinct from most currently used drugs. Specifically, vesicle glycoprotein 2A (SV2A) ligands, non-competitive AMPA-R antagonists, voltage-gated potassium channel (KCNQ2/Q3) activators and galanin receptor modulators are discussed. In addition, structure activity relationships of these novel groups of drugs are also described. The next article of the issue deals with the role of astrocytes in epileptogenesis. Apart from the well-established role of removing glutamate from the extracellular space, astrocytes may have a variety of additional neuronal functions by which they can affect neuronal excitability. László Héja describes the role of gliotransmission, glutamate, GABA and ATP release and gap junctional communication in a review article. In addition, the contribution of glial cells to blood-brain barrier dysfunction, inflammatory pathways and alterations in mircoRNA expression profile is also discussed in the article. Apart from classical neurotransmitters, neuromodulators with slower actions can also affect epileptogenesis. Neuropeptides are particularly suitable candidates to affect neuronal excitability because they are released only in response to excessive stimulation and possess G protein-coupled receptors. A large number of neuropeptides have been implicated in epileptogenesis, which are summarized in a review article by Dobolyi et al. Drugs acting on the receptors of neuropeptides that are involved in epilepsy are also described as they represent potential lead compounds for further drug development. Another group of neuromodulator compounds that can affect epileptogenesis is the nucleosides. Adenosine is the best known nucleoside that has anti-seizure activity. Drugs that enhance the extracellular level of adenosine (e.g. adenosine kinase inhibitors and adenosine uptake inhibitors), and adenosine-releasing implants may have beneficial effects on epileptic seizures. The article of Kovács et al. summarizes recent progress in the description of the adenosine system and its involvement in epilepsy. In addition, the paper also discusses the potential role of other nucleosides (uridine, guanosine, inosine) in the control of neuronal excitability and epileptogenesis. It was concluded that the nucleoside system is a promising target in the treatment of epilepsy.

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Why is it important?

Epilepsy is composed of a group of neurological disorders manifested as spontaneous periodically appearing seizures. About 50 million people have epilepsy worldwide thus development of new therapeutic approaches and antiepileptic drugs is one of the most important tasks for epilepsy research.

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