Current Medicinal Chemistry - Volume 21, Issue 6, 2014

Neuronal synchronization supports different physiological states such as cognitive functions and sleep, and it is mirrored by identifiable EEG patterns ranging from gamma to delta oscillations. However, excessive neuronal synchronization is often the hallmark of epileptic activity in both generalized and partial epileptic disorders. Here, I will review the synchronizing mechanisms involved in generating epileptiform activity in the limbic system, which is closely involved in the pathophysiogenesis of temporal lobe epilepsy (TLE). TLE is often associated to a typical pattern of brain damage known as mesial temporal sclerosis, and it is one of the most refractory adult form of partial epilepsy. This epileptic disorder can be reproduced in animals by topical or systemic injection of pilocarpine or kainic acid, or by repetitive electrical stimulation; these procedures induce an initial status epilepticus and cause 1-4 weeks later a chronic condition of recurrent limbic seizures. Remarkably, a similar, seizure-free, latent period can be identified in TLE patients who suffered an initial insult in childhood and develop partial seizures in adolescence or early adulthood. Specifically, I will focus here on the neuronal mechanisms underlying three abnormal types of neuronal synchronization seen in both TLE patients and animal models mimicking this disorder: (i) interictal spikes; (ii) high frequency oscillations (80-500 Hz); and (iii) ictal (i.e., seizure) discharges. In addition, I will discuss the relationship between interictal spikes and ictal activity as well as recent evidence suggesting that specific seizure onsets in the pilocarpine model of TLE are characterized by distinctive patterns of spiking (also termed preictal) and high frequency oscillations.

Temporal lobe epilepsy (TLE) is frequently associated with hippocampal sclerosis, possibly caused by a primary brain injury that occurred a long time before the appearance of neurological symptoms. This type of epilepsy is characterized by refractoriness to drug treatment, so to require surgical resection of mesial temporal regions involved in seizure onset. Even this last therapeutic approach may fail in giving relief to patients. Although prevention of hippocampal damage and epileptogenesis after a primary event could be a key innovative approach to TLE, the lack of clear data on the pathophysiological mechanisms leading to TLE does not allow any rational therapy. Here we address the current knowledge on mechanisms supposed to be involved in epileptogenesis, as well as on the possible innovative treatments that may lead to a preventive approach. Besides loss of principal neurons and of specific interneurons, network rearrangement caused by axonal sprouting and neurogenesis are well known phenomena that are integrated by changes in receptor and channel functioning and modifications in other cellular components. In particular, a growing body of evidence from the study of animal models suggests that disruption of vascular and astrocytic components of the blood-brain barrier takes place in injured brain regions such as the hippocampus and piriform cortex. These events may be counteracted by drugs able to prevent damage to the vascular component, as in the case of the growth hormone secretagogue ghrelin and its analogues. A thoroughly investigation on these new pharmacological tools may lead to design effective preventive therapies.

Currently available antiepileptic drugs (AEDs) were developed to suppress seizure activity but less for prevention of epileptogenesis or for treatment of epileptogenic encephalopathies. Despite considerable efforts towards pharmacological control of seizures, about 30 % of epileptic patients do not achieve complete seizure control, and these numbers are even higher in patients suffering from partial seizures - a common form of epilepsy in adults. The mechanisms behind drug-resistance are far from being understood. Likely several unrelated mechanisms might lead in concert to reduced efficacy of the AEDs. Consequently, there is a need for predictive biomarkers of susceptibility to pharmacoresistant seizures and for new therapies interfering with epileptogenesis and preventing development of drug-resistance instead of merely suppressing seizures. This also necessitates the design of novel in vitro and in vivo epilepsy models that would better mimic the progressive nature of epilepsy and resemble the state of a chronic epileptic tissue. In this review we discuss current theories of drug-resistance and give a short summary of the epilepsy models that are frequently used for testing AEDs. We will also highlight caveats of the different models and consider novel approaches to overcome these difficulties. Finally we give a short outlook on unconventional therapies interfering with epileptogenesis as well as with drug delivery and retention.

The WAG/Rij model is a well characterized and validated genetic animal epilepsy model in which the for absence epilepsy highly characteristic spike-wave discharges (SWDs) develop spontaneously. In this review we discuss first some older and many new studies, with an emphasis on pharmacological and neurochemical studies towards the role of GABA and glutamate and the ion channels involved in the pathological firing patterns. Next, new insights and highlights from the last 5-10 years of reaearch in WAG/Rij rats are discussed. First, early environmental factors modulate SWD characteristics and antiepileptogenesis is possible. Also new is that the classically assumed association between sleep spindles and SWDs seems no longer valid as an explanatory role for the occurrence of SWDs in the genetic rodent models. A role of cortical and thalamic glial cells has been revealed, indicating a putative role for inflammatory cytokines. Neurophysiologic and signal analytical studies in this and in another rodent model (GAERS) point towards a cortical site of origin, that SWDs do not have a sudden onset, and propose a more important role for the posterior thalamus than was previously assumed. Finally it is proposed that the reticular nucleus of the thalamus might be heterogeneous with respect to its role in propagation and maintenance of SWDs. The presence of a well-established cortical region in which SWDs are elicited allows for research towards new non-invasive treatment options, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). The first results show the feasibility of this new approach.

Despite notable success over years in the discovery and development of new antiepileptic drugs (AEDs), about 30-40% of the patients are resistant to drug treatment. There is a still significant need to develop novel AEDs that demonstrate superior efficacy, broad spectrum of activities and good safety profile. The synaptic vesicle glycoprotein 2A (SV2A), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) and voltage-gated potassium channels (KCNQ2/Q3) are clinically validated as new molecular targets for epilepsy. The discovery of SV2A as a target for levetiracetam, 2,3-benzodiazepine GYKI 52466 as a non-competitive AMPA-R antagonist and retigabine as a KCNQ2/Q3 channels activator provided a rational basis to develop novel AEDs. The optimization of SV2A binding affinity of levetiracetam led to the discovery of novel high affinity SV2A ligands that displayed superior efficacy and protective index in animal models of epilepsy. The high-throughput screening (HTS) and medicinal chemistry efforts yielded many non-competitive AMPA-R antagonists of which perampanel was recently approved as a first-in-a new class. The efficacy and lack of sub-type selectivity of retigabine prompted many research efforts to discover several potent and selective KCNQ2/Q3 channel activators of distinct chemical scaffolds that are at various stages of clinical development. Despite the known role of galanin and galanin receptor (Gal-R) in epilepsy over a decade, development of potent and brainpenetrant Gal-R agonists is very challenging. The discovery of selective Gal-R2 positive allosteric modulator, CYM 2503, offers a valuable and an alternative approach. The review focuses on the available structure-activity relationships and preclinical efficacy of novel antiepileptic compounds that are distinct from most of the approved AEDs, specifically SV2A ligands, non-competitive AMPA-R antagonists, KCNQ2/Q3 channels activators and Gal-R modulators.

Although glial proliferation of the epileptic loci is recognized for more than a century in certain focal epilepsies, the role of astrocytes in epileptic conditions is receiving significant attention only in recent years. The present review will highlight current knowledge about the various ways astrocytes control neuronal excitability and contribute to genesis, maintenance and suppression of seizures. Besides the widely recognized astrocytic tasks like glutamate clearance, the role of gliotransmission, glutamate, GABA and ATP release as well as gap junctional communication will also be discussed along with the contribution of blood-brain barrier dysfunction, inflammatory pathways and alterations in mircoRNA expression profile to epilepsy. The mechanisms described will help to understand the astrocytic mechanisms contributing to the antiepileptic effect of existing anti-epileptic drugs (AEDs) and current therapeutic strategies and also signifies the potential of specific astrocyte-based AED development.

Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre- and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have receptors implicated in epilepsy and many of them are considered to participate in endogenous neuroprotective actions. Neuropeptide receptors, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic targets. Receptors of hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and receptors of some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin- releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Activation and inhibition of receptors by oral application of peptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration of peptides through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of agonists and antagonists within the central nervous system will also be discussed.

Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.