The Anti-Epileptic Effects of Carbenoxolone In Vitro and In Vivo

Gap junctions (GJs) are intercellular junctions that allow the direct transfer of ions and small molecules between neighboring cells, and GJs between astrocytes play an important role in the development of various pathologies of the brain, including regulation of the pathological neuronal synchronization underlying epileptic seizures. Recently, we found that a pathological change is observed in astrocytes during the ictal and interictal phases of 4-aminopyridin (4-AP)-elicited epileptic activity in vitro, which was correlated with neuronal synchronization and extracellular epileptic electrical activity. This finding raises the question: Does this signal depend on GJs between astrocytes? In this study we investigated the effect of the GJ blocker, carbenoxolone (CBX), on epileptic activity in vitro and in vivo. Based on the results obtained, we came to the conclusion that the astrocytic syncytium formed by GJ-associated astrocytes, which is responsible for the regulation of potassium, affects the formation of epileptic activity in astrocytes in vitro and epileptic seizure onset. This effect is probably an important, but not the only, mechanism by which CBX suppresses epileptic activity. It is likely that the mechanisms of selective inhibition of GJs between astrocytes will show important translational benefits in anti-epileptic therapies.

Cognitive Impairment in People with Epilepsy

People with epilepsy frequently have cognitive impairment. The majority of cognitive problems is influenced by a variety of interlinked factors, including the early onset of epilepsy and the frequency, intensity and duration of seizures, along with the anti-epileptic drug treatment. With a systematic review, we investigate significant factors about the cognitive impairment in epilepsy. Most cognitive problems in adult people with epilepsy include memory, attention and executive function deficits. However, which cognitive area is mainly affected highly depends on the location of epileptic activity. Moreover, modifications in signalling pathways and neuronal networks have an essential role in both the pathophysiology of epilepsy and in the mechanism responsible for cognitive impairment. Additionally, studies have shown that the use of polytherapy in the treatment of epilepsy with anti-epileptic drugs (AEDs) heightens the risk for cognitive impairment. It can be challenging to distinguish the contribution of each factor, because they are often closely intertwined.

Autism spectrum disorders and epilepsy: dual diagnosis and therapeutic strategies (literature review)

Autism spectrum disorders (ASD) are characterized by significant genetic and clinical polymorphism, comorbidity with neurological and mental disorders. In children with ASD, hotbeds of epileptiform and specific epileptic activity are often registered on the electroencephalogram (EEG), which have a causal relationship with behavioral and emotional disorders. The presence of specific epileptic activity on the EEG, impaired social reciprocity and repetitive behavior may be manifestations of a single pathological process, that results in developmental disorder. The course of ASD can be complicated by epileptic seizures, in particular with the use of neurometabolic drugs. According to the results of some controlled studies, antiepileptic drugs (AED) have shown their effectiveness in the treatment of mental disorders in ASD, including emotional instability, irritability, inhibition of movement. AED which stimulate neurotransmission of γ-aminobutyric acid, are more effective in ASD than blockers of the glutamatergic system. Thymoisoleptic properties of some AED, in particular carbamazepine, valproate acid, lamotrigine in some controlled studies have shown efficacy in the regulation of mood disorders in both children with ASD and children with epilepsy. With the use of carbamazepine, topiramate in children with ASD, there may be impaired attention and cognitive activity; deterioration of attention may be accompanied by increased hyperactivity, impulsivity, motor deceleration. The use of AEDs should be expected to increase the frequency and severity of side effects, including cognitive impairment, motor development, which may lead to impaired general functioning and premature disability, even with seizure control. Specific data on alternative treatments for ASD with seizures such as diet (ketogenic, modified Atkins) are discussed.

Neuroinflammation in Epilepsy—Diagnostics and Therapeutic Perspectives

Epilepsy is a neurological disease that affects approximately 1% of the world’s population. Epilepsy is characterized by the occurrence of repeated epileptic seizures due to abnormal neuronal activity. Although this disorder is currently incurable, it can be controlled for years with the appropriate therapy and patient adherence. Inflammation is an organism’s natural response to a pathological stimulus, aimed at eliminating the triggering factor. Multiple studies point out a significant correlation between an increased level of inflammatory mediators and the frequency of epileptic seizures. Increased levels of IL-1β, IL-2, IL-4, IL-6, IFN-γ, and TNF-α were found in the serum of patients with epilepsy. Additionally, pro-inflammatory cytokines were found to be upregulated during epileptic activity in rodents: CCL2 and CCR2 receptor expression was shown to be upregulated during inflammation induced by lipopolysaccharide administration, and CXCR5 was found to be primarily upregulated in brain cells. Early detection of the described factors may serve as a biomarker for epilepsy but also hold potential in developing novel immunomodulating therapies. Thus, a better understanding of the immune system’s involvement is necessary for the development of new therapeutic perspectives in epilepsy.

Surgical Aspects of Corpus Callosotomy

Corpus callosotomy (CC) is one of the options in epilepsy surgeries to palliate patient seizures, and is typically applied for drop attacks. The mechanisms of seizure palliation involve disrupting the propagation of epileptic activity to the contralateral side of the brain. This review article focuses on the surgical aspects of CC. As a variations of CC, anterior two-thirds, posterior one-third, and total callosotomy are described with intraoperative photographs. As less-invasive surgical variations, recent progress in endoscopic CC, and CC without craniotomy, is described. CC remains acceptable under the low prevalence of complications, and surgeons should make the maximum effort to minimize the complication rate.

Future of Neurology & Technology: Stereo-electroencephalography in Presurgical Epilepsy Evaluation

Stereo-electroencephalography (SEEG) is not only a sophisticated and highly technological investigation but a new and better way to conceptualize the spatial and temporal dynamics of epileptic activity. The first intracranial investigations with SEEG were carried out in France in the mid-twentieth century; however, its use in North America is much more recent. Given its significantly lower risk of complications and its ability to sample both superficial and deep structures as well as both hemispheres simultaneously, SEEG has become the preferred method to conduct intracranial EEG monitoring in most comprehensive epilepsy centers in North America. SEEG is an invasive neurophysiological methodology used for advanced pre-surgical work-up in the 20% of drug-resistant patients with more complex focal epilepsy in whom non-invasive investigations do not allow to decide on surgical candidacy. SEEG uses stereotactically-implanted depth electrodes to map the origin and propagation of epileptic seizures by creating a three-dimensional representation of the abnormal electrical activity in the brain. SEEG analysis takes into account the background, interictal, and ictal activity, as well as the results of cortical electrical stimulation procedures, to reliably delineate the epileptogenic network. By means of a clinical vignette, this article will walk general neurologists, but especially neurology trainees through the immense potential of this methodology. In summary, SEEG enables to accurately identify the epileptogenic zone in patients with drug-resistant focal epilepsy who otherwise would be not amenable to surgical treatment, the best way to improve seizure control and achieve seizure-freedom in this patient population.

PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model.

The transcriptional coactivator, PGC-1α (peroxisome proliferator activated receptor gamma coactivator 1α), plays a key role coordinating energy requirement within cells. Its importance is reflected in the growing number of psychiatric and neurological conditions that have been associated with reduced PGC-1α levels. In cortical networks, PGC-1α is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1a deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1α specifically in the PV-expressing cells (PGC-1αPV-/-) blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell-class specific knock-out of PGC-1α appears to have a novel anti-epileptic effect, as assayed in brain slices bathed in 0 Mg2+ media. The rate of occurrence of pre-ictal discharges developed approximately equivalently in wild-type and PGC-1αPV-/- brain slices, but the intensity of these discharges was lower in PGC-1αPV-/- slices, as evident from the reduced power in the gamma range and reduced firing rates in both PV interneurons and pyramidal cells during these discharges. Reflecting this reduced intensity in the pre-ictal discharges, the PGC-1αPV-/- brain slices experienced many more discharges before transitioning into a seizure-like event. Consequently, there was a large increase in the latency to the first seizure-like event in brain slices lacking PGC-1α in PV interneurons. We conclude that knocking down PGC-1α limits the range of PV interneuron firing, and this slows the pathophysiological escalation during ictogenesis.

Adenosine Receptors Modulate the Exogenous Ketogenic Supplement-Evoked Alleviating Effect on Lipopolysaccharide-Generated Increase in Absence Epileptic Activity in WAG/Rij Rats

It has been previously demonstrated that KEKS food containing exogenous ketogenic supplement ketone salt (KS) and ketone ester (KE) decreased the lipopolysaccharide (LPS)-generated increase in SWD (spike-wave discharge) number in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, likely through ketosis. KEKS-supplemented food-generated ketosis may increase adenosine levels, and may thus modulate both neuroinflammatory processes and epileptic activity through adenosine receptors (such as A1Rs and A2ARs). To determine whether these adenosine receptors are able to modify the KEKS food-generated alleviating effect on LPS-evoked increases in SWD number, an antagonist of A1R DPCPX (1,3-dipropyl-8-cyclopentylxanthine; 0.2 mg/kg) with LPS (50 µg/kg) and an antagonist of A2AR SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; 0.5 mg/kg) with LPS were co-injected intraperitoneally (i.p.) on the ninth day of KEKS food administration, and their influence not only on the SWD number, but also on blood glucose, R-beta-hydroxybutyrate (R-βHB) levels, and body weight were measured. We showed that inhibition of A1Rs abolished the alleviating effect of KEKS food on LPS-generated increases in the SWD number, whereas blocking A2ARs did not significantly modify the KEKS food-generated beneficial effect. Our results suggest that the neuromodulatory benefits of KEKS-supplemented food on absence epileptic activity are mediated primarily through A1R, not A2AR.

Insertion of Calcium-Permeable AMPA Receptors during Epileptiform Activity In Vitro Modulates Excitability of Principal Neurons in the Rat Entorhinal Cortex

Epileptic activity leads to rapid insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) into the synapses of cortical and hippocampal glutamatergic neurons, which generally do not express them. The physiological significance of this process is not yet fully understood; however, it is usually assumed to be a pathological process that augments epileptic activity. Using whole-cell patch-clamp recordings in rat entorhinal cortex slices, we demonstrate that the timing of epileptiform discharges, induced by 4-aminopyridine and gabazine, is determined by the shunting effect of Ca2+-dependent slow conductance, mediated predominantly by K+-channels. The blockade of CP-AMPARs by IEM-1460 eliminates this extra conductance and consequently increases the rate of discharge generation. The blockade of NMDARs reduced the additional conductance to a lesser extent than the blockade of CP-AMPARs, indicating that CP-AMPARs are a more significant source of intracellular Ca2+. The study’s main findings were implemented in a mathematical model, which reproduces the shunting effect of activity-dependent conductance on the generation of discharges. The obtained results suggest that the expression of CP-AMPARs in principal neurons reduces the discharge generation rate and may be considered as a protective mechanism.

Inherited Developmental and Epileptic Encephalopathies

Epileptic encephalopathies often have a genetic etiology. The epileptic activity itself exerts a direct detrimental effect on neurodevelopment, which may add to the cognitive impairment induced by the underlying mutation (“developmental and epileptic encephalopathy”). The focus of this review is on inherited syndromes. The phenotypes of genetic disorders affecting ion channels, metabolic signalling, membrane trafficking and exocytosis, cell adhesion, cell growth and proliferation are discussed. Red flags suggesting family of genes or even specific genes are highlighted. The knowledge of the phenotypical spectrum can indeed prompt the clinician to suspect specific etiologies, expediting the diagnosis.