Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders

The mechanism of action of several antiepileptic drugs (AEDs) rests on their ability tomodulate the activity of voltage-gated sodium currents that are responsible for fast action potentialgeneration. Recent data indicate that lacosamide - a compound with analgesic and anticonvulsanteffects in animal models - shares a similar mechanism. When compared with other AEDs, lacosamidehas the unique ability to interact with sodium channel slow inactivation without affecting fastinactivation. This article reviews these findings and discusses their relevance within the context ofneuronal activity seen during epileptiform discharges generated by limbic neuronal networks in thepresence of chemical convulsants. These seizure-like events are characterized by sustained dischargesof sodium-dependent action potentials supported by robust depolarizations thus providingsynchronization within neuronal networks. Generally, AEDs such as phenytoin, carbamazepine andlamotrigine block sodium channels when activated. By contrasts, lacosamide facilitates slowinactivation of sodium channels both in term of kinetics and voltage-dependency. This effect may berelatively selective for repeatedly depolarized neurons such as those participating in seizure activity inwhich the persistence of sodium currents is more pronounced and promotes neuronal excitation. Theclinical effectiveness of lacosamide has been demonstrated in randomized placebo-controlled doubleblindparallel-group, adjunctive-therapy trials in patients with refractory partial seizures. Furtherstudies should determine whether lacosamide effects in animal models and in clinical settings are fullyexplained by its selective action on sodium current slow inactivation or whether other effects (e.g.,interactions with the collapsin-response mediator protein 2) play a contributory role

Repeated 6-Hz Corneal Stimulation Progressively Increases FosB/\u394FosB Levels in the Lateral Amygdala and Induces Seizure Generalization to the Hippocampus

Exposure to repetitive seizures is known to promote convulsions which depend on specific patterns of network activity. We aimed at evaluating the changes in seizure phenotype and neuronal network activation caused by a modified 6-Hz corneal stimulation model of psychomotor seizures. Mice received up to 4 sessions of 6-Hz corneal stimulation with fixed current amplitude of 32 mA and inter-stimulation interval of 72 h. Video-electroencephalography showed that evoked seizures were characterized by a motor component and a non-motor component. Seizures always appeared in frontal cortex, but only at the fourth stimulation they involved the hippocampus, suggesting the establishment of an epileptogenic process. Duration of seizure non-motor component progressively decreased after the second session, whereas convulsive seizures remained unchanged. In addition, a more severe seizure phenotype, consisting of tonic-clonic generalized convulsions, was predominant after the second session. Immunohistochemistry and double immunofluorescence experiments revealed a significant increase in neuronal activity occurring in the lateral amygdala after the fourth session, most likely due to activity of principal cells. These findings indicate a predominant role of amygdala in promoting progressively more severe convulsions as well as the late recruitment of the hippocampus in the seizure spread. We propose that the repeated 6-Hz corneal stimulation model may be used to investigate some mechanisms of epileptogenesis and to test putative antiepileptogenic drugs

The pilocarpine model of temporal lobe epilepsy

Understanding the pathophysiogenesis of temporal lobe epilepsy (TLE) largely rests on the use of modelsof status epilepticus (SE), as in the case of the pilocarpine model. The main features of TLE are: (i) epilepticfoci in the limbic system; (ii) an “initial precipitating injury”; (iii) the so-called “latent period”; and (iv)the presence of hippocampal sclerosis leading to reorganization of neuronal networks. Many of thesecharacteristics can be reproduced in rodents by systemic injection of pilocarpine; in this animal model, SEis followed by a latent period and later by the appearance of spontaneous recurrent seizures (SRSs). Theseprocesses are, however, influenced by experimental conditions such as rodent species, strain, gender, age,doses and routes of pilocarpine administration, as well as combinations with other drugs administeredbefore and/or after SE. In the attempt to limit these sources of variability,we evaluated themethodologicalprocedures used by several investigators in the pilocarpine model; in particular, we have focused on thebehavioural, electrophysiological and histopathological findings obtained with different protocols. Weaddressed the various experimental approaches published to date, by comparing mortality rates, onset ofSRSs, neuronal damage, and network reorganization. Based on the evidence reviewed here, we proposethat the pilocarpine model can be a valuable tool to investigate the mechanisms involved in TLE, and evenmore so when standardized to reduce mortality at the time of pilocarpine injection, differences in latentperiod duration, variability in the lesion extent, and SRS frequency

Protective but Not Anticonvulsant Effects of Ghrelin and JMV-1843 in the Pilocarpine Model of Status epilepticus.

In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth hormone secretagogue-receptor 1a (GHS-R1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45\ub10.07 mm2 in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P<0.05) and JMV-1843 (P<0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P<0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus

Wearable Electronics for Neurological Applications: a Review of Undergraduate Engineering Programmes

Neuroscientists accept that we are indeed faced with an overwhelming challenge in understanding how the brain works. A better understanding of the brain will ultimately enable us to appreciate how well our students have grasped their learning materials. It will also enable us to diagnose and treat neurological disorders more effectively. Designing and developing the next generation of wearable devices is an important steppingstone towards this endeavor. Consequently, interdisciplinary efforts are required in co-creating educational materials that enable future neuro-engineers to develop these new devices. The aim of this article is to present a review of current undergraduate programmes that deal with this issue. Moreover, we provide recommendations for how new programmes in this field can be organized and delivered to ensure effective benefit for transnational students

Involvement of PPAR\u3b3 in the anticonvulsant activity of EP-80317, a ghrelin receptor antagonist

Ghrelin, des-acyl ghrelin and other related peptides possess anticonvulsant activities. Although ghrelin and cognate peptides were shown to physiologically regulate only the ghrelin receptor, some of them were pharmacologically proved to activate the peroxisome proliferator-activated receptor gamma (PPAR\u3b3) through stimulation of the scavenger receptor CD36 in macrophages. In our study, we challenged the hypothesis that PPAR\u3b3 could be involved in the anticonvulsant effects of EP-80317, a ghrelin receptor antagonist. For this purpose, we used the PPAR\u3b3 antagonist GW9662 to evaluate the modulation of EP-80317 anticonvulsant properties in two different models. Firstly, the anticonvulsant effects of EP-80317 were studied in rats treated with pilocarpine to induce status epilepticus (SE). Secondly, the anticonvulsant activity of EP-80317 was ascertained in the repeated 6-Hz corneal stimulation model in mice. Behavioral and video electrocorticographic (ECoG) analyses were performed in both models. We also characterized levels of immunoreactivity for PPAR\u3b3 in the hippocampus of 6-Hz corneally stimulated mice. EP-80317 predictably antagonized seizures in both models. Pre-treatment with GW9662 counteracted almost all EP-80317 effects both in mice and rats. Only the effects of EP-80317 on power spectra of ECoGs recorded during repeated 6-Hz corneal stimulation were practically unaffected by GW9662 administration. Moreover, GW9662 alone produced a decrease in the latency of tonic-clonic seizures and accelerated the onset of SE in rats. Finally, in the hippocampus of mice treated with EP-80317 we found increased levels of PPAR\u3b3 immunoreactivity. Overall, these results support the hypothesis that PPAR\u3b3 is able to modulate seizures and mediates the anticonvulsant effects of EP-80317

Bioresorbable insertion aids for brain implantable flexible probes: a comparative study on silk fibroin, alginate, and disaccharides

Miniaturized, flexible, and biocompatible neural probes have the potential to circumvent the brain's foreign body response, but the problem of surgical implantation remains. Herein, a probe intended for implantation in the rat hippocampus is coated in four bioresorbable stiffeners to determine which is most effective in aiding insertion. The stiffeners (sucrose, maltose, silk fibroin, and alginate) are evaluated through mechanical, chemical, and dissolution tests. After coating with silk fibroin, the buckling force of the neural probe increases from 0.31 to 75.99 mN. This goes in accordance with subsequent successful insertion tests. Fourier transform infrared spectroscopy results demonstrate the increase in β-sheet content of silk fibroin samples after treatment (e.g., water annealing) and show relevant changes due to dehydration of the alginate hydrogel. Both qualitative and quantitative dissolution studies in artificial cerebrospinal fluid illustrate that alginate and silk fibroin outlasts the disaccharide stiffeners. In this work, a variety of multidisciplinary analyses are carried out to find the best bioresorbable stiffener for deep brain implantable devices with the highest buckling force, longest dissolution time, and the most tunable structure. For the first time, an alginate hydrogel is used as a stiffener to aid insertion, expanding its usefulness beyond neural tissue engineering

Synaptic Reshaping and Neuronal Outcomes in the Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is one of the most common types of focal epilepsy, characterized by recurrent spontaneous seizures originating in the temporal lobe(s), with mesial TLE (mTLE) as the worst form of TLE, often associated with hippocampal sclerosis. Abnormal epileptiform discharges are the result, among others, of altered cell-to-cell communication in both chemical and electrical transmissions. Current knowledge about the neurobiology of TLE in human patients emerges from pathological studies of biopsy specimens isolated from the epileptogenic zone or, in a few more recent investigations, from living subjects using positron emission tomography (PET). To overcome limitations related to the use of human tissue, animal models are of great help as they allow the selection of homogeneous samples still presenting a more various scenario of the epileptic syndrome, the presence of a comparable control group, and the availability of a greater amount of tissue for in vitro/ex vivo investigations. This review provides an overview of the structural and functional alterations of synaptic connections in the brain of TLE/mTLE patients and animal models