Altered GABA Signaling in Early Life Epilepsies

The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAA signaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAA receptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABAA signaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain

Harmonization in preclinical epilepsy research: A joint AES/ILAE translational initiative

Among the priority next steps outlined during the first translational epilepsy research workshop in London, United Kingdom (2012), jointly organized by the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE), are the harmonization of research practices used in preclinical studies and the development of infrastructure that facilitates multicenter preclinical studies. The AES/ILAE Translational Task Force of the ILAE has been pursuing initiatives that advance these goals. In this supplement, we present the first reports of the working groups of the Task Force that aim to improve practices of performing rodent videoâ\u80\u93electroencephalography (vEEG) studies in experimental controls, generate systematic reviews of preclinical research data, and develop preclinical common data elements (CDEs) for epilepsy research in animals

Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed

Elucidation of the role of the mammalian endoproteases furin, PC1, and PC2 in rat prosomatostatin processing

Mammalian prosomatostatin (PSS) is cleaved at an Arg-Lys doublet in order to produce somatostatin-14 (SS-14), and at two singlets, Arg and Lys, in order to release SS-28 and PSS$sb{ lbrack 1{-}10 rbrack}$ respectively. Furin, PC1, and PC2 are three recently cloned mammalian endoproteases, associated with the Golgi (furin) or targeted towards the secretory granules of the regulated pathway (PC1 and PC2). In order to determine the enzymes involved in the proteolytic processing of PSS and localize the endoproteolytic reactions in specific compartments of the secretory pathway, I compared PSS processing in endocrine (AtT-20, GH3, and GH4C1 pituitary cells) or nonendocrine tumor cell lines (COS-7 kidney cells, PC 12 pheochromocytoma, LoVo colon adenocarcinoma cells). The efficiency of PSS processing to SS-14, SS-28, and PSS$sb{ lbrack 1{-}10 rbrack}$ was correlated with: (i) secretion through the constitutive or regulated pathway, (ii) mRNA expression for furin, PC1 and PC2, and (iii) exogenous expression of furin, PC1, and PC2 in cells deficient in these proteinases. Coexpression of PC1 and PC2 with rat PSS was accomplished by transient (COS-7 cells) or stable (GH4C1 cells) cotransfections of their cDNAs in the respective cell lines. In the case of furin, recombinant vaccinia viruses expressing human furin or rat PSS were used to coinfect COS-7 or LoVo cells. Furthermore, I examined the effect of granules on the expression of PC2 and on PSS processing, by incubating GH4C1 cells with insulin, EGF, and $beta$-estradiol, a treatment known to induce granule formation. Cell extracts and secretion media were further analyzed by HPLC and somatostatin specific RIAs.Conclusions. (i) PSS is capable of monobasic processing within the constitutive secretory pathway. (ii) Such cleavages may be effected by furin or related endoproteases but are relatively inefficient. (iii) PC1 is capable of dibasic cleavage of PSS to SS-14 in both constitutive or regulated secretory cells. (iv) PC2 mediates SS-14 conversion only if expressed in regulated secretory cells. (v) The milieu of secretory cells, and not the granules, is required for PC2 activity. (vi) Furin is a mammalian SS-28 convertase, but not the unique one. (vii) A yet unknown endoprotease is responsible for PSS$sb{ lbrack 1{-}10 rbrack}$ cleavage