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Preclinical studies in immature and adult rodents and clinical observations show that neuroinflammation and oxidative stress are rapid onset phenomena occurring in the brain during status epilepticus and persisting thereafter. Notably, both neuroinflammation and oxidative stress contribute to the acute and long-term sequelae of status epilepticus thus representing potential druggable targets. Antiinflammatory drugs that interfere with the IL-1β pathway, such as anakinra, can control benzodiazepine-refractory status epilepticus in animals, and there is recent proof-of-concept evidence for therapeutic effects in children with Febrile infection related epilepsy syndrome (FIRES). Inhibitors of monoacylglycerol lipase and P2X7 receptor antagonists are also promising antiinflammatory drug candidates for rapidly aborting de novo status epilepticus and provide neuroprotection. Antiinflammatory and antioxidant drugs administered to rodents during status epilepticus and transiently thereafter, prevent long-term sequelae such as cognitive deficits and seizure progression in animals developing epilepsy. Some drugs are already in medical use and are well-tolerated, therefore, they may be considered for treating status epilepticus and its neurological consequences. Finally, markers of neuroinflammation and oxidative stress are measureable in peripheral blood and by neuroimaging, which offers an opportunity for developing prognostic and predictive mechanistic biomarkers in people exposed to status epilepticus. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The lack of early biomarkers of epileptogenesis precludes a sound prediction of epilepsy development after acute brain injuries and of the natural course of the disease thus impairing the development of antiepileptogenic treatments. We investigated whether the dimensional changes of nonlinear dynamics in EEG/ECoG signals, that were recorded in the early aftermath of different epileptogenic injuries, provide a measure to be exploited as a sensitive prognostic and predictive biomarker for epilepsy. Using three different models of epilepsy in two rodent species, we report a common and significant decrease of nonlinear dynamics dimension in EEG/ECoG tracings during early epileptogenesis. In particular, the magnitude of this dimensional decrease predicts the severity of ensuing epilepsy, and this measure is modulated by disease-modifying or antiepileptogenic treatments. The broad application of EEG/ECoG monitoring in epilepsy underlines the translational value of these findings for enriching the population of patients at risk for developing epilepsy in clinical investigations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

One major unmet clinical need in epilepsy is the identification of therapies to prevent or arrest epilepsy development in patients exposed to a potential epileptogenic insult. The development of such treatments has been hampered by the lack of non-invasive biomarkers that could be used to identify the patients at-risk, thereby allowing to design affordable clinical studies. Our goal was to test the predictive value of cognitive deficits and brain astrocyte activation for the development of epilepsy following a potential epileptogenic injury. We used a model of epilepsy induced by pilocarpine-evoked status epilepticus (SE) in 21-day old rats where 60-70% of animals develop spontaneous seizures after around 70days, although SE is similar in all rats. Learning was evaluated in the Morris water-maze at days 15 and 65 post-SE, each time followed by proton magnetic resonance spectroscopy for measuring hippocampal myo-Inositol levels, a marker of astrocyte activation. Rats were video-EEG monitored for two weeks at seven months post-SE to detect spontaneous seizures, then brain histology was done. Behavioral and imaging data were retrospectively analysed in epileptic rats and compared with non-epileptic and control animals. Rats displayed spatial learning deficits within three weeks from SE. However, only epilepsy-prone rats showed accelerated forgetting and reduced learning rate compared to both rats not developing epilepsy and controls. These deficits were associated with reduced hippocampal neurogenesis. myo-Inositol levels increased transiently in the hippocampus of SE-rats not developing epilepsy while this increase persisted until spontaneous seizures onset in epilepsy-prone rats, being associated with a local increase in S100β-positive astrocytes. Neuronal cell loss was similar in all SE-rats. Our data show that behavioral deficits, together with a non-invasive marker of astrocyte activation, predict which rats develop epilepsy after an acute injury. These measures have potential clinical relevance for identifying individuals at-risk for developing epilepsy following exposure to epileptogenic insults, and consequently, for designing adequately powered antiepileptogenesis trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We studied whether pharmacological blockade of the IL-1β-mediated signaling, rapidly activated in forebrain by epileptogenic injuries, affords neuroprotection in two different rat models of status epilepticus (SE). As secondary outcome, we measured treatment's effect on SE-induced epileptogenesis. IL-1β signaling was blocked by systemic administration of two antiinflammatory drugs, namely human recombinant IL-1 receptor antagonist (anakinra), the naturally occurring and clinically used competitive IL-1 receptor type 1 antagonist, and VX-765 a specific non-peptide inhibitor of IL-1β cleavage and release. Antiinflammatory drugs were given 60min after antiepileptic (AED) drug-controlled SE induced by pilocarpine, or 180min after unrestrained electrical SE, for 7days using a protocol yielding therapeutic drug levels in brain. This drug combination significantly decreased both IL-1β expression in astrocytes and cell loss in rat forebrain. Neuroprotection and the antiinflammatory effect were more pronounced in the electrical SE model. Onset of epilepsy, and frequency and duration of seizures 3months after electrical SE were not significantly modified. Transcriptomic analysis in the hippocampus showed that the combined treatment did not affect the broad inflammatory response induced by SE during epileptogenesis. In particular, the treatment did not prevent the induction of the complement system and Toll-like receptors, both contributing to cell loss and seizure generation. We conclude that the IL-1β signaling represents an important target for reducing cell loss after SE. The data highlight a new class of clinically tested agents affording neuroprotection after a delayed post-injury intervention. Earlier blockade of this rapid onset inflammatory pathway during SE, or concomitant treatment with antiinflammatory drugs targeting additional components of the broad inflammatory response to SE, or co-treatment with AEDs, is likely to be required for optimizing beneficial outcomes., (© 2013.)

Pharmacological blockade of NR2B-containing N-methyl-d-aspartate receptors (NMDARs) during epileptogenesis reduces neurodegeneration provoked in the rodent hippocampus by status epilepticus. The functional consequences of NMDAR activation are crucially influenced by their synaptic vs extrasynaptic localization, and both NMDAR function and localization are dependent on the presence of the NR2B subunit and its phosphorylation state. We investigated whether changes in NR2B subunit phosphorylation, and alterations in its neuronal membrane localization and cellular expression occur during epileptogenesis, and if these changes are involved in neuronal cell loss. We also explored NR2B subunit changes both in the acute phase of status epilepticus and in the chronic phase of spontaneous seizures which encompass the epileptogenesis phase. Levels of Tyr1472 phosphorylated NR2B subunit decreased in the post-synaptic membranes from rat hippocampus during epileptogenesis induced by electrical status epilepticus. This effect was concomitant with a reduced interaction between NR2B and post-synaptic density (PSD)-95 protein, and was associated with decreased CREB phosphorylation. This evidence suggests an extra-synaptic localization of NR2B subunit in epileptogenesis. Accordingly, electron microscopy showed increased NR2B both in extra-synaptic and pre-synaptic neuronal compartments, and a concomitant decrease of this subunit in PSD, thus indicating a shift in NR2B membrane localization. De novo expression of NR2B in activated astrocytes was also found in epileptogenesis indicating ectopic receptor expression in glia. The NR2B phosphorylation changes detected at completion of status epilepticus, and interictally in the chronic phase of spontaneous seizures, are predictive of receptor translocation from synaptic to extrasynaptic sites. Pharmacological blockade of NR2B-containing NMDARs by ifenprodil administration during epileptogenesis significantly reduced pyramidal cell loss in the hippocampus, showing that the observed post-translational and cellular changes of NR2B subunit contribute to excitotoxicity. Therefore, pharmacological targeting of misplaced NR2B-containing NMDARs, or prevention of these NMDAR changes, should be considered to block excitotoxicity which develops after various pro-epileptogenic brain injuries., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Oil-soluble calcium carbonate colloids are used as detergent additives in lubricating oils. They are colloidal dispersions of calcium carbonate particles stabilized by different surfactants; in this study alkyl-aryl-sulfonates and sulfurized alkyl-phenates, widely used in the synthesis of these additives, are considered. The physical properties of surfactant layers surrounding the surfaces of calcium carbonate particles were analyzed by using some nitroxide spin-probes (stable free radicals) and observing the corresponding ESR spectra. The spin-probe molecules contain polar groups which tend to tether them to the carbonate particle polar surface. They can reach these surfaces only if the surfactant layers are not very compact, hence the relative amounts of spin-probe molecules accessing carbonate surfaces are an index of the compactness of surfactant core. ESR signals of spin-probe molecules dissolved in oil or "locked" near the carbonate surfaces are different because of the different molecular mobility. Through deconvolution of the ESR spectra, the fraction of spin-probes penetrating surfactant shells have been calculated, and differences were observed according to the surfactant molecular structures. Moreover, by using specially labeled spin-probes based on stearic acids, functionalized at different separations from the carboxylic acid group, it was possible to interrogate the molecular physical behavior of surfactant shells at different distances from carbonate surfaces. Molecular modeling was applied to generate some three-dimensional micellar models of the colloidal stabilizations of the stabilized carbonate particles with different molecular structures of the surfactant. The diffusion of spin-probe molecules into the surfactant shells were studied by applying a starting force to push the molecules towards the carbonate surfaces and then observing the ensuing behavior. The simulations are in accordance with the ESR data and show that the geometrical organization of the surfactants depends on their molecular structure. The compactness of surfactant shells influences the properties of overbased detergents, especially their stability, their interaction with other additives used in lubricating oil formulations and with the acids produced by the combustion of fuel., (Copyright 2010 Elsevier Inc. All rights reserved.)