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Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures. To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology. High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease. In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy., Competing Interests: Declaration of Competing Interest Toshiya Nishi and Shinichi Kondo are employed by Takeda Pharmaceutical Company Limited. Matthew During and Brett Abrahams were/are employed by Ovid Therapeutics., (Copyright © 2022. Published by Elsevier Inc.)

Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing seizures or improving disease prognosis, including neurological comorbidities. The search of pathogenic mechanisms of epileptogenesis highlighted that neuroinflammatory cytokines [i.e. interleukin-1β (IL-1β), tumour necrosis factor-α (Tnf-α)] are induced in human and experimental epilepsies, and contribute to seizure generation in animal models. A major role in controlling the inflammatory response is played by specialized pro-resolving lipid mediators acting on specific G-protein coupled receptors. Of note, the role that these pathways have in epileptogenic tissue remains largely unexplored. Using a murine model of epilepsy, we show that specialized pro-resolving mechanisms are activated by status epilepticus before the onset of spontaneous seizures, but with a marked delay as compared to the neuroinflammatory response. This was assessed by measuring the time course of mRNA levels of 5-lipoxygenase (Alox5) and 15-lipoxygenase (Alox15), the key biosynthetic enzymes of pro-resolving lipid mediators, versus Il1b and Tnfa transcripts and proteins. In the same hippocampal tissue, we found a similar delayed expression of two main pro-resolving receptors, the lipoxin A4 receptor/formyl peptide receptor 2 and the chemerin receptor. These receptors were also induced in the human hippocampus after status epilepticus and in patients with temporal lobe epilepsy. This evidence supports the hypothesis that the neuroinflammatory response is sustained by a failure to engage pro-resolving mechanisms during epileptogenesis. Lipidomic LC-MS/MS analysis showed that lipid mediator levels apt to resolve the neuroinflammatory response were also significantly altered in the hippocampus during epileptogenesis with a shift in the biosynthesis of several pro-resolving mediator families including the n-3 docosapentaenoic acid (DPA)-derived protectin D1. Of note, intracerebroventricular injection of this mediator during epileptogenesis in mice dose-dependently reduced the hippocampal expression of both Il1b and Tnfa mRNAs. This effect was associated with marked improvement in mouse weight recovery and rescue of cognitive deficit in the novel object recognition test. Notably, the frequency of spontaneous seizures was drastically reduced by 2-fold on average and the average seizure duration was shortened by 40% after treatment discontinuation. As a result, the total time spent in seizures was reduced by 3-fold in mice treated with n-3 DPA-derived protectin D1. Taken together, the present findings demonstrate that epilepsy is characterized by an inadequate engagement of resolution pathways. Boosting endogenous resolution responses significantly improved disease outcomes, providing novel treatment avenues.

Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies.

Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing seizures or improving disease prognosis, including neurological comorbidities. The search of pathogenic mechanisms of epileptogenesis highlighted that neuroinflammatory cytokines [i.e. interleukin-1β (IL-1β), tumour necrosis factor-α (Tnf-α)] are induced in human and experimental epilepsies, and contribute to seizure generation in animal models. A major role in controlling the inflammatory response is played by specialized pro-resolving lipid mediators acting on specific G-protein coupled receptors. Of note, the role that these pathways have in epileptogenic tissue remains largely unexplored. Using a murine model of epilepsy, we show that specialized pro-resolving mechanisms are activated by status epilepticus before the onset of spontaneous seizures, but with a marked delay as compared to the neuroinflammatory response. This was assessed by measuring the time course of mRNA levels of 5-lipoxygenase (Alox5) and 15-lipoxygenase (Alox15), the key biosynthetic enzymes of pro-resolving lipid mediators, versus Il1b and Tnfa transcripts and proteins. In the same hippocampal tissue, we found a similar delayed expression of two main pro-resolving receptors, the lipoxin A4 receptor/formyl peptide receptor 2 and the chemerin receptor. These receptors were also induced in the human hippocampus after status epilepticus and in patients with temporal lobe epilepsy. This evidence supports the hypothesis that the neuroinflammatory response is sustained by a failure to engage pro-resolving mechanisms during epileptogenesis. Lipidomic LC-MS/MS analysis showed that lipid mediator levels apt to resolve the neuroinflammatory response were also significantly altered in the hippocampus during epileptogenesis with a shift in the biosynthesis of several pro-resolving mediator families including the n-3 docosapentaenoic acid (DPA)-derived protectin D1. Of note, intracerebroventricular injection of this mediator during epileptogenesis in mice dose-dependently reduced the hippocampal expression of both Il1b and Tnfa mRNAs. This effect was associated with marked improvement in mouse weight recovery and rescue of cognitive deficit in the novel object recognition test. Notably, the frequency of spontaneous seizures was drastically reduced by 2-fold on average and the average seizure duration was shortened by 40% after treatment discontinuation. As a result, the total time spent in seizures was reduced by 3-fold in mice treated with n-3 DPA-derived protectin D1. Taken together, the present findings demonstrate that epilepsy is characterized by an inadequate engagement of resolution pathways. Boosting endogenous resolution responses significantly improved disease outcomes, providing novel treatment avenues. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) has a dismal prognosis even with the best available treatment. Different studies have suggested a possible impact of antiepileptic drugs (AED) on survival in patients with GBM. A recent pooled analysis of prospective clinical trials in newly diagnosed GBM found no significant survival benefit in GBM patients treated with AED. We performed a retrospective study on adult patients with GBM in order to evaluate the impact of AED therapy on overall survival (OS), after adjusting for known prognostic factor (age, extent of surgery, Karnofsky performance status, radiochemotherapy). A total of 285 patients were analyzed. Of them 144 received a non-enzyme-inducing (NEIAED) and 95 an enzyme-inducing AED (EIAED). At univariate analysis the OS of patients receiving AED was not significantly different from that of patients not receiving an AED (HR 0.98, 95%CI 0.69-1.4, p = 0.925), moreover OS was not significantly different between patients receiving EIAED or NEIAED. At multivariate analysis a trend to more prolonged survival (HR 0.8, 95% CI 0.59-1.08, p = 0.15) was detected in patients treated with NEIAED. The question whether treatment with AED may increase OS in GBM patients remains unanswered and randomized extremely large controlled clinical trial would be necessary to elucidate the possible impact of AED on prognosis. In the meantime the use of AED in GBM patients, based on the presumed potential antitumour activity, is not recommended. [ABSTRACT FROM AUTHOR]

CXCL1, a functional murine orthologue of the human chemokine CXCL8 (IL-8), and its CXCR1 and CXCR2 receptors were investigated in a murine model of acquired epilepsy developing following status epilepticus (SE) induced by intra-amygdala kainate. CXCL8 and its receptors were also studied in human temporal lobe epilepsy (TLE). The functional involvement of the chemokine in seizure generation and neuronal cell loss was assessed in mice using reparixin (formerly referred to as repertaxin), a non-competitive allosteric inhibitor of CXCR1/2 receptors. We found a significant increase in hippocampal CXCL1 level within 24 h of SE onset that lasted for at least 1 week. No changes were measured in blood. In analogy with human TLE, immunohistochemistry in epileptic mice showed that CXCL1 and its two receptors were increased in hippocampal neuronal cells. Additional expression of these molecules was found in glia in human TLE. Mice were treated with reparixin or vehicle during SE and for additional 6 days thereafter, using subcutaneous osmotic minipumps. Drug-treated mice showed a faster SE decay, a reduced incidence of acute symptomatic seizures during 48 h post-SE, and a delayed time to spontaneous seizures onset compared to vehicle controls. Upon reparixin discontinuation, mice developed spontaneous seizures similar to vehicle mice, as shown by EEG monitoring at 14 days and 2.5 months post-SE. In the same epileptic mice, reparixin reduced neuronal cell loss in the hippocampus vs vehicle-injected mice, as assessed by Nissl staining at completion of EEG monitoring. Reparixin administration for 2 weeks in mice with established chronic seizures, reduced by 2-fold on average seizure number vs pre-treatment baseline, and this effect was reversible upon drug discontinuation. No significant changes in seizure number were measured in vehicle-injected epileptic mice that were EEG monitored in parallel. Data show that CXCL1-IL-8 signaling is activated in experimental and human epilepsy and contributes to acute and chronic seizures in mice, therefore representing a potential new target to attain anti-ictogenic effects. • CXCL1 is increased in mouse brain and not in blood during acute and chronic seizures. • CXCL1/IL-8 and their receptors are induced in neurons and glia in epileptic mice and human TLE. • Reparixin by inhibiting CXCR1/2 receptors reduces seizures and neuronal loss in mice. • CXCL1/IL-8 signaling represents a potential new target to attain anti-ictogenic effects. [ABSTRACT FROM AUTHOR]

A retraction is presented to the article "Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy".