The metabotropic glutamate receptor subtype 2 (mGlu2 ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2 -acting compounds.The anticonvulsant efficacy of two selective mGlu2 -positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model.In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED50 ) values were determined for JNJ-42153605 (3.8 mg/kg), JNJ-40411813 (12.2 mg/kg), and LY404039 (10.9 mg/kg). At the 44 mA stimulus intensity, ED50 values were determined for JNJ-42153605 (5.9 mg/kg), JNJ-40411813 (21.0 mg/kg), LY404039 (14.1 mg/kg), and LEV (345 mg/kg). In addition, subprotective doses of each mGlu2 -acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED50 for LEV by >25-fold. When JNJ-42153605 was administered at varying doses in combination with a single dose of LEV (10 mg/kg), the potency of JNJ-42153605 was increased 3.7-fold. Similarly, when a moderately effective dose of LEV (350 mg/kg) was administered in combination with varying doses of JNJ-40411813, the potency of JNJ-40411813 was increased approximately 14-fold. Plasma levels of JNJ-40411813 and LEV were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects.These studies suggest a potential positive pharmacodynamic effect of mGlu2 -acting compounds in combination with LEV. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.
Central nervous system infection with Theiler's murine encephalomyelitis virus (TMEV) in C57BL/6J mice can model acquired epileptogenesis. Diet alters the acute seizure incidence in TMEV-infected mice; yet it is unclear whether intestinal dysbiosis may also impact acute or chronic behavioral comorbidities. This study thus assessed the impact of diet sterilization in a specific pathogen-free vivarium on acute seizure presentation, the composition of the gut microbiome, and chronic behavioral comorbidities of epilepsy.
Abstract Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID‐19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27‐30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2‐deoxy‐D‐glucose, GAO‐3‐02, JNJ‐40411813, NBI‐921352, NTX‐001, sec ‐butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.
The results of a retrospective study of human leptospirosis cases occurring in Barbados during the period 19-68-74, and of serological findings among high risk occupational groups, fever cases and health centre patients monitored for the disease during 1975-77, indicate that infection by serotype fort-bragg of the Autumnalis group is widespread in this Caribbean island. The occupational groups most affected are sanitation workers and sugar-cane workers. Results of serological tests conducted at the principle hospital are comparable with the results obtained by the microscopic agglutination reference test procedure conducted at the Pan American Zoonosis Centre (CEPANZO).
Summary Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis, and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Herein we discuss the progress on animal models of epilepsy and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler's murine encephalomyelitis virus ( TMEV ) mouse model of viral encephalitis–induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of proinflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti‐inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling‐induced seizures or seizure susceptibility, as well as long‐term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both inflammation‐based models. Utilization of these models may facilitate the identification of age‐specific, syndrome‐ or etiology‐specific therapies for the epilepsies and attendant comorbidities, including the drug‐resistant forms.
