Since 1993, over 20 new anti-seizure drugs (ASDs) have been identified in well-established animal seizure and epilepsy models and subsequently demonstrated to be clinically effective in ...double-blinded, placebo-controlled clinical trials in patients with focal onset seizures. All clinically-available ASDs on the market today are effective in at least one of only three preclinical seizure and epilepsy models: the acute maximal electroshock (MES), the acute subcutaneous pentylenetetrazol (scPTZ) test, or the kindled rodent with chronic evoked seizures. Thus, it reasons that preclinical ASD discovery does not need significant revision to successfully identify ASDs for the symptomatic treatment of epilepsy. Unfortunately, a significant need still persists for more efficacious and better tolerated ASDs. This is particularly true for those patients whose seizures remain drug resistant. This review will focus on the continued utility of the acute MES and scPTZ tests, as well as the kindled rodent for current and future ASD discovery. These are the only “clinically validated” rodent models to date and been heavily used in the search for novel and more efficacious ASDs. This is to say that promising ASDs have been brought to the clinic on the basis of efficacy in these particular seizure and epilepsy models alone. This review also discusses some of the inherent advantages and limitations of these models relative to existing and emerging preclinical models. It then offers insight into future efforts to develop a preclinical model that will advance a truly transformative therapy for the symptomatic treatment of difficult to treat focal onset epilepsy.
This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.
•All antiseizure drugs (ASDs) are effective in just three rodent seizure models.•Preclinical ASD development likely thus does not need revision to identify ASDs.•Yet pharmacoresistant epilepsy patients still need more efficacious ASDs.•There is thus continued utility of the acute MES and scPTZ tests for ASD discovery.•The kindled rodent also will be of significant benefit to future ASD development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, SAZU, SBCE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Epilepsy is broadly characterized by aberrant neuronal excitability. Glutamate is the predominant excitatory neurotransmitter in the adult mammalian brain; thus, much of past epilepsy research has ...attempted to understand the role of glutamate in seizures and epilepsy. Seizures induce elevations in extracellular glutamate, which then contribute to excitotoxic damage. Chronic seizures can alter neuronal and glial expression of glutamate receptors and uptake transporters, further contributing to epileptogenesis. Evidence points to a shared glutamate pathology for epilepsy and other central nervous system (CNS) disorders, including depression, which is often a comorbidity of epilepsy. Therapies that target glutamatergic neurotransmission are available, but many have met with difficulty because of untoward adverse effects. Better understanding of this system has generated novel therapeutic targets that directly and indirectly modulate glutamatergic signaling. Thus, future efforts to manage the epileptic patient with glutamatergic-centric treatments now hold greater potential.
Since the early 1990s, many new antiepileptic drugs (AEDs) that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug-drug ...interactions have entered the market. However, despite the therapeutic arsenal of old and new AEDs, approximately 30% of patients with epilepsy still suffer from seizures. Thus, there remains a substantial need for the development of more efficacious AEDs for patients with refractory seizures. Here, we briefly review the emerging knowledge on the pathological basis of epilepsy and how it might best be used in the design of new therapeutics. We also discuss the current approach to AED discovery and highlight some of the unique features of newer models of pharmacoresistance and epileptogenesis that have emerged in recent years.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract We recently discovered that forebrain activation of the IL-1 receptor/Toll-like receptor (IL-1R1/TLR4) innate immunity signal plays a pivotal role in neuronal hyperexcitability underlying ...seizures in rodents. Since this pathway is activated in neurons and glia in human epileptogenic foci , it represents a potential target for developing drugs interfering with the mechanisms of epileptogenesis that lead to spontaneous seizures. The lack of such drugs represents a major unmet clinical need. We tested therefore novel therapies inhibiting the IL-1R1/TLR4 signaling in an established murine model of acquired epilepsy. We used an epigenetic approach by injecting a synthetic mimic of micro(mi)RNA-146a that impairs IL1R1/TLR4 signal transduction, or we blocked receptor activation with antiinflammatory drugs. Both interventions when transiently applied to mice after epilepsy onset, prevented disease progression and dramatically reduced chronic seizure recurrence, while the anticonvulsant drug carbamazepine was ineffective. We conclude that IL-1R1/TLR4 is a novel potential therapeutic target for attaining disease-modifications in patients with diagnosed epilepsy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Myocardial extracellular volume (ECV) is elevated in fibrosis or infiltration and can be quantified by measuring the haematocrit with pre and post contrast T1 at sufficient contrast equilibrium. ...Equilibrium CMR (EQ-CMR), using a bolus-infusion protocol, has been shown to provide robust measurements of ECV using a multibreath-hold T1 pulse sequence. Newer, faster sequences for T1 mapping promise whole heart coverage and improved clinical utility, but have not been validated.
Multibreathhold T1 quantification with heart rate correction and single breath-hold T1 mapping using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) were used in equilibrium contrast CMR to generate ECV values and compared in 3 ways.Firstly, both techniques were compared in a spectrum of disease with variable ECV expansion (n=100, 50 healthy volunteers, 12 patients with hypertrophic cardiomyopathy, 18 with severe aortic stenosis, 20 with amyloid). Secondly, both techniques were correlated to human histological collagen volume fraction (CVF%, n=18, severe aortic stenosis biopsies). Thirdly, an assessment of test:retest reproducibility of the 2 CMR techniques was performed 1 week apart in individuals with widely different ECVs (n=10 healthy volunteers, n=7 amyloid patients).
More patients were able to perform ShMOLLI than the multibreath-hold technique (6% unable to breath-hold). ECV calculated by multibreath-hold T1 and ShMOLLI showed strong correlation (r(2)=0.892), little bias (bias -2.2%, 95%CI -8.9% to 4.6%) and good agreement (ICC 0.922, range 0.802 to 0.961, p<0.0001). ECV correlated with histological CVF% by multibreath-hold ECV (r(2)= 0.589) but better by ShMOLLI ECV (r(2)= 0.685). Inter-study reproducibility demonstrated that ShMOLLI ECV trended towards greater reproducibility than the multibreath-hold ECV, although this did not reach statistical significance (95%CI -4.9% to 5.4% versus 95%CI -6.4% to 7.3% respectively, p=0.21).
ECV quantification by single breath-hold ShMOLLI T1 mapping can measure ECV by EQ-CMR across the spectrum of interstitial expansion. It is procedurally better tolerated, slightly more reproducible and better correlates with histology compared to the older multibreath-hold FLASH techniques.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, UILJ, UKNU, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
► Synthesis, packaging, release, and termination of neurotransmitters alter activity. ► Metabolizing enzymes and membrane transporters are integral therapeutic targets. ► Genetically altered mice ...offer insight into the roles of GABA/glutamate. ► GABA and glutamate are targets for antiepileptic and neuroprotective therapies.
The synthesis, release, reuptake, and metabolism of the excitatory and inhibitory neurotransmitters glutamate and GABA, respectively, are tightly controlled. Given the role that these two neurotransmitters play in normal and abnormal neurotransmission, it is important to consider the processes whereby they are regulated. This brief review is focused entirely on the metabolic aspects of glutamate and GABA synthesis and neurotransmission. It describes in limited detail the synthesis, release, reuptake, metabolism, cellular compartmentation and pharmacology of the glutamatergic and GABAergic synapse. This review also provides a summary and brief description of the pathologic and phenotypic features of the various genetic animal models that have been developed in an effort to provide a greater understanding of the role that each of the aforementioned metabolic processes plays in controlling excitatory and inhibitory neurotransmission and how their use will hopefully facilitate the development of safer and more efficacious therapies for the treatment of epilepsy and other neurological disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective
The formation of 24S‐hydroxycholesterol is a brain‐specific mechanism of cholesterol catabolism catalyzed by cholesterol 24‐hydroxylase (CYP46A1, also known as CH24H). CH24H has been ...implicated in various biological mechanisms, whereas pharmacological lowering of 24S‐hydroxycholesterol has not been fully studied. Soticlestat is a novel small‐molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications.
Methods
The anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6‐Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady‐state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics.
Results
Among models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6‐Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S‐hydroxycholesterol lowering in the brain, suggesting that 24S‐hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition.
Significance
The data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012. About 100 basic scientists, clinical pharmacologists ...and neurologists from 20 countries attended the conference, whose main themes included “Indications overlapping with epilepsy” and “Securing the successful development of an investigational antiepileptic drug in the current environment”. Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec -propylbutylacetamide (SPD), VX-765 and YK3089. Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary
Objective
Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol (CBD) in a ...battery of acute seizure models. Additionally, we defined the disease‐modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus–spontaneous recurrent seizures (RISE‐SRS) model of temporal lobe epilepsy (TLE).
Methods
We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure, 6‐Hz psychomotor seizure, and pentylenetetrazol acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective or behavioral toxic dose was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg single dose) in a rat model of pilocarpine‐induced status epilepticus. We defined the effect of chronic CBD administration (200 mg/kg orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE‐SRS model of TLE.
Results
CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine‐induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD's acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time‐dependent increase in seizure burden and improved TLE‐associated motor comorbidities of epileptic rats in the RISE‐SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task.
Significance
The present study illustrates that CBD is a well‐tolerated and effective antiseizure agent and illustrates a potential disease‐modifying effect of CBD on reducing both seizure burden and associated comorbidities well after the onset of symptomatic seizures in a model of TLE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Highlights • Lacosamide was identified by virtue of activity in the maximal electroshock test. • The profile of lacosamide in animal seizure models is similar to that of sodium channel blocking ...antiepileptic drugs. • The biophysical characteristics of lacosamide block of voltage-gated sodium channels is distinct from that of other sodium channel blocking antiepileptic drugs, conferring unique properties.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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