Epilepsy
Around 30% of people living with epilepsy do not respond to currently available antiseizure medications (ASMs), and new mechanisms and approaches are needed to serve them. Our team has worked in epilepsy drug discovery since 2009 and has supported five ASMs into clinical trials, one of which is now widely prescribed. We offer a broad range of well-validated preclinical seizure and epilepsy models, supported by EEG, bioanalytics, biomarkers and side-effect assessment.
Integrated epilepsy drug discovery
No single acute seizure test identifies every clinically used antiseizure drug. We therefore help clients select the most suitable assays. Study designs can combine efficacy endpoints with neurological, behavioral, cognitive, electrophysiological, histological and bioanalytical measures.
Capabilities
- MES, MES-T, 6 Hz, subcutaneous PTZ, intravenous PTZ and kainic acid in mice and/or rats, plus audiogenic seizure in DBA/2 mice.
- Efficacy profiling for novel chemical entities, emerging modalities (gene therapies, mRNA-based therapeutics and antisense oligonucleotides (ASOs)) and dietary interventions.
- We routinely complement efficacy studies with bioanalysis, behavioral and neurological testing, giving you a richer dataset from every study
- We pride ourselves on adapting our models to suit each type of therapy, from small molecules to gene-based treatments and dietary interventions
- Rapid turnaround.
- Mouse corneal kindling, rat amygdala kindling, Scn1a+/- Dravet syndrome and lithium-pilocarpine status epilepticus.
- Assess established seizures, epileptogenesis, spontaneous seizures and relevant comorbidities.
- PK/PD, plasma and brain exposure, neurological and cognitive testing, biomarkers, histology
- Drug combinations including isobolograms
- Relate efficacy to exposure, tolerability, mechanism and combination effects
- TaiNi mouse EEG
- Motion Sequencing (MoSeq)
Seizure and epilepsy models
Electrically induced
MES is the most widely used first-line screen for anticonvulsant activity and models generalized tonic-clonic seizures. A brief corneal stimulus reliably evokes tonic hindlimb extension, and protection against it is the primary endpoint.
MES-T uses an up-and-down current titration approach to estimate seizure threshold. An increased threshold indicates an anticonvulsive effect, while a reduced threshold indicates a proconvulsive effect. Both approaches are available in mice and rats and have been benchmarked with reference antiseizure drugs.
Read the full description: Maximal electroshock seizure and seizure threshold tests (MES and MES-T)
The 6 Hz test models psychomotor seizures following low-frequency corneal stimulation. Study designs include ED50 (median effective dose), seizure-threshold and drug-combination assessments. 32 mA is the commonly used current, while 44 mA provides a more pharmacoresistant challenge for evaluating candidates intended for drug-resistant epilepsy.
Chemically induced
During intravenous PTZ infusion, the amount of PTZ required to trigger defined seizure endpoints is calculated after test-article administration. The assay can detect anticonvulsive or proconvulsive effects. Endpoints include myoclonus, forelimb clonus and hindlimb tonus.
Subcutaneous PTZ can be used in mice and rats to evaluate protection, latency to seizure and maximum seizure severity. The model is responsive to reference compounds from several pharmacological classes, including diazepam, sodium valproate and retigabine.
Kainic acid, a glutamate receptor agonist, is given subcutaneously to mice or rats to induce limbic seizures that can progress to status epilepticus. This makes it a model of temporal lobe seizures and excitotoxic injury. Studies can assess percentage protection, latency to seizure, stage progression, time spent in seizure and maximum severity, with exploratory biomarkers of neuronal injury and inflammation.
Chronic and disease-relevant
Repeated subconvulsive corneal stimulation progressively produces stable stage 4–5 seizures. Candidates may be tested acutely after kindling is established or during kindling development to evaluate effects on epileptogenesis. The model can also be used to investigate epilepsy-related comorbidities: kindled mice show reduced risk-assessment behavior, hyperactivity and faster fear extinction without motor impairment, alongside marked hippocampal gliosis in the absence of neuronal loss. These behavioral, histological and molecular endpoints can be combined with seizure scoring in the same study.
A single bipolar electrode, implanted unilaterally in the basolateral amygdala, both delivers the stimulus and records the resulting EEG after-discharge while rats move freely. Study endpoints can include after-discharge duration, behavioral seizure severity, seizure threshold, neurological assessments, body temperature, motor activity, plasma exposure and PK/PD relationships. Acute repeated-measures and chronic treatment designs are available.
Scn1a+/- mice have reduced NaV1.1 expression and a lower threshold for hyperthermia-induced seizures. The model supports pharmacological assessment of febrile seizures and can incorporate spontaneous seizure, survival and behavioral comorbidity endpoints. Exhibited phenotypes include changes in social behavior, anxiety-associated behavior, reward-related behavior, learning and memory.
Systemic pilocarpine is used to induce status epilepticus. Following a latent period, animals develop spontaneous seizures and can show motor and cognitive impairments. The model may be used to investigate effects on epileptogenesis, spontaneous seizure burden, disease-related comorbidities and potential disease modification. EEG, behavioral testing and biomarkers relating to neuronal injury, inflammation and gliosis can be added.
EEG and additional NCE profiling
Lightweight head-mounted TaiNi technology enables simultaneous EEG and behavior measurements in mice, including genetic models. The system supports up to 16 EEG/EMG channels, sampling up to 20 kHz and recordings of up to seven days.
An automated analysis method distinguishes spike-wave discharges from sleep spindles in EEG recordings. The approach has been validated in the WAG/Rij rat model of absence epilepsy and can be applied to other animal EEG datasets where absence-seizure detection is required.
From efficacy signal to therapeutic window
Anticonvulsant activity is most informative when interpreted alongside exposure and tolerability. Depending on the program, studies can include:
- Plasma and brain exposure measurements to support PK/PD interpretation and estimation of exposure-response relationships.
- Neurological and motor assessments, including Irwin screening, rotarod, beam walk, tremor analysis, locomotor activity and automated LABORAS monitoring.
- Cognitive and behavioral testing using novel object recognition, radial-arm maze, Morris water maze, fear conditioning and operant methods.
- EEG measures, tissue collection, histology and biomarker analysis, including markers of neuronal injury, astrocytosis, microglial activation and inflammation.
- Motion Sequencing (MoSeq) to provide unbiased, behavioral phenotyping and identify treatment-related changes in movement structure that may not be captured by conventional neurological or locomotor assessments.
- Isobolographic analysis to characterize whether drug combinations show additive, synergistic or antagonistic interactions.
Tailored study design
Our team brings extensive experience designing and conducting preclinical epilepsy studies across a wide range of targets, mechanisms and therapeutic approaches. We are highly adaptable in our study design, to support the specific mechanism of action and development needs of your program.
Our scientists have worked with thousands of compounds, as well as other antiseizure approaches including gene therapies, ASOs, mRNA-based therapeutics and dietary interventions. We use that breadth of experience to help clients select the most informative models and endpoints, troubleshoot emerging questions and generate data that can support progression through the development pipeline.
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Have a program in mind?
Work with our epilepsy scientists to choose the best model and build the right study design to identify promising therapeutic candidates and generate the data needed to advance them.