Over 65 million people worldwide are living with epilepsy of whom around 30% do not respond to the currently available anticonvulsants1. Transpharmation has worked with clients for more than a decade in the search to find a cure for epilepsy. We have been able to expand our scientific capabilities and together we offer an extensive array of highly behaviourally and pharmacologically validated preclinical epilepsy models.
Our services cover testing potential anticonvulsant compounds in preclinical models of both partial and generalised seizures and these are already benchmarked against clinical gold standard antiepileptic drugs. Additionally, we provide concomitant assessment of therapeutic index utilising rotarod and highly sophisticated automated system such as LABORAS. Unique to the CRO platform, our epilepsy team consists of scientists from a diverse background including veterinary medicine, pharmacology and neuroscience with specialisation in preclinical epilepsy research. You can be confident about the outcome of the studies we run.
We understand clients might want to test their compound in a different epilepsy model other than our existing ones and our highly qualified epilepsy research team are happy to accommodate the development of these models accordingly. With new studies underway, we are in the process of developing intracerebroventricular penicillin induced partial seizure, kainate kindling and Dravet syndrome models.
Please contact us even if you think your required model is not listed here.
Examples of models we offer:
The maximal electroshock seizure threshold (MEST) test is widely used to evaluate pro- or anti-convulsant properties of test compounds. MEST is an ideal choice for screening a large number of compounds in a relatively shorter period of time. Here, an alternating current is applied bilaterally for a short period of time (0.1-0.3s) through corneal electrodes in rodents to produce tonic hindlimb extensor seizure. An increase in seizure threshold is indicative of an anticonvulsive effect whereas a reduction in seizure threshold is indicative of a proconvulsive effect2-3.
The supramaximal electroshock seizure (MES) is another extensively utilised electroshock seizure model for testing anti-convulsant properties of test compounds. Here a predetermined high level electrical stimulus of sufficient intensity is used to reliably produce tonic hindlimb extensor seizures in 100% of control animals. As such the supramaximal electroshock test provides a rigorous evaluation of anticonvulsant efficacy. Antiepileptic drugs including the sodium channel blockers (e.g. Lamotrigine) with clinically proven efficacy against generalised tonic-clonic seizures exhibit anti-convulsant properties in this test2-3.
The 6 Hz test is an invaluable tool for screening novel anticonvulsants against therapy resistant epilepsy. In this model, the animal exhibits marginal convulsive or non-convulsive seizures with automatised behaviours (psychomotor seizures) following application of a low frequency (6 Hz) corneal stimulation for a period of 3 s. Multiple stimulus intensities can be used in this model e.g. 22 mA, 32 mA, 44 mA however, 44 mA current intensity is used as a model of drug resistant seizure4.
Intravenous pentylenetetrazole (i.v. PTZ) infusion seizure test is a standard model to assess the anti/pro-convulsive effect of a test compound. PTZ acts predominantly by antagonising GABAergic inhibition via acting on the picrotoxin binding site of the GABAA receptor. In this model, the test drug is administered before the start of intravenous PTZ infusion and the amount of PTZ required to produce seizures is calculated5.
Subcutaneous PTZ model is another popular test to assess antiepileptic interventions. Here, PTZ is injected subcutaneously after a specific pre-treatment time of the test compound. Latency to seizure as well as seizure behaviours are scored allowing us to identify changes to seizure threshold from pharmacological treatments [Silenieks et al., 2019]5.
Acute Kainic acid (KA) model of partial seizure is widely used to identify novel anticonvulsants for their efficacy against human focal seizure. Kainic acid is a selective agonist of kainate ionotropic glutamate receptors. Systemic administration of KA in rodents produce seizures characterised by myoclonic jerking movements, clonic convulsions and/or forelimb and hindlimb tonic extension. The behavioural endpoints that are normally assessed in this model are latency to different Racine stages, percentage of animals exhibiting each of the stages, total time spent and maximum seizure severity6.
We are able to offer repeated subconvulsive electrical stimulations leading to the induction (kindling) of overt generalized seizures. We offer amygdala kindling in rats as well as corneal kindling in mice. This is thought to model human partial seizures with secondary generalisation. Typical endpoints are (a) behavioural assessment of seizure intensity (Racine scale), and (b) electrophysiological assessment of after-discharge EEG. Potential compounds may be tested either as a pretreatment to examine a block of an already established kindled seizure or administered during kindling development to assess antiepileptogenic potential. Today the kindling model is the most used chronic model widely used in most antiepileptic drug (AED) screening programs7.
Dravet syndrome is a severe genetic form of myoclonic epilepsy in children. Mutation in the SCN1A gene which encodes voltage gated NaV1.1 channel is primarily involved in this type of epilepsy. We use the Scn1a+/- mouse model of Dravet syndrome to test efficacy of novel compounds against spontaneous seizures and premature mortality8. These and other genetically modified mice are also susceptible to febrile seizures, exhibiting lower temperature related seizure threshold. We are also able to induce hyperthermia-induced seizures in these mice, which can be prevented with various pharmacological interventions9.
- Patra PH et al (2019) Cannabidiol reduces seizures and associated behavioural comorbidities in a range of animal seizure and epilepsy models. Epilepsia, 60: 303- 14.
- Löscher W, Fassbender CP, Nolting B (1991) The role of technical, biological, and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res. 8: 79-84
- Löscher W (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure. 20:359-68.
- Barton ME, Klein BD, Wolf HH, White HS (2001) Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 47: 217-27.
- Silenieks, L. B., Carroll, N. K., Van Niekerk, A., Van Niekerk, E., Taylor, C., Upton, N., & Higgins, G. A. (2019). Evaluation of selective 5-HT2C agonists in acute seizure models.
- Maxime Lévesque & Massimo Avoli (2013) The kainic acid model of temporal lobe epilepsy Neurosci Biobehav Rev. 37: 2887-99.
- Bialer & White (2010) Key factors in the discovery and development of new antiepileptic drugs. Nature Rev. Drug Discovery 9: 68-82.
- Patra PH, Serafeimidou-Pouliou E, Bazelot M, Whalley BJ, Williams CM, McNeish AJ (2020) Cannabidiol improves survival and behavioural co-morbidities of Dravet syndrome in mice. Br J Pharmacol. 177: 2779-92.
- Hawkins, N. A., Anderson, L. L., Gertler, T. S., Laux, L., George Jr, A. L., & Kearney, J. A. (2017). Screening of conventional anticonvulsants in a genetic mouse model of epilepsy. Annals of clinical and translational neurology, 4(5), 326-339.