Creative Biolabs has established different models of epileptic seizures and models of epilepsy for preclinical epilepsy research as well as the discovery and development of antiepileptic drugs (ADEs). Specifically, we provide simple seizure models such as the maximal electroshock seizure (MES) test and the s.c. pentylenetetrazole (PTZ) test for the screening of drug candidates. Moreover, we provide chronic models of temporal lobe epilepsy (TLE) for a more advanced phase of the screening procedure, including the most commonly used pilocarpine model, kindling models, and the lithium-pilocarpine model.
Introduction of Epilepsy
Epilepsy is the second most common neurological disorder with a predisposition to the occurrence of frequent seizures, affecting about 65 million people worldwide. The most common form of epilepsy in humans is the TLE, in which seizures spread to neighboring cortices and hippocampal neuron loss and other neuropathological changes may take place. Despite the successful development of various new AEDs (e.g., phenobarbitals and benzodiazepines) in recent decades, the search for new therapies with better efficacy and tolerability remains a chief concern.
Overview of Epilepsy Models
A large number of models of epilepsy and epileptic seizures have been developed, which can be divided into different categories. For instance, some models present spontaneously occurring seizures while some models need to be chemically or electrically induced; some are acute seizure models that are frequently used for ADE screening while some are chronic models used for further characterization. Moreover, some models produce partial seizures (e.g., MES, PTZ) while some models produce generalized seizures (e.g., electrical or chemical kindling). It should be mentioned that in the discovery and development of new ADEs, different animal models of seizures or epilepsy should be chosen based on the stages of development and the intention of the experiment.
Maximal Electroshock (MES)-Induced Convulsions
MES-induced convulsion belongs to acute seizure models that are frequently used for ADE screening. Technically, tetracaine in a concentration of 0.5% in saline is applied on the eyes before the experiment and then 50 mA, 60 Hz, 0.2 s current in mice and 150 mA, 60 Hz, 0.2 s current in rat are applied through the corneal electrode. The endpoint in this test is tonic hindlimb extension, and the test is thought to be a predictive model for generalized tonic-clonic seizures.
Pentylenetetrazol (PTZ)-Induced Convulsions
PTZ is a non-competitive GABA antagonist, whose convulsing action is due to the blocking of GABAA receptor and the inhibition of the chloride channels opening. In the PTZ seizure test, a convulsive dose of PTZ enough to induce a clonic seizure is subcutaneously (s.c.) injected and animals are observed for a post-injection period of usually 30 min for the occurrence of such a "threshold" seizure. The PTZ-induced convulsion is widely used as acute seizure models, and not as animal models of epilepsy. It may be useful for rapid screening of AED action but do not necessarily result in chronic epilepsy.
Fig. 1 Mechanism of epileptogenesis and potential therapeutic intervention with AMPA-receptor antagonists. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate. (Hanada, 2015)
Pilocarpine is a muscarinic acetylcholine receptor agonist. Systemic or intracerebral injection of pilocarpine causes seizures that build up into a limbic SE. Structural damages and subsequent development of spontaneous recurrent seizures resemble those of human complex partial seizures. This model appears to be highly isomorphic with the human disease, so it has been used in many laboratories since its first description a quarter of a century ago.
Whereas the MES and PTZ models induce seizures in healthy, neurologically intact rodents, kindling is a chronic model in which the repeated application of electrical stimuli via a depth electrode in the limbic system (amygdala or hippocampus) of rats induces permanently enhanced seizure susceptibility and other enduring brain alterations that are similar to those occurring in human TLE. It is the only model that adequately predicts the clinical utility of novel AEDs against partial seizures in patients with epilepsy.
Lithium-Pilocarpine Model of SE
It is a variation of the pilocarpine model. Generally, lithium chloride is administered 24 h before the injection of pilocarpine for the induction of SE. In this model, lithium is given to increase the effect of pilocarpine. This also reduces the dose of pilocarpine required to produce SE and induces more stable convulsions in rats.
The neurological platform of Creative Biolabs provides an extensive range of rodent neurological disease models. If you are interested, click the following links for more detailed description of each model:
Creative Biolabs offers the most comprehensive and reliable preclinical efficacy services at the most competitive prices. We help to guide the selection of the most suitable epilepsy model for therapeutic evaluation of your compounds. Besides, we provide study-specific protocols responsive to your exact research needs. If you are interested in our services, please contact us to start the conversation now.
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