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Disease Models | Animal Models of Epilepsy

Introduction:

Epilepsy is a chronic disorder characterized by sudden, abnormal neuronal discharges in the brain that result in transient disturbances of brain function. According to epidemiological data from China, the overall prevalence of epilepsy in the country is 7.0%. Based on this estimate, there are approximately 9 million people with epilepsy in China, with about 400,000 new cases diagnosed each year. In China, epilepsy has become the second most common neurological condition, surpassed only by headache.

Epilepsy is a chronic, recurrent disorder characterized by sudden-onset dysfunctions of brain function, marked by the abrupt, abnormally high-frequency discharge of neuronal activity that spreads to surrounding areas, and it has a high prevalence. At present, research into the pathogenic mechanisms of human epilepsy, the development of therapeutic strategies, and the screening of novel antiepileptic drugs still relies primarily on animal models.

There are numerous methods for generating such models, including gene‑knockout and transgenic animal models, chemically induced epilepsy models, chronic experimental epilepsy models, and acute epilepsy models, among others. The choice of model‑generation method depends on the specific research objectives. Today, we will introduce several commonly used approaches for establishing these models.

Chronic experimental epilepsy model

Chronic experimental epilepsy model induced by electrical stimulation of the model

Kindling is induced by repeated subconvulsive electrical stimulation of a specific brain region, ultimately leading to robust partial or generalized seizures. Once established, kindling can persist for an extended period, even throughout the lifetime of the animal. This model is currently widely recognized as one that more closely mimics human epilepsy, is frequently employed, and has been extensively studied.

Animal selection: SD rats weighing 250–300 g, male, were used.

Build Method ： After anesthetizing the animal, it is secured in a stereotaxic apparatus. The hair on the top of the head is removed, the coordinates of the amygdala are localized, and a small dental drill is used to penetrate the skull. An electrode is then inserted into the amygdala. Following surgery, kanamycin or gentamicin is administered by intramuscular injection for three consecutive days to prevent infection. One week later, the formal experiment begins: at a fixed time each day, the animal receives an electrical stimulation lasting 3 seconds; the stimulation intensity is increased daily until afterdischarges are elicited at the stimulated site.

Model features:

(1) Even in the absence of further electrical stimulation, the regularity of cortical electroencephalographic activity and epileptiform discharges can persist for more than one year. (2) Repeated electrical stimulation can again elicit clonic seizures.

(3) A small number of animals can develop the condition spontaneously.

(4) The seizure is triggered by synaptic transmission.

In addition, there are other methods for establishing chronic experimental epilepsy models, including those induced by aluminum hydroxide, cobalt, ferrous sulfate, zinc sulfate, and penicillin, among others.

Chemical‑induced epilepsy model

Pentylenetetrazol (PTZ)–induced epilepsy model

PTZ is a tetrazole derivative that, when administered systemically, produces consistent convulsive effects in mice, rats, cats, and primates. The subcutaneous injection of pentylenetetrazol (PTZ)–induced seizure model can mimic the myoclonic generalized seizures observed in humans; the antiepileptic drug ethosuximide was discovered using this model.

The PTZ seizure model is easy to establish, offers high efficiency in screening antiepileptic compounds, and has successfully identified compounds with clinically proven antiepileptic efficacy. Consequently, over the past several decades, the MES and PTZ models have served as the gold standard for initial drug discovery in epilepsy.

Animal selection: Select males Mice, weighing 18–25 g.

Build Method ： Following fasting, PTZ was administered via the tail vein in saline, and postural rigidity and clonic seizures in the hind limbs were observed.

Model features: The PTZ model can replicate the clinical features of generalized myoclonic seizures in humans. It is easy to prepare and offers high efficiency in screening antiepileptic compounds.

Kainic acid (KA)-induced epilepsy model

Kainic acid is an exogenous amino acid extracted from kainic acid‑producing algae; it serves as a specific agonist of excitatory amino acid receptors and exerts potent central nervous system–stimulating effects.

Animal selection: This model can be established in a variety of animal species, including mice, rats, cats, and non-human primates. In practical experiments, the most commonly used species is the mouse (male, 18–25 g).

Build Method ： After anesthetizing the animals, the hair on the top of the head was removed, and KA was administered either intracerebroventricularly or systemically. The incidence of seizures was monitored over a 30-minute observation period.

Model features: The experimental procedure is simple and rapid, the reagents are inexpensive, and the model exhibits long-term stability. The KA model shares similarities with humans in terms of the incubation period, behavioral symptoms, the duration of the incubation phase, and the electroencephalographic characteristics during both the incubation and chronic phases.

Racine Classification of Seizure Types

Level 0: Normal Behaviorology

Grade I: Staring, facial twitching, head shaking, chewing;

Grade II: Rhythmic head nodding accompanied by chewing at the corners of the mouth;

Grade III: Clonic movements of the forelimbs;

Grade IV: Clonic jerking of both forelimbs; hind limbs stand in a kangaroo-like posture.

Grade V: Generalized convulsions, loss of balance, and falling.

Acute epilepsy model

Maximum electroshock model ( m maximal electroshock model, MES model )

The MES model is one of the most widely used and thoroughly studied models; it is frequently employed to simulate human generalized tonic‑clonic seizures and can also be applied to screen for anti‑tonic‑clonic seizure drugs. The classic antiepileptic drug phenytoin was discovered using the MES model.

Because the MES and PTZ seizure models are easy to establish and exhibit high efficiency in screening antiepileptic compounds, and have successfully identified compounds with clinically proven antiepileptic efficacy, these models have served as the gold standard for initial drug discovery in epilepsy over the past several decades.

Gene-knockout and transgenic animal models of epilepsy

In theory, any gene encoding a protein whose structure can enhance neuronal excitability and reduce inhibitory tone during epileptic seizures may serve as a candidate target for research. Examples include the Tottere mouse model (tg/tg strain), the cystatin B knockout mouse model (a model of progressive myoclonic epilepsy, PME), and the transgenic Q54 mouse model.

Some genetically engineered mice exhibit an epileptic phenotype. For example, APP/Ps1 mice on a C57BL/6 background are at risk of developing epilepsy. Data indicate that hemizygous mice on the C57BL/6 background (N9B6) display a high incidence of seizures: 25% of (B6) APP/Ps1 mice experience at least one seizure between 3 and 3.5 months of age. By 4.5 months, the seizure incidence rises to 55%, and a subset of mutant mice develop spontaneous seizures during the course of the study.

Reference:

[1] Methodology for the Replication of Animal Models of Human Diseases / Edited by Zhou Guangxing et al. — Shanghai: Shanghai Scientific & Technological Literature Publishing House, Jan. 2008.

[2] Animal Models of Human Diseases (2nd Edition) / Edited by Liu Enqi et al. – Published by People’s Medical Publishing House

[3] Dong Bosi, Qiu Xiangmiao, Lai Wanlin, et al. Advances in research on animal models of epilepsy [J]. Chinese Journal of Comparative Medicine, 2021, 31(3): 128–138. DOI: 10.3969/j.issn.1671-7856.2021.03.020.

[4]Tang S , Luo Z , Qiu X , et al. Interactions between GHRH and GABAARs in the brains of patients with epilepsy and in animal models of epilepsy.[J]. Nature Publishing Group, 2017(1).

[5] Tang Lipeng. Advances in Research on Animal Models of Epilepsy [J]. Journal of Graduate Studies, Sun Yat-sen University: Natural Sciences and Medicine Edition, 2011, 32(2): 38–45.

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