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Epilepsy (Epilepsy) is one of the common diseases of the nervous system. Patients often present with sudden and short-term abnormalities in movement, sensation, consciousness or spirit. Repeated seizures seriously affect the patient's life and psychology, and even impair cognitive function. Data show that the quality of life of patients with epilepsy is significantly lower than that of the normal population, and lower than that of patients with other chronic diseases, such as hypertension and diabetes. According to epidemiological surveys, the annual prevalence rate of the general population is 5‰～7‰[1], and the prevalence rate of active epilepsy (with seizures within 5 years) is 4.6‰. At present, there are more than 9 million epilepsy patients in my country, of which 5 million to 6 million are patients with active epilepsy, and the number of new patients each year is 650,000 to 700,000. However, its pathogenesis is very complex and has not been fully elucidated so far. Recent studies have shown that epilepsy is closely related to ion channels, neurotransmitters, glial cells, contact transmission and gap junctions.
Figure 1. Overlap of cortical areas associated with seizures.
Epilepsy is a chronic encephalopathy characterized by epileptic seizures. Epilepsy syndromes are defined as epilepsy syndromes that have special etiology, specific pathogenesis, special clinical manifestations, and require special treatment. The International League Against Epilepsy defines "epilepsy syndrome" as a group of special manifestations composed of typical clinical and EEG features supported by specific etiology (structural, genetic metabolism, immunity and infection) [2-6]. Manifestations are usually age-dependent and have a specific set of complications.
Currently widely used is the 1985 International League Against Epilepsy classification criteria for epilepsy syndromes [7]. With the advancement of medical technology, especially the development of quantitative EEG and fMRI, and the in-depth understanding of epilepsy neural networks, the International League Against Epilepsy will propose a new classification of epilepsy syndromes in 2022. The new classification still follows the basic framework of the previous classification according to age, and is divided into four categories: onset in neonatal period and infancy, onset in childhood, onset in different ages, and primary hereditary epilepsy syndrome. The classification is refined for clinical application [2-6,8].
Figure 2: Pathological changes progress and change with the development of epileptogenesis and epilepsy.
Ion channels are the structural basis for the regulation of excitability in excitable tissues in vivo, and are closely related to the occurrence of epilepsy [9].Other studies have shown that epilepsy is an ion channel disease, which may be due to mutations in the gene encoding ion channel proteins, resulting in changes in ion channel function, resulting in abnormal excitability or inhibitory changes in nervous tissue, and then leading to epileptic seizures[10] ]. The function of ion channels is to selectively allow corresponding ions to pass through. Currently, it has been found that ion channels related to epilepsy include sodium, potassium, and calcium ion channels. After ions pass through ion channels, they will cause changes in the cell membrane potential, resulting in neuronal excitation or inhibition. Benedictus MR et al. [11] found that ion exchange imbalance can also cause ion channel diseases, that is, epilepsy induced by anions or cations. Hyperactivated cyclic nucleotide (HCN)-gated channels in ion channels are associated with temporal lobe seizures [12]. Sun Hong et al. [13] found that the down-regulation of HCN channels and protein expression can cause a decrease in ion concentration, which in turn makes neurons overexcited and induces epileptic seizures. In short, the seizures of epilepsy may be caused by multiple ion channels, but the final pathway is the same, all of which are abnormal changes in electrolyte distribution and transport, leading to ion channel dysfunction, which further excites neurons and causes epileptic seizures.
Epilepsy has a complex relationship with genetics, and may be associated with a variety of genetic changes. Some patients with epilepsy syndrome may be caused by excessive neuronal excitation caused by mutations in genes encoding ion channel proteins, and gene mutations may include single or multiple gene mutations, chromosomal abnormalities, mitochondrial mutations, etc. Zhang Wei [19] showed that GABAa receptor mutations are associated with childhood absence epilepsy, autosomal dominant juvenile myoclonic epilepsy, autosomal dominant inheritance and febrile epilepsy, which may be due to the existence of the above diseases such as genetic susceptibility Common pathogenesis including sensory and environmental factors. However, the specific pathological mechanism remains to be further explored. Although the development of modern molecular biology can provide references for the susceptibility genes of epilepsy-related polygenic genetic diseases, the environmental factors are still difficult to predict.
Figure 3: Mutations that lead to the development of epilepsy may affect genes directly involved in the generation and transmission of nerve impulses (I), or affect genes responsible for nervous system development and metabolism (II). In the second case, the violation of the functions of ion channels and specific synaptic proteins occurs indirectly.
At present, there are many experimental animal models of epilepsy, which can be classified in many ways according to their seizure conditions, seizure types, and preparation methods, but there is no one model that can perfectly simulate various types of human epilepsy.
| Category | Model Name | Introduction | Advantages/Disadvantages |
| chemistry medicine |
Pentylenetetrazol, PTZ |
The most classic chemical drug is to block GABA to transmit pathogenic PTZ, which can be used to build animal models of acute and chronic epilepsy. | |
| kainic acid,KA | Intracerebral injection of KA can be used to study the effect of epileptogenic focus on surrounding and normal brain tissue, while systemic injection of KA. KA is commonly used to study the susceptibility of multiple regions of the brain to epileptogenesis and drug research. | The KA model exhibits similarities with humans in terms of latency period, behavioral symptoms, duration of latency period, and EEG characteristics during both the latency and chronic phases. | |
| Pilocarpine | The ability of pilocarpine (pilocarpine) to induce epilepsy may depend on the activation of M1 receptors, and can cause the increase of glutamate levels in the hippocampus and the activation of NMDA receptors after seizures, thereby maintaining seizures. | The model has recurrent spontaneous seizures, typical hippocampal sclerosis moss fiber germination and other characteristics. Pilocarpine model compared to the above-mentioned drug attacks are more durable, more reliable, and the experimental time shorter and lowest cost. | |
| Penicillin | The penicillin model is more commonly used to mimic drug-resistant absence seizures, which can be exacerbated by PTZ, photostimulation, and GABAergic agonists. However, when intramuscularly injected into rodents, it does not continuously produce bilateral synchronous spike wave discharges (SWDs) similar to cats, but instead produces multifocal spikes. However, pretreatment of rats with penicillin can increase the induction of SWDs by other chemicals [17], which is very useful for studying the cellular mechanisms related to spike-wave bursts and the role of cortex on subcortical structures when spike-wave bursts are generated. |
Low-dose penicillin-induced focal epilepsy model is suitable for research analysis of the spread of seizure activity in epileptic seizures. | |
| AY-9944 | AY-9944 is a compound that inhibits the degradation of 7-dehydrocholesterol into cholesterol. It is the only permanent model of atypical absence. Its induction mechanism is not yet fully understood. | This model has advantages over genetic models in terms of reliability, spontaneity, relapse, and chronic seizures that induce dementia. However, the EEG monitoring required to identify and quantify experimental absence seizures is more demanding. | |
| Hydroxybutyrate, GHB |
The use of biologically active GHB precursor (GBL) produces the exact same EEG and behavioral effects as GHB, but the effects are relatively more sustained and rapid. |
The GHB model is a recognized model of absence seizures, and double Laterally synchronized with cessation of behavior, facial myoclonus, and tremor jerks Twitch related SWDs. |
|
| Physical method | Electrical stimulation | The use of biologically active GHB precursor (GBL) produces the exact same EEG and behavioral effects as GHB, but the effects are relatively more sustained and rapid. | This model exhibits a high similarity in both overt manifestations and EEG patterns to psychomotor seizures. It is also considered a screening tool for potential therapeutic drugs for drug-resistant epilepsy. However, it is unrelated to hippocampal sclerosis, and the damage is dissimilar to temporal lobe epilepsy. Spontaneous seizures occur relatively infrequently compared to drug-induced ones. |
| Low temperature | The low temperature injury model is a model that can induce focal epilepsy without injecting exogenous drugs into the body. | The seizures can last for several days, are repeatable, and have a low mortality rate (<5%). Spontaneous seizures can occur, but the effects of animal age and systemic administration on seizure threshold in this model are not yet clear. | |
| Genetic model | Several neuronal nicotinic acetylcholine receptor genes (CHRNA4, CHRNB2, CHRNA2) and KCNT1 cause autosomal dominant nocturnal frontal lobe epilepsy and LGI1 in rodent models with autosomal dominant epilepsy with auditory features. | ||
| Neonatal Convulsion Model | Hypoxia-ischemia,HI | The rapid ischemia-hypoxia model replicated some structural abnormalities and cognitive impairments seen in neonatal seizure. However, there is no obvious brain damage in this model, and differences between strains are minimal. | The HI model typically does not induce seizures in younger (P5) and adult (P60) rats, which may involve other mechanisms. |
| Febrile seizures,FSs | FS does not involve significant neuronal loss, and seizures in animals are induced by hyperthermia, which differs from the disease process in humans. |
Symptom Grading of Epilepsy Models - Racines Epilepsy Behavioral Scale
This grading later became a unified standard for observing the seizure behavior of the epilepsy model and judging whether the model is successful. Now this standard has been widely adopted by scholars from all over the world.
In addition to the above-mentioned characteristics, an animal model of epilepsy should be resistant to most antiepileptic drugs, and neuropathologically specific hippocampal damage is related to hippocampal sclerosis in temporal lobe epilepsy.
Taken together, these animal models have played a pivotal role in uncovering the underlying mechanisms of epilepsy, determining the efficacy of drugs to treat specific epilepsy types, and preventing the development of epilepsy. However, it is difficult for us to design an animal model that can summarize all the characteristics of epilepsy, and the current models are not perfect, so we should be aware of the limitations of various models. But it needs to be emphasized that animal models should be simple representations of complex systems, mimicking specific aspects of disease, and by no means attempt to replicate all the complexities of human disease. Therefore, whenever an animal model is used, it is critical to define a specific problem and ensure that the chosen model is fit for purpose, making and selecting a model for the purpose.
Literature citation
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