Epilepsy is a common and prevalent neurological condition. In the past 20 years, several new antiepileptic drugs (AEDs) have been introduced and used in clinical practice, but still 1/3 of patients with epilepsy cannot be controlled intentionally and have poor drug treatment effect, which is called intractable epilepsy, refractory epilepsy, drug-resistant epilepsy, medically refractory epilepsy. Drug-resistant epilepsy is very disabling and has a great impact on patients’ quality of life and social function, which is an important medical problem facing the society. In order to further improve the effectiveness of epilepsy drug therapy, it is necessary to clarify the cellular molecular biology mechanism of drug-resistant epilepsy in order to develop new antiepileptic drugs that can overcome or escape the drug resistance mechanism. In recent years, research on drug resistance mechanisms in drug-resistant epilepsy has begun to gain attention, and this paper only reviews the research in this area. 1, the establishment of drug-resistant epilepsy model According to the research object, the research on the phenomenon of drug resistance in epilepsy and its mechanism includes the following aspects: (1) patients with drug-resistant epilepsy: from the clinical point of view, there is not a clear unified concept of drug-resistant epilepsy, and generally qualify drug-resistant epilepsy in this way: under the guidance of blood drug concentration monitoring, the effect of regular antiepileptic drug treatment is poor. However, it is not clear how many drugs and for how long can be used for orthodox treatment and trials. However, most experienced epileptologists are aware that if a patient is not sensitive to the commonly used first-line antiepileptic drugs such as phenytoin sodium, carbamazepine and sodium valproate after several years of repeated experimental drug therapy, basically other drug therapy is also ineffective. Therefore, some scholars believe that the establishment of drug resistance in epilepsy should not be done indefinitely, and that drug-resistant epilepsy can be identified if the treatment with adequate amounts of phenytoin sodium, carbamazepine, and sodium valproate is not effective. More than half of drug-resistant epilepsies are suitable for surgical treatment and are surgically remediable epileptic syndrome, such as epilepsy associated with focal brain lesions and medial temporal lobe epilepsy associated with hippocampal sclerosis, and these patients can be treated with resective sugery. Surgical specimens can be used for studies on the cellular and molecular mechanisms of drug resistance in epilepsy. (2) Animal models of drug-resistant epilepsy: Establish an electrically stimulated amygdala-ignited rat model of epilepsy or a pentazocine ignited rat model of epilepsy, followed by the administration of antiepileptic drugs such as phenytoin sodium and phenobarbital for screening to establish an animal model of drug-resistant epilepsy, which can be used to study the mechanisms of drug resistance in drug-resistant epilepsy. (3) In vitro neuronal culture to observe the changes in neuronal cells at the molecular level after the addition of antiepileptic drugs in the culture medium, which can be used to study the adaptive changes of ion channels to antiepileptic drugs, for example. (2) Possible mechanisms of drug resistance in drug-resistant epilepsy: The molecular mechanisms of drug resistance in drug-resistant epilepsy are still unclear, and may be: (1) the disappearance or change of the targets of AEDs, such as sodium channels or GABA receptors, and the insensitivity of nerve cells to AEDs; (2) the decrease in the amount of drugs entering the extracellular fluid of the brain parenchyma due to changes in drug transmigration on the blood-brain barrier, so that the blood concentration may be in the therapeutic range, but the concentration in the extracellular fluid of the brain is not sufficient. However, the concentration in the brain extracellular fluid is not sufficient to achieve the therapeutic effect; (3) changes in the drug transporter on the nerve cell membrane, resulting in insufficient amount of drug in the intracellular fluid, and the drug cannot effectively exert antiepileptic effects through the intracellular mechanism. 3, drug-resistant epilepsy and multidrug resistance gene and its expression product P-glycoprotein: Currently, studies have shown that the expression of multidrug resistance gene (MDR1) is upregulated and its expression product (p-gp) is increased in relation to the phenomenon of drug resistance in intractable epilepsy. The MDR1 gene, also known as the ABCB1 gene, is a large gene (209 kb) that encodes the product p-glycoprotein 170 (p-gp170), a transmembrane ATP-dependent molecular pump that is actively expressed in the intestine, placenta, blood-brain barrier, kidney and liver, and whose main physiological functions are related to cellular secretion and exocytosis. It is known that p-gp170 mediates the exocytosis process of many substrates, which include more than 50 commonly used drugs, such as immunosuppressants, lambda glycoside cardiotonic agents, protease inhibitors, β-blockers, etc. Most AEDs are lipophilic and should theoretically be substrates for p-gp170. Some studies have shown that p -gp170 is related to at least carbamazepine, phenytoin, valproic acid, etc. transport. In addition drug resistance in epilepsy is often not drug selective and is generally resistant to multiple drugs at the same time, also suggesting that the resistance mechanism is related to drug transport. Studies on the relationship between the phenomenon of drug resistance in intractable epilepsy and the upregulation of MDR1 expression include the following. (1) Animal models of epilepsy have shown that seizures can cause upregulation of MDR1 expression in the brain. The experimental animals are mainly rodents, including Wistar rats and SD rats. The epilepsy models were acoustically stimulated epilepsy model, electrically stimulated epilepsy model, drug-induced model of making monk and ignition model. Northern blot hybridization, Western blot hybridization, PCR and immunocytochemistry were mainly used to determine MDR1 gene expression in vascular endothelial cells, astrocytes and neurons. In rodents, the MDR1 gene has two isoforms: MDR1a and MDR1b. Kwan et al. studied genetically epilepsy-prone rats (GEPR), which were executed 4h, 24h, and 7 days after a single audiogenic seizure, and RT-PCR was used to determine the expression of MDR1 a and MDR1b in the cerebral cortex, midbrain, pontine/medulla, and hippocampus. The expression of MDR1a and MDR1b was increased in the cortex and midbrain at 24 h and remained high in the cortex at 7 days compared to the control group, but there was no significant change in MDR1a in the pontine/prolonged medulla and hippocampus. Lazarowski et al. used 3-mercaptopropionic acid (MP) to induce epilepsy in the Wistar rat model. Rats were executed after intraperitoneal injection of MP 45 mg/kg for 4 or 7 days, and brain p-gp-170 content was measured by immunohistochemistry. The presence of p-gp-170 immunostaining in the hippocampus, striatum and some fine vascular endothelial cells, glia and neurons in the cerebral cortex indicates that MP-induced seizures can cause regional and cellular selective expression of the MDR1 gene.Van Vliet et al. used an electrical stimulation-induced rat temporal lobe epilepsy model to study the expression of MDR1a and MDR1b in the right temporal lobe after electrical stimulation of the left temporal lobe to induce persistent epilepsy in rats.Using real-time PCR assays, they found that MDR1b was P-gp immunostaining was enhanced in endothelial cells and glial cells. (2) Study of surgical excision of pathogenic epileptic foci in patients with intractable epilepsy A significant proportion of intractable epilepsy, especially focal epileptic syndromes associated with some lesions in the brain, can be treated by surgical excision of epileptogenic foci, which offers the possibility to study the correlation between MDR1 gene expression status and drug resistance phenomena from a clinical perspective. Tuberous sclerosis is an autosomal dominant syndrome that can involve multiple systems, but primarily affects the brain, skin, and kidneys. Multiple gray matter ectopic nodules may be present in the brain. Lazarowski et al. reported three cases of tuberous sclerosis combined with intractable epilepsy in which seizures were treated by surgical removal of brain nodules, and immunohistochemistry was used to observe the expression of the MDR1 gene or multidrug resistance-associated protein (MRP-1) in the nodules. The results showed strong positive immunostaining for MDR1 and MRP-1 in abnormal spherical swelling cells, dysplastic neurons, astrocytes, microglia, and some endothelial cells. Focal cortical dysplasia (FCD) and neuronal glioma (GG) are the two main pathological types causing surgically treatable intractable seizures.Aronica et al. studied surgically resected specimens from 15 patients with FCD and 15 patients with GG, all of whom had intractable epilepsy, using non-brain tumor non-epileptic autopsy brain specimens as controls. It was found that in the control group, p-g p could not be measured and MRP-1 expression was found only in the vasculature; MRP-1 and p-gp expression was seen in the dysplastic neurons of 11/15 cases of FCD and in the neuronal components of 14/15 cases of GG, and increased MRP-1 and p-gp expression was also seen in astrocytes and vascular endothelial cells within the lesions, relative to The expression of MRP-1 and p-gp was also increased in astrocytes and vascular endothelial cells within the lesion, but not in neurons and vascular endothelial cells around the lesion compared to normal brain tissue. (3) Study of the correlation between MDR1 gene polymorphisms and drug resistance in intractable epilepsy In clinical practice, it is often found that some patients with the same type of epilepsy are sensitive to AEDs, while others are resistant to them. Based on the above studies, this may be related to genetic polymorphisms.Siddiqui et al. studied 315 patients with epilepsy, 115 of whom were sensitive to drug therapy, 200 with drug-resistant intractable epilepsy, and 200 normal controls. Using peripheral blood specimens to observe the ABCB1C3435T polymorphism, it was found that in patients with drug-resistant epilepsy, in ABCB1 3435, there was a higher chance of having the CC genotype than having the TT genotype. (4), the relationship between upregulation of MDR1 expression in the epileptogenic foci of intractable epilepsy and drug resistance The hypothesis has been proposed that in intractable epilepsy, MDR1 expression is upregulated, resulting in increased p-gp in vascular endothelial cells, astrocytes and neurons. Increased p-gp in vascular endothelial cells reduces the amount of antiepileptic drugs entering the extracellular fluid of brain tissue, and increased p-gp in astrocytes drives the transfer of antiepileptic drugs from the extracellular fluid of brain tissue to the bloodstream, with the result that drug concentrations in the extracellular fluid of brain tissue are low despite blood concentrations within the therapeutic range. Increased p-gp expression in neurons results in low intracellular concentrations of antiepileptic drugs. This prevents AEDs from acting effectively on epileptogenic neurons within the epileptogenic foci and makes the epilepsy intractable. Therefore, the development of p-gp inhibitors or drugs affecting MDR1 expression at the genetic level may become an important direction for the development of new antiepileptic drugs. 4. Drug-resistant epilepsy and human glutathione-S-transferase (GST): GST is one of the major members of the tumor resistance gene family, with at least four types: α, μ, π and microsomal GST. These isoforms differ in substrate specificity, response to inhibitors, tissue/cellular distribution, subunit composition and antigenic composition. π GST is distributed in the thyroid, urinary tract, respiratory tract, gastrointestinal tract, uterus and hepatobiliary epithelium. It is present in adenocarcinoma tissues of the stomach, kidney, uterus and ovary, as well as in squamous carcinoma cells of the head and neck, melanoma, mesothelioma, lung carcinoid tumors and lymphoma, and is a reliable marker of cervical tumors. The current research on the relationship between GST and drug resistance in drug-resistant epilepsy focuses on GST π. Some scholars used gene microarray technology to study phenytoin sodium-resistant lit mice and found that GST π expression was enhanced in drug-resistant epileptic mice, and the antiepileptic drug Toltea was found to induce GST π expression by neuronal culture method. GST π expression was also found to be significantly enhanced in blood from patients with drug-resistant epilepsy compared with those with non-drug-resistant epilepsy, suggesting that it may be involved in the formation of drug resistance mechanisms in refractory epilepsy. Since the expression of GST π is regulated, improving its expression may cause a decrease in drug resistance in patients with refractory epilepsy and thus improve the treatment of refractory epilepsy, and these findings need to be confirmed in brain tissue from patients with refractory epilepsy. The GST π content in the brain tissue of patients with refractory epilepsy was determined by immunohistochemistry using a total of 54 surgically resected specimens from 5 epilepsy surgery centers, including 40 lobar specimens and 14 hippocampal specimens, and it was found that the neuronal cell membranes and cytoplasm of the case group were stained to different degrees, and the GST π expression was significantly enhanced compared with that of the control neurons. There was no significant difference in GST π expression between case groups. It was found that GST π expression in brain tissue of drug-resistant epilepsy patients was positively correlated with the duration of epilepsy, suggesting that enhanced GST π expression in brain tissue of drug-resistant epilepsy patients may be involved in the formation of drug-resistant epilepsy. Physiological studies have found that after the entry of foreign toxic substances into the body, in addition to detoxification by phase 1 metabolic enzymes such as cytochrome P-450 enzymes, another important metabolic detoxification mechanism is metabolism by phase II metabolic enzymes, and GST π is one of the main components of phase II metabolic enzymes and an important catalyst that can catalyze the binding of electrophilic substances to reduced glutathione or convert toxic drugs bound to lipophilic cells to lipophilic cells. The GST π is an important catalyst that can protect the body while reducing the efficacy of drugs by catalyzing the binding of electrophilic substances to reduced glutathione or converting toxic drugs bound to lipophilic cells into hydrophilic substances for excretion, thus forming an important physiological line of defense. Antiepileptic drugs are not intrinsic to the body, and these chemicals, which are important for the disease, are harmful substances to the human body, and when they enter the body, they inevitably trigger the body’s defense system, causing intracellular reduced glutathione to bind to antiepileptic drugs catalyzed by increased GST π, and excreting them through a series of closely interlocking steps to protect the cells from drug attack, protecting the body while reducing their antiepileptic effects. The enhanced GST π expression did not differ significantly between brain regions and was also found to be enhanced in blood, suggesting that the enhanced GST π expression may be a systemic response induced by epilepsy or antiepileptic drugs and may be related to the expression of genes that predispose the organism to drugs or toxicants.