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A patient with epilepsy was shown to have neurobiological, psychological, cognitive, and social issues as a result of recurring seizures, which is regarded as a chronic brain disease. However, despite numerous drug treatments, approximately, 30%-40% of all patients are resistant to antiepileptic drugs. Therefore, newer therapeutic modalities are introduced into clinical practice which involve neurostimulation and direct stimulation of the brain. Hence, we review published literature on vagus nerve stimulation, trigeminal nerve stimulation, applying responsive stimulation systems, and deep brain stimulation (DBS) in animals and epileptic patient with an emphasis on drug-resistant epilepsy., Competing Interests: Conflict of interest The authors declared no conflict of interest., (Copyright© 2023 Iranian Neuroscience Society.)

Background & Aims: Type 2 diabetes is the most common endocrine disease occurs due to glucose intolerance due to imbalance between reserves and insulin demand. Diabetes can also cause damage and cell death or apoptosis (1, 2).Recent research shows the vital role of p53 in the development of diabetes. The aim of this study was to study changes in p53 gene expression in liver tissue and insulin resistance index after HIIT and Zataria multiflora (Thyme) extract in obese type 2 diabetic rats. Methods: The statistical population of the study consisted of male Wistar rats from Royan Institute. All rats were fed a high-fat diet (45 to 60% fat) for 5 months or 20 weeks. after the Rats became obese and reached an average weight of about 407 ± 50 g, to create a type 2 diabetic model, 25mg/kg STZ was injected intraperitoneally. Rats with fasting glucose between 150 to 400 mg/dl was considered as a criterion for diabetes and all rats were diabetic divided into 4 groups control, HIIT, Thyme, HIIT-Thyme. HIIT protocol, performed for five sessions per week with 2-minute alternation of 2 and 8 intervals with 80 to 90% VO2max and a one-minute rest cycle with 50 to 56% vo2max. Running time increased from 16 minutes in the first week to 34 minutes in the eighth week. Thyme extract was given by gavage at a dose of 200 mg / kg 5 days a week for eight week. At the end of the training period and 48 hours after the last training session, the experimental training groups and after 12 hours of fasting, the rats were anesthetized and sacrificed by ether anesthetic. Blood samples were collected from the heart. Glucose was measured using an auto-analyzer. Insulin measured by a special kit of Pars Azmoun Company. The insulin resistance index was calculated using the formula and the expression of liver tissue P53 genes expression was also measured by RT-PCR. Statistical analyze performed with one-way ANOVA and two-factor analysis of variance test for comparison between groups and determination of the effect size and post-hoc method. Results: According to the results, these findings were observed: The mean weight in the experimental groups of exercise, thyme and HIIT-Thyme groups increased slightly compared to control group. The mean concentration of glucose in the exercise group was significantly lower than the control group (P = 0.001) and also in the HIIT-Thyme group, there was no significant difference (P = 0.99) compared to the thyme group. Moreover, in the Thyme-HIIT group there was a significant decrease (P = 0.001) compared to the control group. Also, HIIT led to a significant reduction in glucose and insulin resistance index (P<0.05). The mean insulin concentration in the HIIT group was significantly higher than the control group (P = 0.005) group and in the HIIT-Thyme group was not significantly different compared to the thyme group (P = 0.218); however, the Thyme group had a significant increase compared to the control group. The mean insulin resistance index in the HIIT group (2.04) and ThymeHIIT was significantly lower than the control group but Thyme group was not significantly different from the control group (P = 0.994).HIIT reduced P53 gene expression in hepatocytes compared with controls (P <0.009). HIIT and consumption of Thyme extract also significantly reduced P53 gene expression in hepatocytes compared with the control group (P <0.05). Conclusion: The P53 gene, which is a tumor suppressor gene, is mutated and inactive in a wide range of cancers, this gene has been given the title of "protector of the genome", now new research shows that this gene has profound effects on metabolism and other Its activation can lead to obesity and type 2 diabetes, and for this reason another name was given to this gene "protector against obesity" (11). While the role of this gene is well known during decades of cancer research, little information is available about its role in metabolism. Previous studies have shown that the role of P53 in metabolism and its function is important for tumor suppression (12), this gene also has effects on heart disease, obesity and type 2 diabetes (13).P53 gene regulates glucose transporters. Maintaining proper function of glucose transporters is crucial in glucose homeostasis and suppression of diabetes (11). P53 regulates the function of glucose transporters by influencing their transcription and transport. For example, p53 activated by genotoxic stress can directly bind to GLUT1 and GLUT4 promoters and repress their transcription. P53 also suppresses GLUT3 expression, but this occurs through an indirect mechanism by inhibiting IkB kinase or IKK (11). P53 gene negatively regulates glycolysis. It affects glucose levels by directly regulating degradation (glycolysis) and synthesis (gluconeogenesis). Following DNA damage, p53 can reprogram the cell's energy production strategies from glycolysis to mitochondrial respiration (or oxidative phosphorylation) in order to suppress tumor progression (11). The first p53 target gene identified to inhibit glycolysis is TIGAR (TP53-induced glycolysis and apoptosis regulator) (30). TIGAR overexpression reduces the level of fructose 2, 6-bisphosphate (Fru-2, 6-P2), which activates the glycolysis promoter PFK1 (6-phosphofructo-1-kinase). P53 also regulates the stability of phosphoglycerate mutase (PGM), another enzyme important for the completion of glycolysis through the conversion of 3-phosphoglycerate (3-PG) to 2- phosphoglycerate (2-PG). It has been shown that the pentose phosphate pathway (PPP), an alternative mechanism for glucose consumption for energy production, is partially blocked by p53 through a direct interaction between p53 and its rate-limiting enzyme, glucose 6-phosphate dehydrogenase (G6PD). 30). P53 also negatively regulates pyruvate dehydrogenase kinase-2 (PDK2) through both transcriptional and post-translational mechanisms to activate the PDH complex that converts pyruvate to acetyl-CoA to shift the balance from glycolysis to mitochondrial respiration (28, 31). The results of the present study show a significant decrease in the expression of the P53 gene in the liver tissue in the intense interval training group, and also the decrease in the expression of this gene in the interaction group of interval training - thyme can indicate the effect of interval training on the decrease in the expression of the P53 gene in the liver tissue. According to the mentioned regulatory pathways, but in the thyme group alone, no significant decrease in the expression of this gene was observed, which can be inferred that when using thyme extract to use its medicinal, antioxidant and anti-inflammatory properties, performing periodic exercises its effectiveness can be improved by further reducing the expression of the P53 gene. Suppression of hepatic glucose production by reducing the expression of the P53 gene can effectively improve diabetes and be used to treat it, in a way, it can be said that targeting components in the gluconeogenic pathway can improve hyperglycemia (10, 11). HIIT with thyme extract in diabetic rats led to improved glycemic profile and changes in glucose and insulin levels, as well as positive and appropriate changes in the expression of P53 gen expression in hepatic tissue. [ABSTRACT FROM AUTHOR]