SA4503, a sigma-1 receptor agonist,prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression

Many studies suggest that antidepressants act as neuroprotective agents in the central nervous system (CNS), though the underlying mechanism has not been fully elucidated. In the present study, we examined the effect of SA4503, which is a sigma-1 receptor agonist and a novel antidepressant candidate, on oxidative stress-induced cell death in cultured cortical neurons. Exposure of the neurons to H₂O₂ induced cell death, while pretreatment with SA4503 inhibited neuronal cell death. The SA4503-dependent survival effect was reversed by co-application with BD1047 (an antagonist of sigma-1/2 receptors). Previously we found that H₂O₂ triggers a series of events including over-activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and intracellular Ca²⁺ accumulation via voltage-gated Ca²⁺ channels and ionotropic glutamate receptors, resulting in neuronal cell death (Numakawa et al. (2007) [20]). Importantly, we found in this study that SA4503 reduced the activation of the MAPK/ERK pathway and down-regulated the ionotropic glutamate receptor, GluR1. Taking these findings together, it is possible that SA4503 blocks neuronal cell death via repressing activation of the MAPK/ERK pathway and, consequently, expression levels of glutamate receptors.     

PI3K–ERK1/2 activation contributes to extracellular H2O2 generation in amyloid β toxicity

Amyloid β peptide (Aβ) induces hydrogen peroxide (H₂O₂) and superoxide generation, leading to neuronal death. Many studies have shown the involvement of NADPH oxidase, but the isotype-specific role was not assessed. Moreover, the activation status of phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) 1/2 is unclear in extracellular H₂O₂ generation. In this paper, we showed that Aβ1–42 induced extracellular H₂O₂ generation and the resulting cytotoxicity in a concentration-dependent manner. Nox2- and Nox4-specific siRNAs suppressed H₂O₂ and superoxide generation. LY294002 and U0126, inhibitors of PI3K and ERK1/2, respectively, reduced H₂O₂ generation in concentration-dependent manners. Furthermore, PI3K activation is responsible for ERK1/2 phosphorylation. An additional increase in H₂O₂ generation and corresponding cytotoxicity was observed after treatment with Aβ1–42 and glutamate. These results suggest that Aβ1–42 enhances the neuronal vulnerability to oxidative injury in Alzheimer's disease (AD) by increasing H₂O₂ generation.     

Cyclophosphamide promotes cell survival via activation of intracellular signaling in cultured cortical neurons

Cyclophosphamide (CP) has been used as an antitumour agent or immunosuppressant clinically, though the potential biological role of CP in the central nervous system (CNS) has not been clarified. In the present study, we found that pretreatment with CP prevented neuronal cell death caused by serum deprivation in cultured cortical neurons. Interestingly, CP stimulated activation of PI3K (phosphatidylinositol 3 kinase) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathways, which are known as survival-promoting intracellular signalings. Furthermore, CP increased the expression of Bcl2, an anti-apoptotic factor. In the presence of inhibitors for PI3K or MAPK/ERK pathways, the CP-dependent neuronal survival and Bcl-2 up-regulation were both abolished. Importantly, significant increase in BDNF (brain-derived neurotrophic factor) expression was induced by CP application, implying that BDNF up-regulation is involved in the CP effect. We propose that CP has a protective effect on CNS neurons via the activation of intracellular signalings, and up-regulation of Bcl2 and BDNF.     

Cryptotanshinone protects primary rat cortical neurons from glutamate-induced neurotoxicity via the activation of the phosphatidylinositol 3-kinase/Akt signaling pathway

Excitotoxicity contributes to neuronal death and is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD). In the present study, cryptotanshinone, an active ingredient from a Chinese plant, Salvia miltiorrhiza, was investigated to assess its neuroprotective effects against glutamate-induced toxicity in primary culture of rat cortical neurons. Cryptotanshinone reversed glutamate-induced neuronal toxicity, which was characterized by decreased cell viability, increased lactate dehydrogenase release, neuronal DNA condensation, and the alteration of the expression of Bcl-2 family proteins. The neuroprotective effects of cryptotanshinone could be blocked by LY294002 and wortmannin, two inhibitors of PI3K. The importance of the PI3K pathway was further confirmed by the activation of Akt and anti-apoptotic Bcl-2 by cryptotanshinone in a PI3K-dependent manner. These results suggest that cryptotanshinone protects primary cortical neurons from glutamate-induced neurotoxicity through the activation of PI3K/Akt pathway. Such neuroprotective effects may be of interest in AD and other neurodegenerative diseases.     

Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling

To reduce damage from toxic insults such as glutamate excitotoxicity and oxidative stresses, neurons may deploy an array of neuroprotective mechanisms. Recent reports show that progranulin (PGRN) gene null or missense mutations leading to inactive protein, are linked to frontotemporal lobar degeneration (FTLD), suggesting that survival of certain neuronal populations needs full expression of functional PGRN. Here we show that extracellular PGRN stimulates phosphorylation/activation of the neuronal MEK/extracellular regulated kinase (ERK)/p90 ribosomal S6 kinase (p90RSK) and phosphatidylinositol-3 kinase (PI3K)/Akt cell survival pathways and rescues cortical neurons from cell death induced by glutamate or oxidative stress. Pharmacological inhibition of MEK/ERK/p90RSK signaling blocks the PGRN-induced phosphorylation and neuroprotection against glutamate toxicity while inhibition of either MEK/ERK/p90RSK or PI3K/Akt blocks PGRN protection against neurotoxin MPP⁺. Inhibition of both pathways had synergistic effects on PGRN-dependent neuroprotection against MPP⁺ toxicity suggesting both pathways contribute to the neuroprotective activities of PGRN. Extracellular PGRN is remarkably stable in neuronal cultures indicating neuroprotective activities are associated with full-length protein. Together, our data show that extracellular PGRN acts as a neuroprotective factor and support the hypothesis that in FTLD reduction of functional brain PGRN results in reduced survival signaling and decreased neuronal protection against excitotoxicity and oxidative stress leading to accelerated neuronal cell death. That extracellular PGRN has neuroprotective functions against toxic insults suggests that in vitro preparations of this protein may be used therapeutically.     

Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells

Hydrogen peroxide (H₂O₂) is a major reactive oxygen species that has been implicated in various neurodegenerative diseases. Quercetin, one of the plant flavonoids, has been reported to harbor various physiological properties including antioxidant activity. In this study, we investigated the neuroprotective effects of quercetin against H₂O₂-induced apoptosis in human neuronal SH-SY5Y cells. H₂O₂-mediated cytotoxicity and lactate dehydrogenase release were suppressed in a quercetin concentration-dependent manner. In addition, quercetin repressed the expression of the pro-apoptotic Bax gene and enhanced that of the anti-apoptotic Bcl-2 gene in SH-SY5Y cells. Moreover, quercetin effectively inhibited the activation of the caspase cascade that leads to DNA fragmentation, a key feature of apoptosis, and subsequent cell death. These results indicate the importance of quercetin in protecting against H₂O₂-mediated neuronal cell death. Thus, quercetin might potentially serve as an agent for prevention of neurodegenerative diseases caused by oxidative stress and apoptosis.     

Opposing role of JNK-p38 kinase and ERK1/2 in hydrogen peroxide-induced oxidative damage of human trophoblast-like JEG-3 cells

Trophoblasts play a crucial role in embryo implantation and maintenance of normal pregnancy. Recently, oxidative stress has been considered as one important factor in the pathogenesis of spontaneous abortion and preeclampsia. Many studies have reported that the plasma levels of hydrogen peroxide (H₂O₂) are significantly increased in women with preeclampsia, but the mechanisms involved in H₂O₂-induced cell cytotoxicity in trophoblasts are still not completely explained. Our present study was undertaken to provide a united understanding of the role of oxidative stress generated by H₂O₂ on human trophoblasts and the underlying intracellular signaling pathways. Exposure to H₂O₂ resulted in a concentration-dependent growth decrease and apoptosis in human trophoblast-like JEG-3 cells. H₂O₂ treatment also caused intracellular reactive oxygen species (ROS) production and concomitant dissipation of the mitochondrial membrane potential. The three MAPK subfamilies, ERK1/2, JNK and p38 kinase, were all activated under H₂O₂-induced oxidative stress. Blocking the activation of JNK and p38 kinase increased cell viability and decreased apoptosis induced by H₂O₂ with their respective inhibitors, SP600125 and SB203580. However, preventing ERK1/2 activation further increased H₂O₂-induced cell death with U0126, an inhibitor of ERK upstream kinase MEK1/2. Taken together, these findings suggest that the mitochondria-dependent pathways and JNK-p38 kinase pathways are involved in H₂O₂-induced oxidative damage of human trophoblast-like JEG-3 cells, while ERK1/2 pathway may play an active role in cell survival following oxidant injury.     

ERK1/2和PI3-K通路在蛛网膜下腔出血大鼠海马区对神经细胞自噬的调控作用

目的:探讨细胞外信号调节激酶(extracellular regulated protein kinases,ERK1/2)和磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase,PI3-K)通路对大鼠蛛网膜下腔出血(subarachnoid hemorrhage,SAH)后神经细胞自噬的调控作用。方法:雄性SD大鼠160只,分为假手术(Sham)组、模型(SAH)组、ERK1/2抑制剂U0126组和PI3-K抑制剂LY294002组。采用二次注血法制作SAH大鼠模型,HE染色观察海马区神经细胞的形态变化;免疫组织化学染色法检测海马区磷酸化ERK1/2、PI3-K、自噬相关蛋白Beclin-1和微管相关蛋白1轻链(LC3)-II的表达实时荧光定量PCR检测海马区ERK1/2、PI3-K、自噬相关蛋白Beclin-1和微管相关蛋白LC3的表达。结果:SAH组海马区神经细胞存活率低于Sham组,ERK1/2、PI3-K、Beclin-1和LC3的表达水平高于Sham组(P0.05);U0126组和LY294002组海马区神经细胞存活率均高于SAH组,ERK1/2、PI3-K、Beclin-1和LC3表达均低于SAH组(P0.05);U0126组和LY294002组两组间海马区神经细胞存活率差异无统计学意义(P0.05),U0126组ERK1/2、Beclin-1和LC3表达水平低于LY294002组(P0.05),PI3-K表达水平高于LY294002组(P0.05)。结论:ERK1/2和PI3-K通路激活共同参与SAH后神经细胞自噬的调节,且以PI3-K通路更为主要。     

Vanadium pentoxide increased PTEN and decreased SHP1 expression in NK-92MI cells,affecting PI3K-AKT-mTOR and Ras-MAPK pathways

Vanadium is an air pollutant that imparts immunosuppressive effects on NK cell immune responses, in part, by dysregulating interleukin (IL)-2/IL-2R-mediated JAK signaling pathways and inducing apoptosis. The aim of the present study was to evaluate effects of vanadium pentoxide (V₂O₅) on other IL-2 receptor-mediated signaling pathways, i.e. PI3K-AKT-mTOR and Ras-MAPK. Here, IL-2-independent NK-92MI cells were exposed to different V₂O₅ doses for 24?h periods. Expression of PI3K, Akt, mTOR, ERK1/2, MEK1, PTEN, SHP1, BAD and phosphorylated forms, as well as caspases-3, -8, -9, BAX and BAK in/on the cells were then determined by flow cytometry. The results show that V₂O₅ was cytotoxic to NK cells in a dose-related manner. Exposure increased BAD and pBAD expression and decreased that of BAK and BAX, but cell death was not related to caspase activation. At 400?µM V₂O₅, expression of PI3K-p85 regulatory subunit increased 20% and pPI3K 50%, while that of the non-pPI3K 110α catalytic subunit decreased by 20%. At 200?μM, V₂O₅ showed significant decrease in non-pAkt expression (p?2O₅. No differences were found with non-phosphorylated ERK-1/2. PTEN expression increased significantly at 100?μM V₂O₅ exposure whereas pPTEN decreased by 18% at 25?μM V₂O₅ concentrations, but remained unchanged thereafter. Lastly, V₂O₅ at all doses decreased SHP1 expression and increased expression of its phosphorylated form. These results indicated a toxic effect of V₂O₅ on NK cells that was due in part to dysregulation of signaling pathways mediated by IL-2 via increased PTEN and decreased SHP1 expression. These results can help to explain some of the known deleterious effects of this particular form of vanadium on innate immune responses_.     

Sodium pyruvate protects against H2O2 mediated apoptosis in human neuroblastoma cell line-SK-N-MC

Free radicals are involved in neuronal damage. The present study was aimed to investigate the protective effect of sodium pyruvate—a free radical scavenger against hydrogen peroxide (H₂O₂) induced apoptosis in human neuroblastoma cell line-SK-N-MC. On exposure to H₂O₂ (0.025 mM) cells exhibited apoptosis within 24 h, demonstrating a high caspase 3 activity by 3 h followed by cleavage of PARP that was maximum at 24 h. A break down in the mitochondrial membrane potential was observed 3 h onwards. Sodium pyruvate protected cells significantly (P<0.05) against apoptosis in a dose dependent manner as assessed for cell viability by dye exclusion method and apoptosis by TUNEL. Sodium pyruvate significantly inhibited caspase 3 activity, cleavage of PARP and breakdown of mitochondrial membrane potential. These data suggest that sodium pyruvate protects neuronal damage caused by H₂O₂.     

Protection against hydrogen peroxide-induced injury by Z-ligustilide in PC12 cells

Z-ligustilide (Z-LIG) is the primary lipophilic compound of the Chinese medicine Danggui (Radix Angelica sinensis). Previous studies demonstrated that Z-LIG had significant neuroprotective potential in both transient and permanent cerebral ischemia, possibly through antioxidant and anti-apoptotic mechanisms. The present study examined the mechanisms of Z-LIG on hydrogen peroxide (H₂O₂)-induced injury in PC12 cells. Following exposure of the cells to H₂O₂ (500 μM), a significant reduction in cell survival and total antioxidant capacity (TAC), as well as increased intracellular reactive oxygen species (ROS), were observed. In addition, H₂O₂ treatment significantly upregulated Bax expression, cleaved-caspase 3, and cytosolic cytochrome-c, and decreased Bcl-2 protein levels. Pretreatment of the cells with Z-LIG (0.1, 1.0, 2.5, or 5.0 μg/ml) significantly attenuated H₂O₂-induced cell death, attenuated increased intracellular ROS levels, and decreased Bax expression, cleaved-caspase 3, and cytochrome-c. Further, Z-LIG improved cellular TAC and concentration-dependently upregulated Bcl-2 expression. These results demonstrate that Z-LIG has a pronounced protective effect against H₂O₂-induced cytotoxicity, at least partly through improving cellular antioxidant defense and inhibiting the mitochondrial apoptotic pathway. These findings suggest that Z-LIG may be useful in the treatment of neurodegenerative disorders in which oxidative stress and apoptosis are mainly implicated.     

ERK1/2－STAT3通路在H2O2预处理导致的适应性细胞保护中的作用

目的：探讨ERK1/2-STAT3通路在H₂O₂预处理导致的适应性细胞保护中的作用。方法：在PC12细胞建立H₂O₂预处理对抗氧化应激（300 μmol/L H₂O₂）损伤细胞的模型。应用Hoechst33258核染色法观察细胞调亡的形态学改变；应用碘化丙啶(PI)染色流式细胞术检测细胞凋亡率；免疫印记法(Western blotting) 测定p-ERK1/2和p-STAT3的表达水平。结果：100 μmol/L H₂O₂预处理PC12细胞90 min可明显抑制300 μmol/L H₂O₂作用12 h引起的细胞凋亡，并激活ERK1/2和STAT3；ERK1/2抑制剂UO126和JAK2抑制剂AG-490（10 μmol/L）均可明显地阻断H₂O₂预处理引起的细胞保护作用；UO126（10 μmol/L）亦能明显地抑制H₂O₂预处理对STAT3的上调作用。结论：H₂O₂预处理能激活PC12细胞的ERK1/2-STAT3信号转导旁路，这可能是预处理的细胞保护机制之一。     

Overexpression of Human Arginine Decarboxylase Rescues Human Mesenchymal Stem Cells against H2O2 Toxicity through Cell Survival Protein Activation

In this study, we explored the potentiality of human arginine decarboxylase (ADC) to enhance the survival of mesenchymal stem cells (MSCs) against unfavorable milieu of host tissues as the low survival of MSCs is the issue in cell transplantation therapy. To address this, human MSCs overexpressing human ADC were treated with H₂O₂ and the resultant intracellular events were examined. First, we examined whether human ADC is overexpressed in human MSCs. Then, we investigated cell survival or death related events. We found that the overexpression of human ADC increases formazan production and reduces caspase 3 activation and the numbers of FITC, hoechst, or propidium iodide positive cells in human MSCs exposed to H₂O₂. To elucidate the factors underlying these phenomena, AKT, CREB, and BDNF were examined. We found that the overexpression of human ADC phosphorylates AKT and CREB and increases BDNF level in human MSCs exposed to H₂O₂. The changes of these proteins are possibly relevant to the elevation of agmatine. Collectively, our data demonstrate that the overexpression of human ADC stimulates pro-survival factors to protect human MSCs against H₂O₂ toxicity. In conclusion, the present findings support that ADC can enhance the survival of MSCs against hostile environment of host tissues.     

西红花酸对H2O2诱发心肌细胞凋亡及相关调控蛋白caspase-3、Bcl-2表达改变的影响

目的：探讨西红花酸对过氧化氢（H₂O₂）诱导的培养心肌细胞凋亡及相关调控蛋白caspase-3、Bcl-2表达改变的作用。 方法： 通过光镜观察细胞形态、碘化丙啶（PI）染色法和流式细胞术相结合检测培养细胞凋亡率、免疫荧光染色法和流式细胞术相结合检测细胞中caspase-3、Bcl-2蛋白。 结果： 在本实验使用浓度范围内，各浓度H₂O₂组细胞形态明显改变、凋亡率明显高于正常对照组，1×10^-4 mol·L^-1 H₂O₂可使培养心肌细胞Bcl-2蛋白表达明显减少，而caspase-3表达明显增多；各剂量西红花酸组细胞形态学改变减少、凋亡率明显低于1×10^-4 mol·L^-1 H₂O₂组，细胞中Bcl-2蛋白减少幅度与caspase-3增加幅度均减小，且较高浓度（5×10^-5 mol·L^-1）西红花酸组比较低浓度（5×10^-7 mol·L^-1）西红花酸组作用也更明显（P<0.05）。 结论： 西红花酸能够减轻H₂O₂对培养心肌细胞的损伤性凋亡作用，可能与稳定细胞内凋亡相关调控蛋白caspase-3、Bcl-2的功能有关。     

Modulation of K2P3.1 (TASK-1), K2P9.1 (TASK-3), and TASK-1/3 heteromer by reactive oxygen species

Reactive oxygen species (ROS) generated by mitochondria or NADPH oxidase have been implicated in the inhibition of K⁺ current by hypoxia in chemoreceptor cells. As TASKs are highly active background K⁺ channels in these cells, we studied the role of ROS in hypoxia-induced inhibition of TASKs. In HeLa cells expressing TASKs, H₂O₂ applied to inside-out patches activated TASK-1, TASK-3, and TASK-1/3 heteromer starting at ~16?mM. When applied to cell-attached or outside-out patches, 326?mM H₂O₂ did not affect TASK activity. Other K_2P channels (TREK-1, TREK-2, TASK-2, TALK-1, TRESK) were not affected by H₂O₂ (tested up to 326?mM). A reducing agent (dithiothreitol) and a cysteine-modifying agent (2-aminoethyl methanethiosulfonate hydrobromide) had no effect on basal TASK activity and did not block the H₂O₂-induced increase in channel activity. A TASK mutant in which the C-terminus of TASK-3 was replaced with that of TREK-2 showed a normal sensitivity to H₂O₂. Xanthine/xanthine oxidase mixture used to generate superoxide radical showed no effect on TASK-1, TASK-3, and TASK-1/3 heteromer from either side of the membrane, but it strongly activated TASK-2 from the extracellular side. Acute H₂O₂ (32–326?mM) exposure did not affect hSlo1/b1(BK) expressed in HeLa cells and BK in carotid body glomus cells. In carotid body glomus cells, adrenal cortical cells, and cerebellar granule neurons that show abundant hypoxia-sensitive TASK activity, H₂O₂ (>16?mM) activated the channels only when applied intracellularly, similar to that observed with cloned TASKs. These findings show that ROS do not support or inhibit TASK and BK activity and therefore are unlikely to be the hypoxic signal that causes cell excitation via inhibition of these K⁺ channels.     

Neuroprotective Effects of Hydrogen Sulfide Against Early Brain Injury and Secondary Cognitive Deficits Following Subarachnoid Hemorrhage

Although the neuroprotective effects of hydrogen sulfide (H₂S) have been demonstrated in several studies, whether H₂S protects against early brain injury (EBI) and secondary cognitive dysfunction in subarachnoid hemorrhage (SAH) model remains unknown. This study was undertaken to evaluate the influence of H₂S on both acute brain injury and neurobehavioral changes as well as the underlying mechanisms after SAH. The H₂S donor, NaHS, was administered via an intraperitoneal injection at a dose of 5.6 mg/kg at 2 h, 6 h, 24 h, and 46 h after SAH in rat model. The results showed that NaHS treatment significantly improved brain edema and neurobehavioral function, and attenuated neuronal cell death in the prefrontal cortex, associated with a decrease in Bax/Bcl‐2 ratio and suppression of caspase‐3 activation at 48 h after SAH. NaHS also promoted phospho‐Akt and phospho‐ERK levels. Furthermore, NaHS treatment significantly enhanced the levels of brain‐derived neurotrophic factor (BDNF) and phospho‐CREB. Importantly, NaHS administration improved learning and memory performance in the Morris water maze test at 7 days post‐SAH in rats. These results demonstrated that NaHS, as an exogenous H₂S donor, could significantly alleviate the development of EBI and cognitive dysfunction induced by SAH via Akt/ERK‐related antiapoptosis pathway, and upregulating BDNF‐CREB expression.     

CSF1通过CSF1R/PLCG2/ERK/Nrf2信号通路减少缺氧缺血性脑病大鼠神经元凋亡

目的:探讨集落刺激因子1(CSF1)通过CSF1受体(CSF1R)减轻缺氧缺血性脑病(HIE)大鼠神经元凋亡的下游信号通路.方法:采用原代大鼠皮质神经元建立氧糖剥夺(OGD)神经元损伤模型,重组人CSF1(rh-CSF1)干预该模型,通过CCK-8和MTT检测细胞活力,测定LDH漏出,Western blot检测CSF...     

Hydrogen peroxide induces autophagic cell death in C6 glioma cells via BNIP3-mediated suppression of the mTOR pathway

Oxidative stress by exposure to H₂O₂ induces various types of cell death depending on cell type and conditions. We report herein on a study of the mechanisms underlying H₂O₂-induced cell death in C6 glioma cells. The findings show that H₂O₂ triggers a caspase-independent autophagic cell death in these cells. The findings also show that H₂O₂ induces the dephosphorylation of the mammalian target of rapamycin (mTOR) at Ser 2481 and the p70 ribosomal protein S6 kinase (p70S6K) at Thr389 in a Bcl-2/E1B 19 kDa interacting protein 3 (BNIP3)-dependent manner. BNIP3 has the capacity to inhibit mTOR activity and mTOR inhibition plays a role in autophagic induction. This suggests that BNIP3 may mediate H₂O₂-induced autophagic cell death through the suppression of mTOR. The findings show that the down-regulation of BNIP3 by BNIP3 siRNA prevents C6 cells from undergoing H₂O₂-induced autophagic cell death. Collectively, these results suggest that H₂O₂ induces autophagic cell death in C6 cells via the BNIP3-mediated suppression of the mTOR pathway.     

Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence

Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co‐occurred also in resected brain tissue of patients with epileptogenic cortical malformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug‐resistant epilepsy of different etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX‐2 and NF‐κB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH‐SY5Y in which OS was induced using H₂O₂. OS markers were higher in dysmorphic neurons and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100 µM, but not 50 µM, of H₂O₂ increased expression of TLR4, IL‐1β and COX‐2. We found that NF‐κB signaling was activated only upon stimulation with 100 µM H₂O₂ leading to upregulation of TLR4 signaling and IL‐1β. The NF‐κB inhibitor TPCA‐1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF‐κB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once.