RESUMO
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway mediates many cytokine and growth factor signals. Tyrosine kinase 2 (TYK2), one of the members of this pathway and the first described member of the JAK family. TYK2 associates with inflammatory and autoimmune diseases, cancer and diabetes. Here, we present novel compounds as selective inhibitors of the canonical kinase domain of TYK2 enzyme. These compounds were rationally designed and synthesized with appropriate reactions. Molecular modeling techniques were used to design and optimize the candidates for TYK2 inhibition and to determine the estimated binding orientations of them inside JAKs. Designed compounds potently inhibited TYK2 with good selectivity against other JAKs as determined by in vitro assays. In order to verify its selectivity properties, compound A8 was tested against 58 human kinases (KinaseProfiler™ assay). The effects of the selected seven compounds on the protein levels of members of the JAK/STAT family were also detected in THP-1 monocytes although the basal level of these proteins is poorly detectable. Therefore, their expression was induced by lipopolysaccharide treatment and compounds A8, A15, A18, and A19 were found to be potent inhibitors of the TYK2 enzyme, (9.7 nM, 6.0 nM, 5.0 nM and 10.3 nM, respectively), and have high selectivity index for the JAK1, JAK2, and JAK3 enzymes. These findings suggest that triazolo[1,5-a]pyrimidinone derivatives may be lead compounds for developing potent TYK2-selective inhibitors targeting enzymes' active site.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases , TYK2 Quinase , Humanos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinonas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-Atividade , Triazóis/farmacologia , Triazóis/química , Triazóis/síntese química , TYK2 Quinase/antagonistas & inibidores , TYK2 Quinase/metabolismo , Janus Quinases/química , Janus Quinases/metabolismoRESUMO
The neurodegenerative mechanisms of Alzheimer's disease (AD) are not fully understood, but it is believed that amyloid beta (Aß) peptide causes oxidative stress, neuroinflammation, and disrupts metabotropic glutamate receptor 5 (mGluR5) signaling by interacting with cholesterol and caveolin-1 (Cav-1) in pathogenic lipid rafts. This study examined the effect of 2-hydroxypropyl-ß-cyclodextrin (HP-CD) on cholesterol, oxidative stress (total oxidant status), neuroinflammation (TNF-α), and mGluR5 signaling molecules such as PKCß1, PKCß2, ERK1/2, CREB, BDNF, and NGF in Aß (1-42)-induced neurotoxicity. The Sprague-Dawley rats were divided into four groups: control (saline), Aß (1-42), HP-CD (100 mg/kg), and Aß (1-42) + HP-CD (100 mg/kg). All groups received bilateral stereotaxic injections of Aß (1-42) or saline into the hippocampus. After surgery, HP-CD was administered intraperitoneally (ip) for 7 days. Cholesterol, TNF-α, and TOS levels were measured in synaptosomes isolated from hippocampus tissue using spectrophotometry, fluorometry, and enzyme immunoassay, respectively. The gene expressions of Cav-1, mGluR5, PKCß1, PKCß2, ERK1/2, CREB, BDNF, and NGF in hippocampus tissue were evaluated using reverse transcription PCR after real-time PCR analysis. Treatment with Aß (1-42) significantly elevated cholesterol, TOS, TNF-α, Cav-1, PKCß2, and ERK1/2 levels. Additionally, mGluR5, CREB, and BDNF levels were shown to be lowered. HP-CD reduced cholesterol, TOS, and TNF-α levels while increasing mGluR5, CREB, and BDNF in response to Aß (1-42) treatment. These findings indicate that HP-CD may have neuroprotective activity due to the decreased levels of cholesterol, oxidative stress, and neuroinflammation, as well as upregulated levels of mGluR5, CREB, and BDNF.
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Background and Objectives: In this present study, we investigated the impact of mechanosensitive microRNAs (mechano-miRs) on the collateral development in 126 chronic total occlusion (CTO) patients, selected from 810 undergoing angiography. Materials and Methods: We quantified the collateral blood supply using the collateral flow index (CFI) and assessed the transcoronary mechano-miR gradients. Results: The patients with favorable collaterals had higher CFI values (0.45 ± 0.02) than those with poor collaterals (0.38 ± 0.03, p < 0.001). Significant differences in transcoronary gradients were found for miR-10a, miR-19a, miR-21, miR-23b, miR-26a, miR-92a, miR-126, miR-130a, miR-663, and let7d (p < 0.05). miR-26a and miR-21 showed strong positive correlations with the CFI (r = 0.715 and r = 0.663, respectively), while let7d and miR-663 were negatively correlated (r = -0.684 and r = -0.604, respectively). The correlations between cytokine gradients and mechano-miR gradients were also significant, including Transforming Growth Factor Beta with miR-126 (r = 0.673, p < 0.001) and Vascular Endothelial Growth Factor with miR-10a (r = 0.602, p = 0.002). A regression analysis highlighted the hemoglobin level, smoking, beta-blocker use, miR-26a, and miR-663 as significant CFI determinants, indicating their roles in modulating the collateral vessel development. Conclusions: These findings suggest mechanosensitive microRNAs as predictive biomarkers for collateral circulation, offering new therapeutic perspectives for CTO patients.
Assuntos
Circulação Colateral , Oclusão Coronária , MicroRNAs , Humanos , MicroRNAs/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Circulação Colateral/fisiologia , Oclusão Coronária/fisiopatologia , Oclusão Coronária/diagnóstico , Idoso , Angiografia Coronária/métodos , Doença Crônica , Circulação Coronária/fisiologiaRESUMO
Nigella sativa L. is shown wide spread over the world and contains many useful phytochemicals. Much of the biological activity of the seeds has been shown due to the presence of thymoquinone (TQ). Its poor aqueous solubility of TQ hinders its delivery to target site. The aim of this work was to prepare TQ bigels composed of Carbopol 974 P NF (C974) in PEG 400 (organogel) or C974 in water (hydrogel) with microwave heating method. A novel technique, high speed homogenization followed by microwave heating, was used to prepare organogels. The pH, electrical conductivity, differential scanning calorimetry, rheological properties, and morphological structure of the formulations have been evaluated, and the effect of microwave on drug content and TQ antioxidant activity has been investigated. The bigels of TQ were successfully produced via high-speed homogenization followed by microwave-assisted heating for the first time in this study. Highly lipophilic TQ was successfully dissolved in organogel, and it was not affected from the microwaves. It can be stated that microwave heating is a promising method to obtain C974 organogels and thus bigels with appropriate above indicated investigated physicochemical characteristics. The time and energy consumption could be decreased with microwave-assisted heating, especially for gel preparation in the field of pharmaceuticals.
Assuntos
Hidrogéis , Micro-Ondas , Resinas Acrílicas/química , Benzoquinonas/químicaRESUMO
Chemobrionic systems have attracted great attention in material science for development of novel biomimetic materials. This study aims to design a new bioactive material by integrating biosilica into chemobrionic structure, which will be called biochemobrionic, and to comparatively investigate the use of both chemobrionic and biochemobrionic materials as bone scaffolds. Biosilica, isolated from Amphora sp. diatom, was integrated into chemobrionic structure, and a comprehensive set of analysis was conducted to evaluate their morphological, chemical, mechanical, thermal, and biodegradation properties. Then, the effects of both scaffolds on cell biocompatibility and osteogenic differentiation capacity were assessed. Cells attached to the scaffolds, spread out, and covered the entire surface, indicating the absence of cytotoxicity. Biochemobrionic scaffold exhibited a higher level of mineralization and bone formation than the chemobrionic structure due to the osteogenic activity of biosilica. These results present a comprehensive and pioneering understanding of the potential of (bio)chemobrionics for bone regeneration.
Assuntos
Regeneração Óssea , Diferenciação Celular , Osteogênese , Engenharia Tecidual , Alicerces Teciduais , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Osteogênese/efeitos dos fármacos , Osso e Ossos/fisiologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Diatomáceas , Humanos , AnimaisRESUMO
Mu opioid receptors (MOR) are known to be involved in seizure activity. The main goal of the present study was to characterize the MOR mRNA expression, binding, as well as G protein activation mediated by these receptors in epileptic hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (TLE). In contrast with autopsy samples, hippocampus obtained from patients with mesial TLE demonstrated enhanced MOR mRNA expression (116%). Saturation binding experiments revealed significantly higher (60%) B(max) values for the mesial TLE group, whereas the K(d) values were not statistically different. Although mesial TLE group demonstrated high levels of basal binding for the G proteins (136%), DAMGO-stimulated [(35)S]GTPγS binding did not demonstrate significant alterations. In conclusion, our present data provide strong evidence that the epileptic hippocampus of patients with pharmacoresistant mesial TLE presents significant alterations in MOR. Such changes may represent adaptive mechanisms to compensate for other as yet unknown alterations.
Assuntos
Epilepsia do Lobo Temporal/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Hipocampo/metabolismo , RNA Mensageiro/análise , Receptores Opioides mu/metabolismo , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
INTRODUCTION: Preeclampsia (PE) is a condition affecting 2-8% of all pregnancies and is a leading cause of perinatal morbidity and mortality. In our study; we aim to investigate the differences in endothelin-1 (ET-1) at both tissue and blood level in the placenta, umbilical cord, and maternal blood obtained from different experimental groups and the changes in the contraction response of umbilical arteries in order to explain how PE affects mother and fetus. METHODS: Umbilical cord and placenta samples were obtained from normotensive controls (n = 10) and patients with preeclampsia (n = 10), aged 20-39 years, who delivered by cesarean section at term (between 37 and 39 weeks). All samples were investigated with isolated tissue bath, histopathological, immunohistochemical and real-time PCR methods. RESULTS: ET-1 messenger RNA expression levels and immunoreactivity were found significantly higher in the PE group while microRNA-1 and microRNA-125b (miR-125b) levels were significantly decreased in placenta compared to control. miR-125b levels were found significantly higher in maternal and umbilical cord blood samples of the PE group. The enlargement in intervillous space, decrease in villous branching, increase in syncytial knots and smaller lumen areas in umblicard cord vessels were also observed. In tissue bath experiments, there were no significant differences in ET-1 responses between groups. DISCUSSION: We tried to evaluate molecular mechanisms of PE pathogenesis through expressional regulation and contraction response of ET-1. Although quite abundant work in this field has previously highlighted the importance of ET-1 system, further work is needed to determine the molecular mechanisms underlying expressional regulation of ET-1 in PE.
Assuntos
Endotelina-1 , MicroRNAs , Pré-Eclâmpsia , Cesárea , Endotelina-1/biossíntese , Endotelina-1/genética , Endotelina-1/metabolismo , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
In this study, we investigated the in vitro characteristics of mefenamic acid (MA) microparticles as well as their effects on DNA damage. MA-loaded chitosan and alginate beads were prepared by the ionotropic gelation process. Microsponges containing MA and Eudragit RS 100 were prepared by quasi-emulsion solvent diffusion method. The microparticles were characterized in terms of particle size, surface morphology, encapsulation efficiency, and in vitro release profiles. Most of the formulation variables manifested an influence on the physical characteristics of the microparticles at varying degrees. We also studied the effects of MA, MA-loaded microparticles, and three different polymers on rat brain cortex DNA damage. Our results showed that DNA damage was higher in MA-loaded Eudragit microsponges than MA-loaded biodegradable chitosan or alginate microparticles.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Córtex Cerebral/efeitos dos fármacos , Dano ao DNA , Ácido Mefenâmico/farmacologia , Fármacos Neuroprotetores/farmacologia , Resinas Acrílicas/química , Alginatos/química , Animais , Anti-Inflamatórios não Esteroides/química , Córtex Cerebral/patologia , Química Farmacêutica , Quitosana/química , Formas de Dosagem , Portadores de Fármacos , Composição de Medicamentos , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Ácido Caínico/toxicidade , Cinética , Ácido Mefenâmico/química , Fármacos Neuroprotetores/química , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Tecnologia Farmacêutica/métodosRESUMO
Glutathione (GSH) is a major endogenous antioxidant highly active in human tissues and plays a key role in controlling cellular thiol redox system, maintaining the immune and detoxification system. The determination of GSH levels in tissue is important to estimate endogenous defenses against oxidative stress. In our study, the multi-walled carbon nanotube modified screen-printed electrodes (MWCNT-SPEs) were used to determine the levels of GSH in trichloroacetic acid (TCA)-treated or untreated samples of rat plasma. It was found that the deproteinization of samples with TCA improved the electrochemical detection of GSH particularly in plasma. The oxidation of GSH was measured by using differential pulse voltammetry (DPV) method in combination with MWCNT-SPE (n=3), and the detection limit of GSH was found to be 0.47 µM (S/N=3). The GSH levels in plasma samples were also measured spectrophotometrically in order to compare the effectiveness of electrochemical method and we obtained a high correlation between the two methods (R(2)=0.976).
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Técnicas Eletroquímicas/instrumentação , Glutationa/sangue , Nanotubos de Carbono/química , Animais , Eletrodos , Desenho de Equipamento , Limite de Detecção , RatosRESUMO
Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid ß fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC50=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.
Assuntos
Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hidrazonas/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Células Endoteliais , Células HEK293 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
Mefenamic acid, a non-steroidal antiinflammatory drug (NSAID), directly and dose-dependently exhibits neuroprotective activity. In our study, we investigated the effects of mefenamic acid against d-serine on oxidative stress in the hippocampus, cortex and cerebellum of rats. Furthermore, the potential inflammatory and apoptotic effects of d-serine and potential protective effect of mefenamic acid were determined at mRNA and protein levels of TNF-α, IL-1ß, Bcl-2 and Bax. We found that d-serine significantly increased oxidative stress, levels of inflammation- and apoptosis-related molecules in a region specific manner. Mefenamic acid treatment provided significant protection against the elevation of lipid peroxidation, protein oxidation, levels of TNF-α, IL-1ß and Bax. As a conclusion, we suggest that d-serine, as a potential neurodegenerative agent, may have a pivotal role in the regulation of oxidative stress, inflammation and apoptosis; and NSAIDs, such as mefenamic acid, may assist other therapeutics in treating disorders where d-serine-induced neurotoxic mechanisms are involved in.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/efeitos dos fármacos , Ácido Mefenâmico/farmacologia , Serina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Serina/metabolismoRESUMO
It has been known for centuries that exogenous cannabinoids, such as tetrahydrocannabinol have anticonvulsant activity. Recent studies have advanced our understanding of the endogenous cannabinoid system and renewed the interest in cannabinoids as a potential treatment for epilepsy. The endogenous cannabinoid system is rapidly activated after seizure activity but still little is known about the molecular mechanisms underlying the role of the cannabinoid system in epilepsy. In this study epileptiform activity was induced by kainic acid (KA) and effects of the CB1 receptor agonists N-(2-Chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (ACEA) on G-protein signaling using the agonist-stimulated [(35)S]GTPγS binding assay were evaluated. Control and KA treated rat hippocampus and cortex membranes were used. Our results showed that the ACEA displayed a high potency and efficacy in stimulating the G-proteins and when compared to the control animals, significant enhancements were observed in tissues from the KA treated animals. Potency and efficacy values were in particular increased in the hippocampus tissues. Furthermore, gene expression levels of the cannabinoid receptor 1 (CB1) receptor and cannabinoid receptor interacting protein 1 (CRIP1) were measured by RT-PCR, where both CB1 and CRIP1 expressions were found to be elevated in the KA treated animals.
Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica , Ácido Caínico/toxicidade , Receptor CB1 de Canabinoide/metabolismo , Convulsões/metabolismo , Animais , Ácidos Araquidônicos/farmacologia , Canabinoides/biossíntese , Proteínas de Transporte/agonistas , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Convulsões/induzido quimicamenteRESUMO
Excitotoxicity is a contributing factor to the pathogenesis of acute or chronic neurodegenerative disease states. Kainic acid (KA) is an excitotoxic substance and the administration of it to rodents induces seizure activity (status epilepticus, SE) and leads to neurodegeneration. In this study the effect of KA-induced excitotoxicity on the G-protein activations and the gene expression levels of the opioid/nociceptin system receptors as MOPr, KOPr, DOPr, ORL-1, and PNOC (N/OFQ) were investigated, and the regulator effect of naloxone (Nal) on the gene expressions of the opioid system receptors against KA-induced seizures in the rat hippocampus was tested. In addition, the expression levels of stress-toxicity genes were assessed in the hippocampus following KA-induced excitotoxicity in order to determine the potential genetic targets which can be helpful for neuroprotective interventions. Our results indicate that the KA-induced excitotoxicity increased the mRNA levels of MOPr, DOPr, KOPr, PNOC, and ORL-1. However, G-protein activations of MOPr, DOPr, and KOPr remained relatively unchanged while both the potency and efficacy of N/OFQ were significantly increased. The PCR array data showed that KA-induced excitotoxicity altered the expression levels of genes in the cellular stress or toxicity pathways. Our data suggests that the induction of the opioid/nociceptin system may be involved in the cellular stress response following a neurodegenerative insult and that the genes modulated by the KA-treatment in the stress-toxicity pathways may be evaluated as targets of potential neuroprotective interventions.
Assuntos
Hipocampo/efeitos dos fármacos , Ácido Caínico/toxicidade , Peptídeos Opioides/fisiologia , Receptores Opioides/fisiologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia , Animais , Agonistas de Aminoácidos Excitatórios/toxicidade , Hipocampo/fisiologia , Masculino , Peptídeos Opioides/genética , Peptídeos Opioides/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides/genética , Estado Epiléptico/tratamento farmacológico , NociceptinaRESUMO
OBJECTIVES: The aim of this study was to investigate the effect of gamma-glutamylcysteine ethylester (GCEE), a precursor of glutathione biosynthesis, on the levels of glutathione, formation of reactive oxygen species and c-fos mRNA expression in rat hippocampus and cortex in kainic acid-induced excitotoxicity. METHODS: Sprague-Dawley rats were used and divided into four groups: control, kainic acid (10 mg/kg), GCEE (10 mg/kg) and kainic acid (10 mg/kg) + GCEE (10 mg/kg). Kainic acid and GCEE were administered to the rats intraperitoneally. The levels of glutathione and the expressions of c-fos mRNA in hippocampus and cortex tissues were determined using spectrophotometric and reverse transcription followed real-time PCR methods, respectively. Formation of reactive oxygen species was determined using dichlorofluorescin fluorescence in brain synaptosomes treated with kainic acid or GCEE in vitro. KEY FINDINGS: Kainic acid treatment significiantly upregulated the expression of c-fos mRNA in the hippocampus and cortex when compared to the control group. GCEE treatment significantly decreased the levels of c-fos mRNA in the cortex when compared to the kainic acid-treated group. GCEE treatment against kainic acid significantly increased the levels of glutathione in the cortex and hippocampus, and decreased the levels of formation of reactive oxygen species when compared to kainic acid-treated synaptosomes. CONCLUSIONS: The increased levels of glutathione and the reduced levels of reactive oxygen species formation lead us to conclude that GCEE may be beneficial as a potential antioxidant against neurodegenerative processes where excitotoxicity is involved.
Assuntos
Antioxidantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Dipeptídeos/farmacologia , Genes fos , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Ácido Caínico/toxicidade , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/administração & dosagem , Córtex Cerebral/metabolismo , Dipeptídeos/administração & dosagem , Epilepsia Tônico-Clônica/induzido quimicamente , Hipocampo/metabolismo , Injeções Intraperitoneais , Ácido Caínico/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrofotometria , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Fatores de TempoRESUMO
The aim of this study was to investigate the effect of gamma-Glutamylcysteine Ethyl Ester (GCEE) on the levels of GSH, caspase-3 activity, DNA damage and the expressions of Bcl-2, Bax and p53 mRNAs in rat hippocampus after status epilepticus (SE) induced by systemic kainic acid (KA). The male rats were divided into four groups as controls, KA (10 mg/kg), GCEE (10 mg/kg) and KA+GCEE. Glutathione (GSH) levels and caspase-3 activity were determined spectrophotometrically and colourimetrically, respectively. DNA damage and Bcl-2, Bax and p53 mRNA expressions were quantified by comet assay and reverse transcription followed by RT-PCR, respectively. KA treatment significantly depleted GSH levels, induced DNA damage, caspase-3 activity and the expressions of p53 and Bax mRNA. GCEE treatment protected GSH levels, decreased DNA damage and the levels of p53 and Bax/Bcl-2 mRNA against KA injection. These results indicate that GCEE treatment at the dose of 10 mg/kg is capable to protect the depleted levels of GSH and shows an anti-apoptotic activity due to the decreased levels of apoptotic biomarkers in the rat hippocampus after SE induced by KA.