NCBP1 Improves Cognitive Function in Mice by Reducing Oxidative Stress, Neuronal Loss, and Glial Activation After Status Epilepticus.

Status epilepticus (SE) is a severe manifestation of epilepsy which can cause neurologic injury and death. This study aimed to identify key proteins involved in the pathogenesis of epilepsy and find a potential drug target for SE treatment. Tandem mass tag (TMT)-based quantitative proteomic analysis was applied to screen differentially expressed proteins (DEPs) in epilepsy. The adeno-associated virus was employed to overexpress candidate DEP in mice, and kainic acid (KA) was used to generate a mouse model of epilepsy. Then histopathological examination of the hippocampal tissue was performed, and the inflammatory factors levels in serum and hippocampus were measured. The IP-MS analysis was carried out to identify the interacting protein of nuclear cap-binding protein 1 (NCBP1). The results were that NCBP1 was downregulated in the epileptic hippocampus. NCBP1 overexpression alleviated KA-induced cognitive impairment in mice and reduced the apoptosis and damage of hippocampal neurons. Additionally, overexpressed NCBP1 increased the expression of NeuN and reduced the expression of GFAP and IBA-1 in the hippocampus of the mice. Further study indicated that NCBP1 overexpression inhibited the expression of IL-6, IL-1ß, and IFN-γ in serum and hippocampus as well as MDA and LDH in the hippocampus, whereas it increased the SOD levels, suggesting that overexpression of NCBP1 could diminish KA-induced inflammatory responses and oxidative stress. The IP-MS analysis identified that ELAVL4 was the NCBP1-interacting protein. In conclusion, this finding suggests that NCBP1 may potentially serve as a drug target for the treatment of epilepsy.

Combined transcriptomics and proteomics forecast analysis for potential biomarker in the acute phase of temporal lobe epilepsy.

Background: Temporal lobe epilepsy (TLE) is a common chronic episodic illness of the nervous system. However, the precise mechanisms of dysfunction and diagnostic biomarkers in the acute phase of TLE are uncertain and hard to diagnose. Thus, we intended to qualify potential biomarkers in the acute phase of TLE for clinical diagnostics and therapeutic purposes. Methods: An intra-hippocampal injection of kainic acid was used to induce an epileptic model in mice. First, with a TMT/iTRAQ quantitative labeling proteomics approach, we screened for differentially expressed proteins (DEPs) in the acute phase of TLE. Then, differentially expressed genes (DEGs) in the acute phase of TLE were identified by linear modeling on microarray data (limma) and weighted gene co-expression network analysis (WGCNA) using the publicly available microarray dataset GSE88992. Co-expressed genes (proteins) in the acute phase of TLE were identified by overlap analysis of DEPs and DEGs. The least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) algorithms were used to screen Hub genes in the acute phase of TLE, and logistic regression algorithms were applied to develop a novel diagnostic model for the acute phase of TLE, and the sensitivity of the diagnostic model was validated using receiver operating characteristic (ROC) curves. Results: We screened a total of 10 co-expressed genes (proteins) from TLE-associated DEGs and DEPs utilizing proteomic and transcriptome analysis. LASSO and SVM-RFE algorithms for machine learning were applied to identify three Hub genes: Ctla2a, Hapln2, and Pecam1. A logistic regression algorithm was applied to establish and validate a novel diagnostic model for the acute phase of TLE based on three Hub genes in the publicly accessible datasets GSE88992, GSE49030, and GSE79129. Conclusion: Our study establishes a reliable model for screening and diagnosing the acute phase of TLE that provides a theoretical basis for adding diagnostic biomarkers for TLE acute phase genes.

Effects of double-dose statin therapy for the prevention of post-stroke epilepsy: A prospective clinical study.

BACKGROUND: To determine treatment effects on the incidence of post-stroke epilepsy (PSE) using different doses of statin, a prospective hospital-based cohort study was designed to explore whether a double-dose statin treatment can better prevent the occurrence of PSE. METHODS: A total of 1152 patients with newly diagnosed ischemic stroke admitted to our hospital from March to August 2017 were selected, 1033 of whom were followed-up. Patients were divided into two treatment groups:(1) standard-dose (20 mg atorvastatin or 10 mg rosuvastatin,daily oral; 788 patients); and (2) double-dose (40 mg atorvastatin or 20 mg rosuvastatin, daily oral; 245 patients).At 18 months follow-up was conducted to compare the incidence of PSE between groups. RESULTS: In general, in the standard-dose group we observed two cases of early seizure (ES) (0.25%), 22 cases oflate seizure (LS) (2.79%) and 20 cases of PSE (2.54%). In the double-dose group, onepatient had ES (0.41%), two patients had LS (0.82%), and onepatient had PSE (0.41%). The incidence of PSE was significantly lower in the double-dose group as compared to the standard-dose group. There was a higher proportion of PSE in patients younger than 65 years and in males. Three patients had ES; one presented with focal aware seizure (FAS), and two had focal to bilateral tonic-clonic seizure (FBTCS). Among the 21 patients with PSE, there were two cases of FAS, five cases of focal impaired awareness seizure (FIAS), five cases of FBTCS, and nine cases of GTCS, suggesting that partial seizure is the most common type of PSE. Cerebral cortex was involved in 85.75% of cases with PSE, and multiple lobes were involved in 61.9% of cases with PSE. CONCLUSION: Increasing the dose of statin treatment during the acute phase of ischemic stroke reduces the incidence of PSE. Further research is needed to understand the mechanisms underlying the potential preventative effects of statins against PSE.

Silencing MicroRNA-134 Alleviates Hippocampal Damage and Occurrence of Spontaneous Seizures After Intraventricular Kainic Acid-Induced Status Epilepticus in Rats.

Epilepsy is a disorder of abnormal brain activity typified by spontaneous and recurrent seizures. MicroRNAs (miRNAs) are short non-coding RNAs, critical for the post-transcriptional regulation of gene expression. MiRNA dysregulation has previously been implicated in the induction of epilepsy. In this study, we examined the effect of silencing miR-134 against status epilepticus (SE). Our results showed that level of miR-134 was significantly up-regulated in rat brain after Kainic acid (KA)-induced SE. TUNEL staining showed that silencing miR-134 alleviated seizure-induced neuronal apoptosis in the CA3 subfield of the hippocampus. Western blot showed that a miR-134 antagonist suppressed lesion-induced endoplasmic reticulum (ER) stress and apoptosis related expression of CHOP, Bim and Cytochrome C, while facilitated the expression of CREB at 24 h post KA-induced lesion in the hippocampus. Consistently, silencing miR-134 significantly diminished loss of CA3 pyramidal neurons using Nissl staining as well as reducing aberrant mossy fiber sprouting (MFS) in a rat epileptic model. In addition, the results of EEG and behavior analyses showed seizures were alleviated by miR-134 antagonist in our experimental models. These results suggest that silencing miR-134 modulates the epileptic phenotype by upregulating its target gene, CREB. This in turn attenuates oxidative and ER stress, inhibits apoptosis, and decreases MFS long term. This indicates that silencing miR-134 might be a promising intervention for the treatment of epilepsy.

Advances in In-silico B-cell Epitope Prediction.

Identification of B-cell epitopes in target antigens is one of the most crucial steps for epitopebased vaccine development, immunodiagnostic tests, antibody production, and disease diagnosis and therapy. Experimental methods for B-cell epitope mapping are time consuming, costly and labor intensive; in the meantime, various in-silico methods are proposed to predict both linear and conformational B-cell epitopes. The accurate identification of B-cell epitopes presents major challenges for immunoinformaticians. In this paper, we have comprehensively reviewed in-silico methods for B-cell epitope identification. The aim of this review is to stimulate the development of better tools which could improve the identification of B-cell epitopes, and further for the development of therapeutic antibodies and diagnostic tools.

CD70, a novel target of CAR T-cell therapy for gliomas.

Background: Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target. Methods: Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models. Results: CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect. Conclusion: These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.

Antagomirs Targeting MicroRNA-134 Increase Limk1 Levels After Experimental Seizures in Vitro and in Vivo.

BACKGROUND: MiR-134 is enriched in dendrites of hippocampal neurons and plays crucial roles in the progress of epilepsy. The present study aims to investigate the effects of antagomirs targeting miroRNA-134 (Ant-134) on limk1 expression and the binding of miR-134 and limk1 in experimental seizure. METHODS: Status epilepticus (SE) rat model was established by lithium chloride-pilocarpine injection and was treated with Ant-134 by intracerebroventricular injection. Low Mg2+-exposed primary neurons were used as an in vitro model of SE. The expression of miR-134 was determined using real-time PCR. Protein expressions of limk1 and cofilin were determined by Western blotting. Luciferase reporter assay was used to examine the binding between miR-134 and limk1 3'-untranslated region. RESULTS: The expression of miR-134 was markedly enhanced in hippocampus of the SE rats and low Mg2+-exposed neurons. Ant-134 increased the expression of limk1 and reduced the expression of cofilin in the SE hippocampus and Low Mg2+-exposed neurons. In addition, luciferase reporter assay confirmed that miR-134 bound limk1 3'-UTR. MiR-134 overexpression inhibited limk1 mRNA and protein expressions in neurons. CONCLUSION: Blockage of miR-134 upregulates limk1 expression and downregulated cofilin expression in hippocampus of the SE rats. This mechanism may contribute to the neuroprotective effects of Ant-134.

Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/ß-Catenin Signaling.

Purpose: Glioma-initiating cells (GIC) are glioma stem-like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl-prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development.Experimental Design: We analyzed differences in CypA expression between primary tumors and neurospheres from the GDS database, both before and after GIC differentiation. A series of experiments was conducted to investigate the role of CypA in GIC stemness, self-renewal, proliferation, radiotherapy resistance, and mechanism. We then designed glutathione S-transferase (GST) pulldown and coimmunoprecipitation assays to detect signaling activity.Results: In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds ß-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between ß-catenin and TCF4, CypA enhances transcriptional activity.Conclusions: Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radioresistance through Wnt/ß-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy. Clin Cancer Res; 23(21); 6640-9. ©2017 AACR.

Antagomirs Targeting MiroRNA-134 Attenuates Epilepsy in Rats through Regulation of Oxidative Stress, Mitochondrial Functions and Autophagy.

The effects of the existing anti-epileptic drugs are unsatisfactory to almost one third of epileptic patients. MiR-134 antagomirs prevent pilocarpine-induced status epilepticus. In this study, a lithium chloride-pilocarpine-induced status epilepticus model was established and treated with intracerebroventricular injection of antagomirs targeting miR-134 (Ant-134). The Ant-134 treatment significantly improved the performance of rats in Morris water maze tests, inhibited mossy fiber sprouting in the dentate gyrus, and increased the survival neurons in the hippocampal CA1 region. Silencing of miR-134 remarkably decreased malonaldehyde and 4-hydroxynonenal levels and increased superoxide dismutase activity in the hippocampus. The Ant-134 treatment also significantly increased the production of ATP and the activities of mitochondrial respiratory enzyme complexes and significantly decreased the reactive oxygen species generation in the hippocampus compared with the status epilepticus rats. Finally, the Ant-134 treatment remarkably downregulated the hippocampal expressions of autophagy-associated proteins Atg5, beclin-1 and light chain 3B. In conclusion, Ant-134 attenuates epilepsy via inhibiting oxidative stress, improving mitochondrial functions and regulating autophagy in the hippocampus.

Centrosomal Protein of 55 Regulates Glucose Metabolism, Proliferation and Apoptosis of Glioma Cells via the Akt/mTOR Signaling Pathway.

INTRODUCTION: Glioma is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and the progression of glioma are elusive and controversial. Centrosomal protein of 55 (CEP55) was initially described as a highly coiled-coil protein that plays critical roles in cell division, but was recently identified as being overexpressed in many human cancers. The function of CEP55 has not previously been characterized in glioma. We aim to discover the effect and mechanism of CEP55 in glioma development. METHOD: qRT-PCR and immunohistochemistry were used to analyze CEP55 expression. Glucose uptake, western blot, MTS, CCK-8, Caspase-3 activity and TUNEL staining assays were performed to investigate the role and mechanism of CEP55 on glioma cell process. RESULTS: We found that the levels of CEP55 expression were upregulated in glioma. In addition, CEP55 appeared to regulate glucose metabolism of glioma cells. Furthermore, knockdown of CEP55 inhibited cell proliferation and induced cell apoptosis in glioma. Finally, we provided preliminary evidence that knockdown of CEP55 inhibited glioma development via suppressing the activity of Akt/mTOR signaling. CONCLUSIONS: Our results demonstrated that CEP55 regulates glucose metabolism, proliferation and apoptosis of glioma cells via the Akt/mTOR signaling pathway, and its promotive effect on glioma tumorigenesis can be a potential target for glioma therapy in the future.

Antitumor effects of galectin-3 inhibition in human renal carcinoma cells.

Galectins are thought to be prognosticators for survival in renal cell cancer. However, the biological activity of galectin-3 (Gal-3) in renal carcinoma cells is still debated. In this study, immunohistochemical staining confirmed a high expression of Gal-3 in tumor tissue from renal cell carcinoma. Critically, Gal-3 expression was related to tumor cell differentiation. Consistent with Gal-3 expression in renal cell cancer, strong expression of Gal-3 was also observed in several renal tumor cell lines but not in normal renal cells. A Gal-3 high-expression cell line Caki-1 was chosen to study the biological activity of Gal-3. Using short hairpin RNA method, Gal-3 expression in Caki-1 cells was knocked down. We evidenced that Gal-3 knockdown inhibited cell proliferation and invasion, induced Caspase-3-dependent apoptosis and arrested cell cycle at G1 phase. Mechanically, Cyclin D1 expression decreased, but p27 increased after Gal-3 knockdown. Taken together, these results suggest that Gal-3 is related to the development of renal cell cancer and could serve as a target to therapy renal cell cancer.

miR-25 promotes glioma cell proliferation by targeting CDKN1C.

MicroRNAs (miRNA) have oncogenic or tumor-suppressive roles in the development and growth of human glioma. Glioma development is also associated with alteration in the activities and expression of cell cycle regulators, and miRNAs are emerging as important regulators of cell cycle progression. Here, we show that miR-25 is overexpressed in 91% of examined human glioma tissues and 4 out of 6 human glioma cell lines. MiR-25 increases cell proliferation in two independent glioma cell lines. Ectopic expression of miR-25 was found to reduce CDKN1C protein levels by directly targeting its 3'-untranslated region (UTR). Notably, ablation of endogenous miR-25 rescued CDKN1C expression and significantly decreased glioma cell proliferation by facilitating normal cell cycle progression. Our clinical investigation found CDKN1C and miR-25 levels were inversely correlated. Lastly, downregulation of CDKN1 by siRNA blocked the activity of miR-25 on promoting glioma cell proliferation. Overall, our results for the first time show an oncogenic role of miR-25 in human glioma by targeting CDKN1C and that miR-25 could potentially be a therapeutic target for glioma intervention.

miR-340 inhibits glioblastoma cell proliferation by suppressing CDK6, cyclin-D1 and cyclin-D2.

Glioblastoma development is often associated with alteration in the activity and expression of cell cycle regulators, such as cyclin-dependent kinases (CKDs) and cyclins, resulting in aberrant cell proliferation. Recent studies have highlighted the pivotal roles of miRNAs in controlling the development and growth of glioblastoma. Here, we provide evidence for a function of miR-340 in the inhibition of glioblastoma cell proliferation. We found that miR-340 is downregulated in human glioblastoma tissue samples and several established glioblastoma cell lines. Proliferation and neurosphere formation assays revealed that miR-340 plays an oncosuppressive role in glioblastoma, and that its ectopic expression causes significant defect in glioblastoma cell growth. Further, using bioinformatics, luciferase assay and western blot, we found that miR-340 specifically targets the 3'UTRs of CDK6, cyclin-D1 and cyclin-D2, leading to the arrest of glioblastoma cells in the G0/G1 cell cycle phase. Confirming these results, we found that re-introducing CDK6, cyclin-D1 or cyclin-D2 expression partially, but significantly, rescues cells from the suppression of cell proliferation and cell cycle arrest mediated by miR-340. Collectively, our results demonstrate that miR-340 plays a tumor-suppressive role in glioblastoma and may be useful as a diagnostic biomarker and/or a therapeutic avenue for glioblastoma.

miR-603 promotes glioma cell growth via Wnt/ß-catenin pathway by inhibiting WIF1 and CTNNBIP1.

Gliomas are the most common and deadly type of brain tumor. In spite of progressive treatments, patient prognosis has not improved significantly. MicroRNAs are considered promising candidates for glioma therapy. MiR-603 was found overexpressed in both glioma tissues and cell lines. MiR-603 promoted cell proliferation, cell cycle progression and neurosphere formation. Conversely, inhibition of miR-603 remarkably reduced these effects. We confirmed that WIF1 and CTNNBIP1 are bona fide targets of miR-603. The negative correlation between miR-603 and these molecules' expression was shown by Pearson correlation in 50 primary glioma tissue samples. Furthermore, overexpression of miR-603 promoted nuclear ß-catenin levels and TOPflash luciferase activity, indicating that miR-603 activates the Wnt/ß-catenin signaling pathway. Our in vivo results confirmed the positive role of miR-603 in glioma development. We demonstrate that miR-603 regulates glioma development via its WIF1 and CTNNBIP1 targets, which suggests that miR-603 may be a promising candidate for therapeutic applications in glioma treatment.

miR-656 inhibits glioma tumorigenesis through repression of BMPR1A.

Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-ß family, plays critical roles in cell differentiation, modeling and regeneration processes in several tissues. BMP-2 is also closely associated with various malignant tumors. microRNAs negatively and posttranscriptionally regulate gene expression and function as oncogenes or tumor suppressors. Herein, we report that miR-656 expression was significantly downregulated in glioma cell lines and tissues. We identified and confirmed that BMP receptor, type 1A (BMPR1A) is a direct target of miR-656. The expression of BMPR1A was negatively correlated with that of miR-656 in human glioma tissues. We further demonstrated that miR-656 suppressed glioma cell proliferation, neurosphere formation, migration and invasion with or without exogenous BMP-2. Engineered knockdown of BMPR1A diminished the antiproliferation effect of miR-656 in vitro. Moreover, the canonical BMP/Smad and non-canonical BMP/mitogen-activated protein kinase (MAPK) pathways were inhibited by miR-656 overexpression. Several cancer-related signaling molecules, including cyclin B, cyclin D1, matrix metalloproteinase-9, p21 and p27, were also involved in miR-656 function in glioma cells. The tumor-suppressing function of miR-656 was validated using an in vivo intracranial xenograft mouse model. Notably, ectopic expression of miR-656 markedly reduced tumor size and prolonged the survival of mice treated with or without BMP-2. These results elucidate the function of miR-656 in glioma progression and suggest a promising application for glioma treatment.

Treatment of malignant glioma using hyperthermia.

Thirty pathologically diagnosed patients with grade III-IV primary or recurrent malignant glioma (tumor diameter 3-7 cm) were randomly divided into two groups. The control group underwent conventional radiotherapy and chemotherapy. In the hyperthermia group, primary cases received hyperthermia treatment, and patients with recurrent tumors were treated with hyperthermia in com-bination with radiotherapy and chemotherapy. Hyperthermia treatment was administered using a 13.56-MHz radio frequency hyperthermia device. Electrodes were inserted into the tumor with the aid of a CT-guided stereotactic apparatus and heat was applied for 1 hour. During 3 months after hyperthermia, patients were evaluated with head CT or MRI every month. Gliomas in the hyper-thermia group exhibited growth retardation or growth termination. Necrosis was evident in 80% of the heated tumor tissue and there was a decrease in tumor diameter. Our findings indicate that ra-dio frequency hyperthermia has a beneficial effect in the treatment of malignant glioma.

The effects of simvastatin on hippocampal caspase-3 and Bcl-2 expression following kainate-induced seizures in rats.

Status epilepticus (SE) causes neuronal loss and apoptosis by inducing several apoptosis-regulatory genes. Two such genes, cysteinyl aspartate-specific protease-3 (caspase-3), an apoptosis activator, and B-cell leukemia-2 (Bcl-2), an apoptosis suppressor, are tightly regulated for their expression and activation. Statins, inhibitors of HMG-CoA reductase, have been recently recognized as neuroprotective drugs. However, their underlying mechanisms are still unclear. In this study, we examined the neuroprotective effects of simvastatin in a rat model of SE induced by kainic acid (KA). Feeding of simvastatin for 3 days after kainate injection rescued SE-induced neuronal apoptosis, as determined by histological examination of brain sections at the level of the dorsal hippocampus. Semi-quantitative RT-PCR showed that SE treatment markedly increased caspase-3 mRNA expression and reduced Bcl-2 mRNA expression in the hippocampus. Similarly, western blot analysis and immunohistochemical analysis of the rat hippocampus demonstrated that under SE treatment, caspase-3 protein levels significantly increased and peaked at 72 h, whereas Bcl-2 protein levels decreased from 6-24 h following SE. Interestingly, simvastatin could reverse the aforementioned SE-induced changes, suggesting that the neuroprotective effects of simvastatin against neuronal apoptosis may be achieved by inhibiting caspase-3 expression and increasing Bcl-2 expression.

Administration of simvastatin after kainic acid-induced status epilepticus restrains chronic temporal lobe epilepsy.

In this study, we examined the effect of chronic administration of simvastatin immediately after status epilepticus (SE) on rat brain with temporal lobe epilepsy (TLE). First, we evaluated cytokines expression at 3 days post KA-lesion in hippocampus and found that simvastatin-treatment suppressed lesion-induced expression of interleukin (IL)-1ß and tumor necrosis factor-α (TNF-α). Further, we quantified reactive astrocytosis using glial fibrillary acidic protein (GFAP) staining and neuron loss using Nissl staining in hippocampus at 4-6 months after KA-lesion. We found that simvastatin suppressed reactive astrocytosis demonstrated by a significant decrease in GFAP-positive cells, and attenuated loss of pyramidal neurons in CA3 and interneurons in dentate hilar (DH). We next assessed aberrant mossy fiber sprouting (MFS) that is known to contribute to recurrence of spontaneous seizure in epileptic brain. In contrast to the robust MFS observed in saline-treated animals, the extent of MFS was restrained by simvastatin in epileptic rats. Attenuated MFS was related to decreased neuronal loss in CA3 and DH, which is possibly a mechanism underlying decreased hippocampal susceptibility in animal treated with simvastatin. Electronic encephalography (EEG) was recorded during 4 to 6 months after KA-lesion. The frequency of abnormal spikes in rats with simvastatin-treatment decreased significantly compared to the saline group. In summary, simvastatin treatment suppressed cytokines expression and reactive astrocytosis and decreased the frequency of discharges of epileptic brain, which might be due to the inhibition of MFS in DH. Our study suggests that simvastatin administration might be a possible intervention and promising strategy for preventing SE exacerbating to chronic epilepsy.

[Comparison of MGMT and ERCC2 expression in temozolomide for the treatment of malignant glioma drug resistance and their genetic relationship].

OBJECTIVE: To study the impact of two human glioma tissue resistance genes MGMT and ERCC(2) on the temozolomide-based treatment of malignant gliomas and detect the relationship of their expressions. METHODS: A total of 58 malignant glioma patients aged 19 - 68 years old receiving a chemotherapy of temozolomide were followed up and classified as non-sensitive group (n = 30) and sensitive group (n = 28). Immunohistochemistry was employed to detect the expression rates of MGMT and ERCC(2). And the correlation between the expressions of two genes was analyzed by immunohistochemistry and RT-PCR (reverse transcription-polymerase chain reaction). RESULTS: The expression rates of MGMT and ERCC(2) were 10.71% and 3.57% in the sensitive group and 63.33% and 56.67% in the non-sensitive group. It had an obvious correlation with the expressions of MEGT and ERCC(2) through an analysis of immunohistochemistry and RT-PCR (both P < 0.01). CONCLUSION: The expressions of MGMT and ERCC(2) in the sensitive group are markedly lower than those in the non-sensitive group. The expression of two genes may be related to tumor prognosis. Maybe these two genes have an intrinsic link between their expressions. Both participate in the repair of cellular DNA damage and the formation of tumor drug resistance. And the prognosis has obvious relevance.