Involvement of MAPK pathways in NMDA-induced apoptosis of rat cortical neurons.

NMDA-induced excitotoxicity cause severe neuronal damage including apoptosis and necrosis. The present study was aimed to evaluate the proportion of NMDA-induced apoptosis of rat cortical neurons and discover signal transduction mechanism. Caspase inhibitor and lactate dehydrogenase (LDH) assay were used to study the NMDA-induced apoptosis. To explore the involved signal pathways, the primary culture of rat cortical neurons were pretreated by the inhibitors of three MAPK pathways, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. With 2 h of NMDA treatment, cellular apoptosis was measured by caspase-3 activity, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) and Annexin V staining. The results showed that: (1) Caspase-dependent apoptosis accounted for 22.49% in NMDA-induced neuronal death; (2) Pretreatment with p38 MAPK inhibitor SB203580 (10 µmol/L) significantly decreased NMDA-mediated caspase-3 activity by 30.43% (P < 0.05). However, ERK inhibitor PD98059 (20 µmol/L) or JNK inhibitor SP600125 (20 µmol/L) did not influence caspase-3 activity; (3) Pretreatment with SB203580 significantly reduced the number of NMDA-induced TUNEL-positive cells by 33.10% (P < 0.05). PD98059 (20 µmol/L) or SP600125 (20 µmol/L) did not show obvious effect; (4) Pretreatment with SB203580 (10 µmol/L) significantly reduced the number of NMDA-induced early apoptotic neurons by 55.56% (P < 0.05). Also, SP600125 (20 µmol/L) significantly decreased the amount of late apoptotic/dead cells by 67.59% (P < 0.05). There was no effect of PD98059 (20 µmol/L). These results indicate that: (1) NMDA induces neuronal apoptosis besides necrosis; (2) p38 MAPK, but not JNK and ERK, is involved in NMDA-induced neuronal apoptosis, and inhibition of the apoptotic signaling pathway contributes to neuroprotection; (3) JNK activation might contribute to NMDA-induced neuronal necrosis rather than apoptosis.

Identification of Serum miRNAs as Effective Diagnostic Biomarkers for Distinguishing Primary Central Nervous System Lymphoma from Glioma.

Invasive surgical cerebrum biopsy results in delayed treatment for the definitive diagnosis of primary central nervous system lymphoma (PCNSL). The existent research was aimed at confirming the underlying diagnostic miRNAs of distinguishing PCNSL from glioma. A publicly available miRNA expression profiles (GSE139031) from adult PCNSL as well as glioma specimens were provided by GEO datasets. Differentially expressed miRNAs (DEMs) were filtered between 42 PCNSL patients and 170 glioma patients. Candidate miRNAs were identified through SVM-RFE analysis and LASSO model. ROC assays were operated to determine the diagnostic value of serum miRNAs in distinguishing PCNSL from glioma. StarBase v2.0 was applied to screen the targeting genes of miRNAs, and KEGG analysis was applied using the targeting genes of miRNAs. In this study, we identified 12 dysregulated miRNAs between PCNSL and glioma samples. The ten critical miRNAs (miR-6820-3p, miR-6803-3p, miR-30a-3p, miR-4751, miR-3918, miR-146a-3p, miR-548am-3p, miR-371a-3p, miR-487a-3p, and miR-4756-5p) between these two algorithms were ultimately identified. The results of KEGG revealed that the targeting genes of hsa-miR-3918 were primarily related to MAPK signal pathway, PI3K-Akt signal pathway, and human papillomavirus infection. Overall, bioinformatics analysis revealed that ten miRNAs are potential biomarker for distinguishing PCNSL from glioma.

Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress.

There are numerous mechanisms by which the brain generates seizures. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Salidroside (SDS) extracted from Rhodiola rosea L. shows multiple bioactive properties, such as neuroprotection and antioxidant activity in vitro and in vivo. This study explored the role of SDS in kainic acid (KA)-induced SE and investigated the underlying mechanism. Latency to SE increased in the SDS-pretreated mice compared to the KA group, while the percentage of incidence of SE was significantly reduced. These results suggested that pretreatment with SDS not only delayed SE, but it also decreased the incidence of SE induced by KA. KA increased MDA level and reduced the production of SOD and GSH at multiple timepoints after KA administration. SDS inhibited the change of MDA, SOD and GSH induced by KA prior to SE onset, indicating that SDS protects against KA-induced SE via suppressing oxidative stress. Based on these results, we investigated the possible molecular mechanism of SDS. Pretreatment with SDS reversed the KA-induced decrease in AMP-activated protein kinase (AMPK); increased the sirtuin 1 (SIRT1) deacetylase activity in KA-treated mice, which had no demonstrable effect on SIRT1 mRNA and protein; and suppressed the KA-induced increase in Ace-FoxO1. These results showed that AMPK/SIRT1/FoxO1 signaling is possibly the molecular mechanism of neuroprotection by SDS.