Dexmedetomidine Attenuates Apoptosis and Neurological Deficits by Modulating Neuronal NADPH Oxidase 2-Derived Oxidative Stress in Neonates Following Hypoxic Brain Injury

Hypoxic–ischemic brain injury is an important cause of neonatal neurological deficits. Our previous study demonstrated that dexmedetomidine (Dex) provided neuroprotection against neonatal hypoxic brain injury; however, the underlying mechanisms remain incompletely elucidated. Overactivation of NADPH oxidase 2 (NOX2) can cause neuronal apoptosis and neurological deficits. Hence, we aimed to investigate the role of neuronal NOX2 in Dex-mediated neuroprotection and to explore its potential mechanisms. Hypoxic injury was modeled in neonatal rodents in vivo and in cultured hippocampal neurons in vitro. Our results showed that pre- or post-treatment with Dex improved the neurological deficits and alleviated the hippocampal neuronal damage and apoptosis caused by neonatal hypoxia. In addition, Dex treatment significantly suppressed hypoxia-induced neuronal NOX2 activation; it also reduced oxidative stress, as evidenced by decreases in intracellular reactive oxygen species (ROS) production, malondialdehyde, and 8-hydroxy-2-deoxyguanosine, as well as increases in the antioxidant enzymatic activity of superoxide dismutase and glutathione peroxidase in neonatal rat hippocampi and in hippocampal neurons. Lastly, the posthypoxicneuroprotective action of Dex was almost completely abolished in NOX2-deficient neonatal mice and NOX2-knockdown neurons. In conclusion, our data demonstrated that neuronal NOX2-mediated oxidative stress is involved in the neuroprotection that Dex provides against apoptosis and neurological deficits in neonates following hypoxia

Transcriptomic Analysis of Long Noncoding RNA and mRNA Expression Profiles in the Amygdala of Rats with Bone Cancer Pain-Depression Comorbidity

Bone cancer pain (BCP)–depression comorbidity has become a complex clinical problem during cancer treatment; however, its underlying molecular mechanisms have not been clarified. Several long noncoding RNAs (lncRNAs) have been demonstrated to be promising therapeutic targets in depression, but research on the role of lncRNAs in BCP–depression comorbidity has been limited. Therefore, high-throughput RNA sequencing was performed to detect differentially expressed profiles in the amygdala of a BCP–depression rat model in this study. We detected 330 differentially expressed mRNAs (DEmRNAs) and 78 differentially expressed lncRNAs (DElncRNAs) in the BCP–depression comorbidity model and then verified the expression of six DEmRNAs and six DElncRNAs with the greatest degrees of difference by RT-qPCR. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that differentially expressed genes were strongly enriched in inflammatory and immunologic systemic responses. Then the nuclear factor kappa B (NF-κB) signaling pathway and the Th17 differentiation pathway showed significant differences, as determined by Western blot analysis. Finally, we constructed a protein–protein interaction (PPI) network to explore the potential regulatory mechanism of DEmRNAs. In conclusion, our study reveals a new resource for the understanding of dysregulated lncRNAs and mRNAs in BCP–depression comorbidity and provides novel potential therapeutic targets for further approaches

Upregulation of Nav1.6 Mediated by the p38 MAPK Pathway in the Dorsal Root Ganglia Contributes to Cancer-Induced Bone Pain in Rats

Cancer-induced bone pain (CIBP) occurs frequently among advanced cancer patients. Voltage-gated sodium channels (VGSCs) have been associated with chronic pain, but how VGSCs function in CIBP is poorly understood. Here, we aimed to investigate the specific role of VGSCs in the dorsal root ganglia (DRGs) in CIBP. A CIBP rat model was generated by the intratibial inoculation of MRMT-1 breast carcinoma cells. Transcriptome sequencing was conducted to assess the gene expression profiles. The expression levels of key genes and differentiated genes related to activated pathways were measured by Western blotting and qPCR. We implanted a catheter intrathecally for the administration of lentivirus and drugs. Then, the changes in the mechanical withdrawal threshold (MWT) were measured. We identified 149 differentially expressed mRNAs (DEmRNAs) in the DRGs of CIBP model rats. The expression of Nav1.6, which was among these DEmRNAs, was significantly upregulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the DEmRNAs showed that they were mainly enriched in the mitogen-activated protein kinase (MAPK) pathway. The decrease in MWT induced by bone cancer was attenuated by Nav1.6 knockdown. Western blot analysis revealed that a p38 inhibitor decreased the expression of Nav1.6 and attenuated pain behavior. Our study shows that the upregulation of Nav1.6 expression by p38 MAPK in the DRGs of rats contributes to CIBP