Repeated exposure to lidocaine induces hippocampal synaptic and cognitive impairment in aged mice by activating microglia and neurotoxic A1astrocytes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE270941 | GEO | 2024/07/01
REPOSITORIES: GEO
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Project description:This study aimed to explore the possible mechanism of lidocaine-induced neurotoxicity. A total of 40 rats were randomly assigned to 4 groups (n = 10 per group): control group; sham group, received only intrathecal catheter insertion; saline group, received an intrathecal injection of saline; and lidocaine group, received an intrathecal injection of 10% lidocaine. Neurobehavioral tests were performed on rats in each group before injection and 1, 2, 3, and 4 days after the intrathecal injection. On the fourth day, after completing neurobehavioral tests, the spinal cords of all rats from L2 to L6 were removed and immediately stored in liquid nitrogen. In the control and lidocaine groups, parts of the spinal cord tissues of three rats were selected for gene microarray analysis.Based on the results of the gene chip analysis,Five rats in each group underwent real-time quantitative polymerase chain reaction (PCR) and five Western blot analysis to verify Differentially expressed genes at the mRNA transcription and protein levels. The aim of gene chip analysis is to screen potential genes involved in lidocaine-induced neurotoxicity.
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Project description:In order to identify microRNAs (miRNAs) that were involved in the effects of anesthetics on breast cancer cells, Illumina next generation miRNA sequencing was performed to search for any differentially expressed miRNAs in responding to lidocaine and bupivacaine treatments in MCF7 breast cancer cells. The filtering criteria for identifying differentially expressed miRNAs in the lidocaine and bupivacaine groups were fold change ≥ 2.0X and P-value ≤ 0.05. In total, there were 1,228 significantly upregulated miRNAs in lidocaine group and 133 miRNAs in bupivacaine group. On the contrary, there were 25 significantly downregulated miRNAs in lidocaine group and 36 miRNAs in bupivacaine group.
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Project description:Chlorpyrifos (CPF), an organophosphorus pesticide (OP), is one of the most widely used pesticides in the world. Subchronic exposures to CPF that do not cause cholinergic crisis are associated with problems in cognitive function (i.e., learning and memory deficits), but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of subchronic CPF neurotoxicity, adult male Long Evans (LE) rats were administered CPF at 3 or 10mg/kg/d (s.c.) for 21 days. We quantified mRNA and non-coding RNA (ncRNA) expression profiles by RNA-seq, microarray analysis and small ncRNA sequencing technology in the CA1 region of the hippocampus. Hippocampal slice immunohistochemistry was used to determine CPF-induced changes in protein expression and localization patterns. Neither dose of CPF caused overt clinical signs of cholinergic toxicity, although after 21 days of exposure, cholinesterase activity was decreased to 58% or 13% of control levels in the hippocampus of rats in the 3 or 10mg/kg/d groups, respectively. Differential gene expression in the CA1 region of the hippocampus was observed only in the 10mg/kg/d dose group relative to controls. Of the 1382 differentially expressed genes identified by RNA-seq and microarray analysis, 67 were common to both approaches. Differential expression of six of these genes (Bdnf, Cort, Crhbp, Nptx2, Npy and Pnoc) was verified in an independent CPF exposure study; immunohistochemistry demonstrated that CRHBP and NPY were elevated in the CA1 region of the hippocampus at 10mg/kg/d CPF. Gene ontology enrichment analysis suggested association of these genes with receptor-mediated cell survival signaling pathways. miR132/212 was also elevated in the CA1 hippocampal region, which may play a role in the disruption of neurotrophin-mediated cognitive processes after CPF administration. These findings identify potential mediators of CPF-induced neurobehavioral deficits following subchronic exposure to CPF at a level that inhibits hippocampal cholinesterase to less than 20% of control. An equally significant finding is that subchronic exposure to CPF at a level that produces more moderate inhibition of hippocampal cholinesterase (approximately 50% of control) does not produce a discernable change in gene expression.
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