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tic cells in the dentate gyrus GSK2190915 Infection with S. pneumoniae caused apoptosis in the subgranular zone with the dentate gyrus as reported pre viously. At 24 h post infection rep resenting the acute phase with the disease, the imply score of apoptotic neurons was 1. six 0. 1 in saline treated ani mals. In animals treated with vitamin B6 the apoptotic damage score was significantly decrease with a imply score of apoptotic cells of 1. two 0. 1. In contrast, vitamin B6 remedy had no important impact on cortical damage. Microarrays An overview with the workflow of microarray analysis selected for this perform is represented in Figure three. From over 27000 rat genes represented on the chip, 17957 genes have been expressed over background level in the hippocampus of rat brains.
Right after significance testing, the expression of 120 annotated genes was found to become influenced by vitamin B6 remedy. Cluster analysis Functional annotation clustering of significantly regu lated genes by DAVID bioinformatics resulted in clusters of genes with attainable roles in the mode of action NSC 14613 of vitamin B6. The corresponding GO terms found to become overrepresented in our gene list belong to processes with the inflammatory response, circadian rhythm, neuronal signaling and apoptotic cell death. Upon vitamin B6 remedy numerous genes involved in processes with the inflammatory response have been down regulated for instance pro inflammatory cytokines and chemokines. In contrast, the majority of genes involved in processes with the circadian rhythm also as of neuronal signaling and apoptosis have been up regulated.
A important tool to assign a set of genes to cellular pathways could be the KEGG pathway database. The pathways over represented in our set of genes have been related towards the hugely conserved mitogen activated protein kinase cascade also as towards the circadian rhythm. The MAPK pathway is involved in different cellular functions SKI II such as inflammatory processes and neuronal signaling, both processes also found by DAVID bioinformatics. True time PCR To validate the microarray information by an independent sec ond technique the expression levels of five genes have been assessed by true time PCR. These genes have been se lected as a consequence of their RNA polymerase putative significance in the mode of action of vitamin B6 in reducing hippocampal apoptosis, i. e. deriving from the apoptosiscell death cluster, and because their expression levels span a wide signal array of the microarray.
The Pearson correlation among SKI II true time PCR and microarray information was r 0. 962 with a important p worth of 0. 009. Correlation among RNA expression level and apoptosis score Pearson correlation among RNA expression levels of chosen genes and apoptosis score was hugely important with p values among 0. 001 and 0. 005. The transcripts selected for the correlation analysis GSK2190915 have been exactly the same as assessed by true time PCR. As a consequence of these hugely important correlations among expression level and apoptosis score, the chosen genes are candidates for apoptosis markers, despite the fact that the time point is late in regard towards the notion that pro and anti apoptotic components transform at 12 16 h just after infection. Nonetheless, further experiments are necessary to determine the application of these genes as potential apoptosis markers.
NAD levels in hippocampal SKI II tissue Hippocampal NAD levels of rats with BM dropped just after infection, indicating a reduce of cellular power in the course with the disease. In contrast towards the placebo group, the quantity of NAD in the hippocampus of rats treated with vitamin B6 improved during the identical time period. Thus, an impact of vitamin B6 to pre serve cellular power shops, probably by optimizing the sub strate flux in the kynurenine pathway, was found during the acute phase of BM when hippocampal GSK2190915 apoptosis develops. Discussion Apoptosis of cells in the hippocampal dentate gyrus is a characteristic type of brain damage in BM. In experimental models an association of injury towards the den tate gyrus with studying and memory deficits has been shown.
The present study demonstrates that treat ment with vitamin B6 reduces the number of apoptotic SKI II cells in the hippocampal dentate gyrus. We investigated the mechanisms underlying this neuroprotective impact by studying the influence of vitamin B6 on the transcrip tome and on cellular power shops. In the model utilised, hippocampal apoptosis starts to take place during the acute phase of BM with a peak in the sub acute phase at 36 h, and reaches manage levels in the late phase with the disease. Recent studies in our lab showed that in the acute phase of BM, genes which can be significantly expressed in the hippocam pus and cortex are primarily involved in processes with the immune and inflammatory response. The innate im mune program features a predominant part in immune defense in the otherwise immune privileged brain tissue. How ever, neurological complications secondary to BM recommend that the host defense mechanisms are inefficient in eliminating the pathogen and moreover, that the host inflammatory reactions contribute significantly towards the