Cluster analysis of mrna expression levels identifies multiple sequential patterns following focal cerebral ischemia

Abstract

AIM:The purpose of this study is to detect gene expression patterns following focal cerebral ischemia. MATeRIAL and MeTHods:25 male Wistar rats were divided into control (n = 8) and ischemic (n = 17) groups. In the ischemic group, slowly progressing focal ischemia was simulated by two-vein occlusion with spreading depression (SD) a cortical microinjection of KCl induced. Ischemic tissue was removed at 2, 8, 24, or 72 h postischemia. Using semiquantitative reverse transcription polymerase chain reaction, we investigated mRNA expression levels of 13 representative genes related to cerebral ischemia. Cluster analysis of the gene expression levels was done. ResULTs:In the ischemic group, the expression levels of c-fos, cyclin D1, and COX-2 were significantly higher at 2 h postischemia, and those of bcl-2, bcl-xL, and HO-1 at 72 h. Based on the cluster analysis, we statistically divided examined genes into three groups: group A, early expression (COX-2, c-fos, and bcl-2); group B, s expression (c-jun, SOD-1, bad, p53, SOD-2, bcl-xL, and bax); and group C, late expression (cyclin D1, c-myc, and HO-1). CoNCLUsIoN:We statistically classified the genes into three groups after focal ischemia. The genes of the early-and late-expression groups can be possible therapeutic targets for the treatment of cerebral ischemia.

Repetitive Spreading Depolarization induces gene expression changes related to synaptic plasticity and neuroprotective pathways

“…Consistent with previous studies (Kaido et al 2012; Rangel et al 2001; Kokaia et al 1993; Dietrich et al 2000), we found significant changes intermediate early genes ARC, FOS and JUN proto-oncogenes, and early growth response (EGR) genes. Among other DEGs with significantly increased levels were adrenoceptor beta 1 (ADRB1), dual specificity phosphatase (DUSP) gene family, the nuclear receptor subfamily 4 group A member 1 (NR4A1), and prostaglandin-endoperoxide synthase 2 (PTGS2).…”

“…Consistent with previous reports, either from gene array studies or targeted expression analysis, markers of inflammation were also upregulated (Urbach et al, 2006;Sintas et al, 2017). For example, our results are consistent with prior reports of robust increases of the pro-inflammatory mediator COX2 (Kaido et al, 2012;Takizawa et al, 2020;Volobueva et al, 2023). We did not see significant increases in some other inflammatory mediators that had been previously reported (e.g., TNF-α, IL-1β, IL6), perhaps because the time course for peak increases in these mediators is later than the 2-hour time point used in the present study (Takizawa et al, 2020).…”

“…Although our results predict activation of neuroprotective pathways, they are also consistent with prior reports of robust increases of the pro-inflammatory mediator COX2 (Takizawa et al 2020; Kaido et al 2012; Volobueva et al 2023). We did not see significant increases in some other inflammatory mediators (e.g., TNF-α, IL-1β, IL6), perhaps because the time course for peak increases in these mediators is later than the 2-hour time point used in the present study (Takizawa et al 2020).…”

“…Initial studies identified increases in brain derived neurotrophic factor (BDNF), c-Fos and heat shock protein 70 (HSP70) (Dietrich et al 2000; Kokaia et al 1993; Karikó et al 1998; Matsushima, Hogan, and Hakim 1996; Rangel et al 2001). Subsequent studies showed increased expression of pro-inflammatory and apoptotic genes, including tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), interleukin-1 (IL-1) and −6, and cyclooxygenase-2 (COX-2), and B-cell lymphoma 2 (BCL-2) (Eising et al 2017; Jander et al 2001; Kaido et al 2012; Takizawa et al 2020). While most of these studies focused predetermined genes, a relatively recent microarray study has applied gene ontology (GO) and pathway analysis (PA) to the study of SD in rats (Sintas et al 2017).…”

Repetitive spreading depolarization induces gene expression changes related to synaptic plasticity and neuroprotective pathways

“…Initial studies identified increases in brain derived neurotrophic factor (BDNF), c-Fos and heat shock protein 70 (HSP70) (Kokaia et al, 1993;Matsushima et al, 1996;Karikó et al, 1998;Dietrich et al, 2000;Rangel et al, 2001). Subsequent studies showed increased expression of pro-inflammatory and apoptotic genes, including tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), interleukin-1 (IL-1) and -6, and cyclooxygenase-2 (COX-2), and B-cell lymphoma 2 (BCL-2) (Jander et al, 2001;Kaido et al, 2012;Eising et al, 2017;Takizawa et al, 2020). While most of these studies focused on a predetermined set of genes, a microarray study applied gene ontology (GO) and pathway analysis (PA) to examine the effect of SDs in rats (Sintas et al, 2017).…”