Abstract
BackgroundPost-stroke hyperglycemia appears to be associated with poor outcome from stroke, greater mortality, and reduced functional recovery. Focal cerebral ischemia data support that neural stem cells (NSCs) play an important role in post-ischemic repair. Here we sought to evaluate the negative effects of hyperglycemia on the cellular biology of NSCs following anoxia, and to test whether high glucose affects NSC recovery from ischemic injury.ResultsIn this study, we used immortalized adult neural stem cells lines and we induced in vitro ischemia by 6 h oxygen and glucose deprivation (OGD) in an anaerobic incubator. Reperfusion was performed by returning cells to normoxic conditions and the cells were then incubated in experimental medium with various concentrations of glucose (17.5, 27.75, 41.75, and 83.75 mM) for 24 h. We found that high glucose (≥27.75 mM) exposure induced apoptosis of NSCs in a dose-dependent manner after exposure to OGD, using an Annexin V/PI apoptosis detection kit. The cell viability and proliferative activity of NSCs following OGD in vitro, evaluated with both a Cell Counting kit-8 (CCK-8) assay and a 5-ethynyl-2’-deoxyuridine (EdU) incorporation assay, were inhibited by high glucose exposure. Cell cycle analysis showed that high glucose exposure increased the percentage of cells in G0/G1-phase, and reduced the percentage of cells in S-phase. Furthermore, high glucose exposure was found to significantly induce the activation of c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) and suppress extracellular signal-regulated kinase 1/2 (ERK1/2) activity.ConclusionsOur results demonstrate that high glucose induces apoptosis and inhibits proliferation of NSCs following OGD in vitro, which may be associated with the activation of JNK/p38 MAPK pathways and the delay of G1-S transition in the cells.
Highlights
Post-stroke hyperglycemia appears to be associated with poor outcome from stroke, greater mortality, and reduced functional recovery
We further examined whether the activation of mitogen-activated protein kinase (MAPK) signaling molecules is involved in the proliferation and apoptosis of neural stem cells (NSCs), as MAPK signaling plays an important role in central nervous system (CNS) development and differentiation [15]
oxygen and glucose deprivation (OGD)/R was induced by a wash in glucose-free Earle’s balanced salt solution (EBSS) prior to a 2–10 h anaerobic incubation followed by a 24 h post-incubation period
Summary
Post-stroke hyperglycemia appears to be associated with poor outcome from stroke, greater mortality, and reduced functional recovery. Focal cerebral ischemia data support that neural stem cells (NSCs) play an important role in post-ischemic repair. We sought to evaluate the negative effects of hyperglycemia on the cellular biology of NSCs following anoxia, and to test whether high glucose affects NSC recovery from ischemic injury. There are reports showing that low glucose suppresses the proliferation and increases the differentiation of cultured NSCs in vitro [8], and that post-stroke hyperglycemia is seen in up to 50% of patients who have an initial blood glucose above 6.0–7.0 mM [11,12]. Plasma glucose is an important determinant of brain injury in experimental models of focal cerebral ischemia/reperfusion [14], but few studies have explored the effect of high glucose on NSCs or progenitor cells following oxygen and glucose deprivation/reperfusion (OGD/R) insult
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