Hyperglycemia increased brain ischemia injury through extracellular signal-regulated protein Kinase

Institute of Immunopathology, School of Life Science & Technology, Xi'an Jiaotong University, Xi'an 710061, China.
Pathology - Research and Practice (Impact Factor: 1.4). 02/2006; 202(1):31-6. DOI: 10.1016/j.prp.2005.10.002
Source: PubMed


This study was to examine the alterations in the phosphorylation of mitogen-activated protein kinase (MAPK) family in transient brain ischemia under a hyperglycemia and to highlight the molecular mechanisms by which hyperglycemia exacerbates brain damage resulting from stroke. Extracellular signal-regulated protein kinase (ERK) expression was studied in rats subjected to global brain ischemia with pre-ischemic normoglycemic (CIN) and hyperglycemic (CIH) conditions. In another group, the hyperglycemic ischemic rats were pretreated with ERK inhibitor U0126 (U0126). Increased phospho-ERK1/2 immunoreactive neurons in the cingulate cortex and hippocampal CA3 were detected in CIN after ischemia and reperfusion. The numbers of phospho-ERK1/2-positive neurons were further increased significantly in CIH compared to the CIN. Pretreatment with U0126 in CIH rats significantly decreased ERK1/2 immunoreactive cells. Western blot analyses confirmed that phospho-ERK1/2 increased significantly after 30 min ischemia and reperfusion compared to non-ischemic controls in both the CIN and CIH groups. The increase of phospho-ERK1/2 was more prominent in the CIH than in the CIN group after 3 and 6h of reperfusion. Treatment with U0126 significantly reduced phospho-ERK1/2 in the CIH group. The findings presented here suggest that ERK1/2 may play a role in mediating neuronal cells death under hyperglycemic condition.

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    • "Previous studies have demonstrated that hyperglycemia markedly increased phosphorylation of ERK 1/2 in the cingulated cortex and hippocampal CA3 and dentate gyrus areas, structures that are recruited and exacerbated by hyperglycemia when subjected a transient forebrain ischemia (Li et al., 2001; Krupinski et al., 2005; Kurihara et al., 2004). While increased phosphorylation of ERK1/2 may promote cell survival by increasing cell proliferation in vitro, inhibition of the ERK1/2 has been linked to decrease neuronal cell death after transient focal cerebral ischemia under normoglycemic conditions and after transient forebrain ischemia under hyperglycemic conditions (Namura et al., 2001; Zhang et al., 2006). In this study, we observed that GM1 treatment significantly suppressed the phosphorylation of ERK1/2, a critical member in the MAPK family. "
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    ABSTRACT: Monosialotetrahexosy-1 ganglioside (GM1) has been shown to reduce brain damage induced by cerebral ischemia. The objective of this study is to determine whether GM1 is able to ameliorate hyperglycemia-exacerbated ischemic brain damage in hyperglycemia-recruited areas such as the hippocampal CA3 sub regions and the cingulated cortex. Histologic stainings of Haematoxylin and Eosin, Nissl body, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and phospho-ERK1/2 were performed on brain sections that have been subjected to 15 min of forebrain ischemia with reperfusion of 0, 1, 3, and 6h in normoglycemic, hyperglycemic and GM1-pretreated hyperglycemic groups. The results showed that GM1 ameliorated ischemic neuronal injuries in the CA3 area and cingulated cortex of the hyperglycemic animals after ischemia and reperfusion. Immunohistochemistry of phospho-ERK1/2 revealed that the neuroprotective effects of GM1 were associated with suppression of phospho-ERK1/2. The results suggest that GM1 attenuates diabetic-augmented ischemic neuronal injuries probably through suppression of ERK1/2 phosphorylation.
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