Hyperglycemia increased brain ischemia injury through extracellular signal-regulated protein Kinase.
ABSTRACT 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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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.Brain research 07/2010; 1344:200-8. DOI:10.1016/j.brainres.2010.05.044 · 2.83 Impact Factor
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ABSTRACT: Patients with diabetes in the aging population are at high risk of Alzheimer's disease (AD), and reduction of sirtuin 1 (SIRT1) activity occurs simultaneously with the accumulation of hyperphosphorylated tau in the AD-affected brain. It is not clear, however, whether SIRT1 is a suitable molecular target for the treatment of AD. Here, we employed a rat model of brain insulin resistance with intracerebroventricular injection of streptozotocin (ICV-STZ; 3 mg/kg, twice with an interval of 48 h). The ICV-STZ-treated rats were administrated with resveratrol (RSV; SIRT1-specific activator) or a vehicle via intraperitoneal injection for 8 weeks (30 mg/kg, once per day). In ICV-STZ-treated rats, the levels of phosphorylated tau and phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) at the hippocampi were increased significantly, whereas SIRT1 activity was decreased without change of its expression level. The capacity of spatial memory was also significantly lower in ICV-STZ-treated rats compared with age-matched control. RSV, a specific activator of SIRT1, which reversed the ICV-STZ-induced decrease in SIRT1 activity, increases in ERK1/2 phosphorylation, tau phosphorylation, and impairment of cognitive capability in rats. In conclusion, SIRT1 protects hippocampus neurons from tau hyperphosphorylation and prevents cognitive impairment induced by ICV-STZ brain insulin resistance with decreased hippocampus ERK1/2 activity.Age 10/2013; 36(2). DOI:10.1007/s11357-013-9592-1 · 3.45 Impact Factor
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ABSTRACT: Brain edema forms rapidly in the early hours of ischemic stroke by increased secretion of Na, Cl and water into the brain across an intact blood-brain barrier (BBB), together with astrocyte swelling as they take up the ions and water crossing the BBB. Our previous studies provided evidence that luminal BBB Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) participate in ischemia-induced edema formation. NKCC1 and two NHE isoforms, NHE1 and NHE2, reside predominantly at the luminal BBB membrane. Both NKCC and NHE activities of cerebral microvascular endothelial cells (CMEC) are rapidly stimulated by the ischemic factors hypoxia, aglycemia and arginine vasopressin (AVP) and inhibition of these transporters by bumetanide and HOE642, respectively, reduces brain Na uptake and edema in the rat middle cerebral artery occlusion model of stroke. The present study was conducted to further explore BBB NHE responses to ischemia. Here, we examined whether ischemic factor-stimulated NHE activity is sustained over several hours, when the majority of edema forms during stroke. We also examined whether ischemic factors alter NHE1 and/or NHE2 protein abundances. Finally, we conducted initial studies of ERK1/2 MAP kinase involvement in BBB NHE and NKCC responses to ischemia. We found that hypoxia, aglycemia and AVP all increase CMEC NHE activity through 5 hr and that NHE1 but not NHE2 abundance is increased by 1-5 hr exposures to these factors. Further, we found that the factors rapidly increase BBB ERK1/2 activity and that ERK1/2 inhibition reduces or abolishes ischemic factor stimulation of NKCC and NHE activities.AJP Cell Physiology 03/2014; 306(10). DOI:10.1152/ajpcell.00021.2013 · 3.71 Impact Factor