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

ArticleinPathology - Research and Practice 202(1):31-6 · February 2006with2 Reads
DOI: 10.1016/j.prp.2005.10.002 · Source: PubMed
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.
    • "The pathogenesis of tau pathologies needs to be clarified. Phosphorylation of Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) induced by hyperglycemia exacerbates ischemia-induced brain injuries (Farrokhnia et al. 2005; He et al. 2003; Kurihara et al. 2004; Li et al. 2001), whereas inhibition of ERK1/2 and JNK signaling pathways reduces the ischemic brain damage in normo-or hyperglycemic conditions (Guan et al. 2005; Namura et al. 2001; Zhang et al. 2006). The increase in phosphorylated ERK1/2 is also observed in AD-affected brains. "
    [Show abstract] [Hide abstract] 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.
    Article · Oct 2013
    • "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 ( 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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jul 2010
  • [Show abstract] [Hide abstract] ABSTRACT: In this review, we summarize the role of hyperglycemia during cerebral ischemia. Hyperglycemia occurring during experimental and clinical stroke has been associated with increased cerebral damage. Increased oxidative stress resulting from hyperglycemia is believed to contribute to the exacerbated damage. More specifically, superoxide, nitric oxide and peroxynitrite are believed to play an important role in cerebral damage. This also involves increased recruitment of various blood cells to the ischemic zone that contribute to inflammation. We present data from our group and others that demonstrate that free radical production is increased during hyperglycemic stroke in rodents. Recent data suggest that inflammation is an important component of ischemic damage under both normo- and hyperglycemic conditions. We summarize numerous studies that indicate that a variety of antioxidant (inhibition of free radical production, scavenging of free radicals and increasing free radical degradation) and anti-inflammatory strategies decrease cerebral infarction. Finally, we compare the success of some of these strategies in clinical trials compared to the animal models.
    Article · Jul 2007
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