title: Hyperglycemia-induced oxidative stress induces apoptosis by inhibiting PI3-kinase/Akt and ERK1/2 MAPK mediated signaling pathway causing downregulation of 8-oxoG-DNA glycosylase levels in glial cells.
abstract: Glial cells are very important for normal brain function and alterations in their activity due to hyperglycemia, could contribute to diabetes-related cognitive dysfunction. Oxidative insults often cause rapid changes in almost all cells including glial cells. However, pathophysiologic mechanisms that lead to diabetic complications are not completely elucidated. Therefore, we examined whether elevated glucose levels directly or indirectly disrupt antioxidant defense mechanisms causing alterations in signaling pathways, cell cycle dysregulation, and reactive oxygen/nitrogen species-mediated apoptosis in glial cells. Findings of this study demonstrated that exposure of glial cells to high glucose markedly induces cellular and molecular injuries, as evidenced by elevated levels of reactive oxygen/nitrogen species, biomolecules damage, cell cycle dysregulation, decrease in antioxidant enzymes, and decrease in cell viability. Pretreatment of cells with N-acetyl-L-cysteine reduced high glucose-induced cytotoxicity by increasing the levels of antioxidant enzymes, and decreasing the number of apoptotic cells. Further, at molecular level high glucose treatment resulted in a significant increase in phosphorylation of Akt, MAPKs, tuberin, down regulation of 8-oxoG-DNA glycosylase and increase in 8-hydroxydeoxyguanosine accumulations. Pretreatment of cells with N-acetyl-L-cysteine, phosphatidylinositol3-kinase/Akt and ERK1/2 inhibitors completely abolished the apoptotic effects of high glucose. Moreover, N-acetyl-L-cysteine significantly inhibited reactive oxygen/nitrogen species generation, elevated antioxidants levels, inhibited Akt, ERK1/2, tuberin phosphorylation, decreased 8-hydroxydeoxyguanosine accumulation and upregulated 8-oxoG-DNA glycosylase expression. Our results demonstrate that high glucose induces apoptosis and inhibits proliferation of glial cells, which may be mediated by the phosphorylation of tuberin, down regulation of 8-oxoG-DNA glycosylase and 8-hydroxydeoxyguanosine accumulation via activation of Akt and ERK1/2MAPK pathways.
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors.forename: Premranjan
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Ophthalmology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar 751024, India.
authors.forename: G Nageswar
authors.initials: GN
authors.lastname: Rao
authors.affiliation: Regional Medical Research Centre, Nandankanan Road, ECO Railway Complex, Chandrasekharpur, Bhubaneswar 751023, India.
authors.forename: Bibhuti Bhusan
authors.initials: BB
authors.lastname: Pal
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India. Electronic address: arttatrana@yahoo.com.
authors.forename: Arttatrana
authors.initials: A
authors.lastname: Pal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D003545:Cysteine / Q000378:metabolism; D045647:DNA Glycosylases / Q000096:biosynthesis*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005947:Glucose / Q000008:administration & dosage; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; D005947:Glucose; D003545:Cysteine
keywords: Glial cells; Hyperglycemia; N-acetyl cysteine; Oxidative-nitrosative stress; Signaling pathways