title: Hyperglycemia-Induced Oxidative-Nitrosative Stress Induces Inflammation and Neurodegeneration via Augmented Tuberous Sclerosis Complex-2 (TSC-2) Activation in Neuronal Cells.
abstract: Diabetes is a systemic disease mainly characterized by chronic hyperglycemia and with extensive and long-lasting spiteful complications in central nervous systems (CNS). Astrocytes play an important role in the defense mechanism of CNS, with great ability of withstanding accumulation of toxic substances. Apart from functional disorders, hyperglycemia leads to slow progressive structural abnormalities in the CNS through oxidative stress pathways. However, the molecular mechanism by which neurons die under oxidative stress induced by high glucose (HG) remains largely unclear. Here, we report that HG-induced inflammation and neurodegeneration in brain tissues, brain astrocytes (C6), and pheochromocytoma (PC-12) cells are cultured in HG conditions. Our results show that the increases in phosphorylation of Akt and ERK1/2MAPK are associated with increased accumulations of reactive oxygen species (ROS) in neuronal cells, which simultaneously enhanced phosphorylations of tuberous sclerosis complex-2 (TSC-2) and mammalian target of rapamycin (mTOR) in the diabetic brain and in HG-exposed neuronal cells. Pharmacologic inhibition of Akt or ERK1/2 or siRNA-mediated gene silencing of TSC-2 suppressed the strong downregulation of TSC-2-mTOR activation. Findings of this study also demonstrate that HG resulted in phosphorylation of NF-κB, coinciding with the increased production of inflammatory mediators and activation of neurodegenerative markers. Pretreatment of cells with antioxidants, phosphoinositide3-kinase (PI3-K)/Akt, and ERK1/2 inhibitors significantly reduced HG-induced TSC-2 phosphorylation and restored NF-κB protein expression leading to decreased production of inflammatory mediators and neurodegenerative markers. These results illustrate that ROS functions as a key signaling component in the regulatory pathway induced by elevated glucose in neuronal cell activation leading to inflammation and neurodegeneration.
authors.affiliation: Neurobiology Biology Laboratory, School of Biotechnology, KIIT University, Bhubaneswar, 751024, India.
authors.forename: Premranjan
authors.initials: P
authors.lastname: Kumar
authors.affiliation: School of Chemical and Biotechnology, SASTRA University, Thanjavur, India.
authors.forename: Thiagarajan
authors.initials: T
authors.lastname: Raman
authors.affiliation: Neurobiology Biology Laboratory, School of Biotechnology, KIIT University, Bhubaneswar, 751024, India.
authors.forename: Mitali Madhusmita
authors.initials: MM
authors.lastname: Swain
authors.affiliation: Division of Oncology, National Jewish Health, Denver, CO, USA.
authors.forename: Rangnath
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Neurobiology Biology Laboratory, School of Biotechnology, KIIT University, Bhubaneswar, 751024, India. arttatrana@yahoo.com.
authors.forename: Arttatrana
authors.initials: A
authors.lastname: Pal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015538:Nitrosation / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
keywords: Apoptosis; Inflammation; Neurodegeneration; Neuronal cells; Oxidative stress; Tuberous sclerosis complex-2