title: Neuronal protection from glucose deprivation via modulation of glucose transport and inhibition of apoptosis: a role for the insulin-like growth factor system.
abstract: Glucose is the brain's major energy source; therefore, loss of neuronal cells is a potential consequence of hypoglycaemia. Since apoptosis is a major mechanism of neuronal loss following a range of insults, we explored potent anti-apoptotic systems (IGF-I and bcl-2) as means of enhancing neuronal survival in the face of glucose deprivation. Human neuroblastoma cells (SH-SY5Y, SHEP and SHEP-bcl-2) were exposed to low glucose as a model of glucopenia-induced neuronal damage. Administration of IGF-I and/or over-expression of the survival gene bcl-2 were exploited to attempt to limit neuronal loss. Neuronal survival mechanisms and interactions between these systems were investigated. Low glucose (0.25-2.5 mM) adversely affected cell growth and survival; however, IGF-I ameliorated these outcomes. Over-expression of bcl-2 blunted low glucose-induced apoptosis and up-regulated IGF-I receptor, with the effect of IGF-I addition being negligible on apoptosis, while significantly enhancing mitochondrial activity. In SH-SY5Y cells, IGF-I significantly changed >two-fold mRNA levels of the apoptosis-related genes gadd45, fas, iNOS, NFkB, TRAIL, without further affecting bcl-2 expression. In low glucose, IGF-I acutely enhanced glucose transport and translocation of GLUT1 protein to the cell membrane. GLUT1 mRNA expression was up-regulated by both IGF-I and bcl-2. The potent anti-apoptotic systems IGF-I and bcl-2 are both thus able to enhance cell survival in a glucose-deprived human neuronal model. Although we clearly show evidence of positive cross-talk via bcl-2 modulation of IGF-I receptor, IGF-I also has enhancing effects on mitochondrial function outside the bcl-2 pathway. The common effect of both systems on enhancement of GLUT-1 expression suggests that this is a key mechanism for enhanced survival. These studies also point to the potential use of IGF-I therapy in prevention or amelioration of hypoglycaemic brain injury.
authors.affiliation: Centre for Hormone Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville 3052, Victoria, Australia. vince.russo@mcri.edu.au
authors.forename: V C
authors.initials: VC
authors.lastname: Russo
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Najdovska
authors.forename: N L
authors.initials: NL
authors.lastname: Baker
authors.forename: G A
authors.initials: GA
authors.lastname: Werther
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000235:genetics; D001692:Biological Transport; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008928:Mitochondria / Q000187:drug effects; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014178:Translocation, Genetic / Q000187:drug effects
chemical_list: D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; D007456:Iodine Isotopes; D009004:Monosaccharide Transport Proteins; D011518:Proto-Oncogene Proteins; C495677:SLC2A1 protein, human; D007334:Insulin-Like Growth Factor I; D005947:Glucose