Decreased GABA receptor binding in the cerebral cortex of insulin induced hypoglycemic and streptozotocin induced diabetic rats.
ABSTRACT Hypoglycemia is the major problem to blood glucose homeostasis in treatment of diabetes and is associated with severe irreversible consequences including seizures, coma and death. GABAergic inhibitory function in the cerebral cortex plays an important role in controlling the excitability and responsiveness of cortical neurons. Present study analysed effects of insulin induced hypoglycemia and streptozotocin induced diabetes on the cortical GABA receptor binding, GABA(Aά1), GABA(B) receptor subtype expression, GAD and GLUT3 expression. Diabetic rats showed decreased [(3)H] GABA binding in the cerebral cortex compared to control while hypoglycemia exacerbated the decrease. GABA receptor subunits; GABA(Aά1), GABA(B) and GAD expression significantly decreased in diabetic rats whereas hypoglycemia significanly decreased the expression compared to diabetic. GLUT3 expression significantly up regulated during both hypo and hyperglycemia. Our results showed that hypoglycemia and hyperglycemia decreased GABAergic neuroprotective function in the cerebral cortex, which account for the increased vulnerability of cerebral cortex to subsequent neuronal damage during hypo/hyperglycemia.
- SourceAvailable from: Vera Michailovna BondarevaNeurodegenerative Diseases - Processes, Prevention, Protection and Monitoring, 12/2011; , ISBN: 978-953-307-485-6
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ABSTRACT: GAD65 (Glutamic acid decarboxylase 65 KDa isoform) is one of the most important auto-antigens involved in Type 1 diabetes induction. Although it serves as one of the first injury markers of β-islets, the mechanisms governing GAD65 expression remain poorly understood. Since the regulation of GAD65 is crucial for the proper functioning of insulin secreting cells, we investigated the stress induced regulation of GAD65 transcription. The present study shows that SMAR1 regulates GAD65 expression at the transcription level. Using a novel protein-DNA pull-down assay, we show that SMAR1 binding is very specific to GAD65 promoter but not to the other isoform, GAD67. We show that Streptozotocin (STZ) mediated DNA damage leads to upregulation of SMAR1 and p53 expression, resulting in elevated levels of GAD65, in both cell lines as well as mouse β-islets. SMAR1 and p53 act synergistically to up-regulate GAD65 expression upon STZ treatment. We propose a novel mechanism of GAD65 regulation by synergistic activities of SMAR1 and p53.BMC Molecular Biology 09/2012; 13:28. DOI:10.1186/1471-2199-13-28 · 2.06 Impact Factor
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ABSTRACT: Two patients presented with severe hypoglycemia and parasagittal homotopic cerebral hemisphere injury. Days after the initial insult, bilateral, independent, periodic lateralized epileptiform discharges and frequent seizures emerged from the affected homotopic cerebral cortices in both patients. We speculate that synaptic rescaling and increased spontaneous discharges in isolated cerebral cortex may cause epileptogenesis in severe hypoglycemia. Bilateral but temporally independent parasagittal seizures could be a feature of severe hypoglycemia.Epilepsy & Behavior 10/2012; 25(2):263-5. DOI:10.1016/j.yebeh.2012.07.022 · 2.06 Impact Factor