Spreading Depression–Induced Gene Expression Is Regulated by Plasma Glucose

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Abstract
Background and Purpose —Plasma glucose and spreading depression (SD) are both determinants of brain ischemia. The purpose of this study was to examine whether plasma glucose affects SD-induced gene expression in the cortex. Methods —SD was induced by topical application of KCl. Hyperglycemia and hypoglycemia were induced by intraperitoneal injection of glucose and insulin, respectively. The expression of c- fos , cyclooxygenase-2 (COX-2), protein kinase C-δ (PKCδ), and heme oxygenase-1 (HO-1) was determined by in situ hybridization. Results —SD alone induced expression of c- fos (by 340%), COX-2 (210%), HO-1 (470%), and PKCδ (410%). Hypoglycemia (2.4±0.9 mmol/L) alone did not induce gene expression, and hyperglycemia (22.1±3.7 mmol/L) alone induced only c- fos by 42%. When hypoglycemia was induced 30 minutes before SD, c- fos induction was enhanced by 145%, but the induction of HO-1 and PKCδ was reduced to 43% and 64%, respectively. When hyperglycemia was induced 30 minutes before SD, c- fos induction was enhanced by 388% and COX-2 expression by 53%, whereas the induction of PKCδ and HO-1 was reduced to 54% and 51%, respectively. The frequency, amplitude, and duration of direct current potentials were unaltered in hyperglycemic SD animals, whereas in hypoglycemic animals the duration was increased by 47%. Conclusions —While SD induces expression of several genes, the availability of glucose regulates the extent of the gene induction. The effect of glucose is different on early-response genes (c- fos and COX-2) compared with late-response genes. Plasma glucose may contribute to neuronal damage partially by regulating gene expression.