Spreading depression-induced gene expression is regulated by plasma glucose

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-delta (PKC delta), and heme oxygenase-l (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 PKC delta (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-fas by 42%. When hypoglycemia was induced 30 minutes before SD, c-fos induction was enhanced by 145%, but the induction of HO-1 and PKC delta 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 PKC delta and HO-I 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.