Amplification of blood–brain barrier GLUT1 glucose transporter gene expression by brain-derived peptides

Abstract

Glucose is a critical nutrient for the brain, and the transport of this hexose from blood to brain is mediated by the blood-brain barrier (BBB) GLUT1 glucose transporter. The expression of the BBB-GLUT1 gene is compromised in different pathological conditions and it is modulated by brain trophic factors. The brain-derived peptide preparation Cerebrolysin (Cl, EBEWE, Austria) increases the expression of the BBB-GLUT1 via mRNA stabilization. In order to gain more insights into the mechanism of BBB-GLUT1 gene regulation, the present investigation studied the effect of Cl on the expression of both the GLUT1 protein and GLUT1 reporter genes in brain endothelial cultured cells (ECL). Cl markedly increased the expression of reporter genes containing GLUT1 translational control elements and cis-acting elements involved in the stabilization of the GLUT1 mRNA transcript in a dose dependent manner. Cl produced only marginal effects on the reporter gene control lacking the GLUT1 regulatory elements. In parallel experiments, Cl markedly increased the uptake of 3H-2-deoxy-D-glucose and the levels of the GLUT1 protein measured by ELISA. Data presented here demonstrate: (i) that Cl increases the expression of BBB-GLUT1 reporter genes containing regulatory cis-elements involved in the stabilization and translation of the GLUT1 transcript; (ii) that the effect on both regulatory elements cooperates to increase gene expression; and (iii) that the increased levels of the BBB-GLUT1 reporter genes in Cl-treated ECL cells are associated with an increase in the glucose uptake and in the expression of the GLUT1 protein.