Inhibition of Nox-1 Activity Attenuates Diabetic Ketoacidosis-Induced Blood Brain Barrier Permeability and Edema Formation

Diabetic ketoacidosis (DKA) is a condition characterized by hyperglycemia and high ketone bodies production conducting to acidosis. DKA is highly prevalent in pediatric patients. Approximately 0.5%-1% of these children develop cerebral edema, with a mortality rate of 20-90%. Our research examined the effects of DKA in Blood Brain Barrier (BBB) permeability using Ins2^Akita mice as a T1D model. Using magnetic resonance (MR)-based detection of the contrast agent gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA) we observed BBB permeability and fluid accumulation in the brain, during DKA episodes from day 1 to 5. Our data indicated that increased BBB permeability was present in the thalamus, partial cortex and basal forebrai. Furthermore, the analysis of the morphological and functional changes of BBB under DKA conditions both in vitro and in vivo in vitro showed alterations in TJ proteins, manifested as a slight alteration in ZO-1 and Claudin-5 expression which could represent the ground for BBB leakage. We have further identified that DKA promotes the high production of ROS due to Nox-1 activation, leading to actin reorganization, the subsequent TJ disorganization and increased BBB permeability. The inhibition of Nox-1 activity via Nox-1 inhibitor ML-17 improved the BBB integrity and reduced leakage. Collectively, these studies will provide new information related to novel therapeutic strategies to prevent or reverse vascular hyperpermeability in DKA.