Sustained Neuronal DNA Damage and Poly(ADP-ribose) Polymerase Activation Lead to Vascular Endothelial Growth Factor A-mediated Blood-brain Barrier Disruption in Radiation-induced Brain Injury.

Abstract

Cranial radiation therapy is commonly used for the treatment of patients with head and neck tumors, yet a considerable number of patients encounter long-lasting medical complications, including compromised blood-brain barrier (BBB) function and cognitive impairment. The mechanisms underlying BBB leakage after radiation exposure and potential preventive strategies remain elusive. Brain tissue and primary cultured neurons were collected and the expression level of targeted molecule were identified by immunofluorescence staining, immunohistochemistry, western blot, quantitative real-time polymerase chain reaction and RNA scope. Cognition was assessed by the Novel object recognition test and Y maze test. Blood structure was monitored by two-photon in vivo imaging. In this study, we reported persistent accumulation of unrepaired DNA damage and poly(ADP)-ribose polymerase (PARP) hyperactivation in neurons of both patients with radiation-induced brain injury and a mouse model. Importantly, PARP inhibition prevented radiation-induced nicotinamide adenine dinucleotide depletion, DNA damage, and neuronal degeneration. Furthermore, PARP inhibition ameliorated radiation-induced BBB leakage, perivascular astrogliosis, and cognitive impairment, accompanied by a significant decrease in vascular endothelial growth factor A expression in the cortex. These findings demonstrate PARP's role in vascular degeneration and suggest a potential therapeutic approach to address radiation-induced BBB leakage with neuroprotective benefits.