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.

PURPOSE: 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.

METHODS AND MATERIALS: 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.

RESULTS

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.

CONCLUSIONS

These findings demonstrate PARP's role in vascular degeneration and suggest a potential therapeutic approach to address radiation-induced BBB leakage with neuroprotective benefits.