Noradrenergic Agonists as Treatment Opportunity of Radiation-Induced Cognitive Decline

Purpose: Pediatric patients undergoing cranial irradiation are at risk of developing neurocognitive impairments, with radiation-induced damage to the hippocampi playing a central role in this process. This damage is primarily driven by loss of neural stem/progenitor cells (NSCs/NPCs) and neuroinflammation. Noradrenergic agonists can potentially protect against radiation-induced hippocampal damage by reducing cell death and neuroinflammation. This study aims to assess whether pharmacologic boosting of noradrenaline (NA) can reduce radiation-induced hippocampal injury and prevent memory decline. Materials and Methods: Mice were exposed to cranial irradiation of 10 Gy at postnatal day 22, and treated with noradrenergic agonists, reboxetine (REB), or atipamezole (ATI). At 6 hours, 1 week, and 1 month postirradiation, hippocampal cell death, phosphorylated cAMP responsive element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) expression, loss of hippocampal NSCs/NPCs, and microglial inflammation were histologically investigated. At 1 month postirradiation, memory deficits and hippocampal atrophy were investigated by a behavioral test battery and ex vivo magnetic resonance imaging, respectively. Results: We report that REB and ATI significantly mitigate radiation-induced hippocampal toxicity. Treatment with noradrenergic agonists reduces radiation-induced apoptosis, microglial inflammation, and preserves pCREB and BDNF expression in the hippocampus early after irradiation. It also attenuates the loss of hippocampal NSCs/NPCs and immature neurons. After radiation therapy, considerable hippocampal volume loss is observed, which is prevented by REB treatment. Finally, behavioral testing revealed that REB treatment after radiation therapy successfully mitigates radiation-induced memory dysfunction. Conclusions: The present findings uncover the marked benefits of NA treatment against radiation-induced hippocampal injury. We demonstrate that REB is able to mitigate radiation-induced memory dysfunction, which highlights the potential of NA treatment for addressing long-standing complications faced by pediatric brain tumor survivors.