Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
Glia. 2024 Mar;72(3):568-587. doi: 10.1002/glia.24491. Epub 2023 Nov 27.
Radiation-induced damage to the blood-brain barrier (BBB) is the recognized pathological basis of radiation-induced brain injury (RBI), a side effect of head and neck cancer treatments. There is currently a lack of therapeutic approaches for RBI due to the ambiguity of its underlying mechanisms. Therefore, it is essential to identify these mechanisms in order to prevent RBI or provide early interventions. One crucial factor contributing to BBB disruption is the radiation-induced activation of astrocytes and oversecretion of vascular endothelial growth factor (VEGF). Mechanistically, the PI3K-AKT pathway can inhibit cellular autophagy, leading to pathological cell aggregation. Moreover, it acts as an upstream pathway of VEGF. In this study, we observed the upregulation of the PI3K-AKT pathway in irradiated cultured astrocytes through bioinformatics analysis, we then validated these findings in animal brains and in vitro astrocytes following radiation exposure. Additionally, we also found the inhibition of autophagy and the oversecretion of VEGF in irradiated astrocytes. By inhibiting the PI3K-AKT pathway or promoting cellular autophagy, we observed a significant amelioration of the inhibitory effect on autophagy, leading to reductions in VEGF oversecretion and BBB disruption. In conclusion, our study suggests that radiation can inhibit autophagy and promote VEGF oversecretion by upregulating the PI3K-AKT pathway in astrocytes. Blocking the PI3K pathway can alleviate both of these effects, thereby mitigating damage to the BBB in patients undergoing radiation treatment.
辐射诱导的血脑屏障（BBB）损伤是头颈部癌症治疗相关放射性脑损伤（RBI）的公认病理基础。由于其潜在机制不明确，目前 RBI 缺乏治疗方法。因此，识别这些机制对于预防 RBI 或提供早期干预至关重要。导致 BBB 破坏的一个关键因素是辐射诱导的星形胶质细胞激活和血管内皮生长因子（VEGF）过度分泌。从机制上讲，PI3K-AKT 通路可以抑制细胞自噬，导致病理性细胞聚集。此外，它还是 VEGF 的上游通路。在这项研究中，我们通过生物信息学分析观察到辐照培养的星形胶质细胞中 PI3K-AKT 通路的上调，然后在动物大脑和辐照后的体外星形胶质细胞中验证了这些发现。此外，我们还发现辐照星形胶质细胞中自噬被抑制和 VEGF 过度分泌。通过抑制 PI3K-AKT 通路或促进细胞自噬，我们观察到对自噬的抑制作用显著改善，导致 VEGF 过度分泌和 BBB 破坏减少。总之，我们的研究表明，辐射可以通过上调星形胶质细胞中的 PI3K-AKT 通路来抑制自噬并促进 VEGF 过度分泌。阻断 PI3K 通路可以缓解这两种作用，从而减轻接受放射治疗的患者 BBB 的损伤。
