Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1010, USA.
Radiat Res. 2010 Jan;173(1):49-61. doi: 10.1667/RR1821.1.
Cognitive dysfunction develops in approximately 50% of patients who receive fractionated whole-brain irradiation and survive 6 months or more. The mechanisms underlying these deficits are unknown. A recent study demonstrated that treatment with the angiotensin II type 1 receptor antagonist (AT(1)RA) L-158,809 before, during and after fractionated whole-brain irradiation prevents or ameliorates radiation-induced cognitive deficits in adult rats. Given that (1) AT(1)RAs may function as anti-inflammatory drugs, (2) inflammation is thought to contribute to radiation injury, and (3) radiation-induced inflammation alters progenitor cell populations, we tested whether the cognitive benefits of L-158,809 treatment were associated with amelioration of the sustained neuroinflammation and changes in neurogenesis that are induced by fractionated whole-brain irradiation. In rats examined 28 and 54 weeks after irradiation, L-158,809 treatment did not alter the effects of radiation on the number and activation of microglia in the perirhinal cortex and hippocampus, nor did it prevent the radiation-induced decrease in proliferating cells and immature neurons in the hippocampus. These findings suggest that L-158,809 does not prevent or ameliorate radiation-induced cognitive deficits by modulation of chronic inflammatory mechanisms, but rather may reduce radiation-induced changes that occur earlier in the postirradiation period and that lead to cognitive dysfunction.
认知功能障碍在接受分割全脑照射并存活 6 个月或更长时间的约 50%的患者中发展。这些缺陷的机制尚不清楚。最近的一项研究表明，在分割全脑照射之前、期间和之后用血管紧张素 II 型 1 型受体拮抗剂（AT(1)RA）L-158,809 治疗可预防或改善成年大鼠的辐射引起的认知缺陷。鉴于 (1) AT(1)RAs 可能作为抗炎药物发挥作用，(2) 炎症被认为有助于辐射损伤，以及 (3) 辐射诱导的炎症改变祖细胞群体，我们测试了 L-158,809 治疗的认知益处是否与改善分割全脑照射引起的持续神经炎症和神经发生变化有关。在照射后 28 和 54 周检查的大鼠中，L-158,809 治疗并未改变辐射对边缘皮层和海马中小胶质细胞数量和激活的影响，也未预防辐射引起的海马中增殖细胞和未成熟神经元减少。这些发现表明，L-158,809 并未通过调节慢性炎症机制来预防或改善辐射引起的认知缺陷，而是可能减轻照射后早期发生的辐射诱导变化，从而导致认知功能障碍。
