Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Radiat Oncol. 2010 Feb 1;5:6. doi: 10.1186/1748-717X-5-6.
Sublethal doses of whole brain irradiation (WBI) are commonly administered therapeutically and frequently result in late delayed radiation injuries, manifesting as severe and irreversible cognitive impairment. Neural progenitors within the subgranular zone (SGZ) of the dentate gyrus are among the most radiosensitive cell types in the adult brain and are known to participate in hippocampal plasticity and normal cognitive function. These progenitors and the specialized SZG microenvironment required for neuronal differentiation are the source of neurogenic potential in the adult dentate gyrus, and provide a continuous supply of immature neurons which may then migrate into the adjacent granule cell layer to become mature granule cell neurons. The extreme radiosensitivity of these progenitors and the SGZ microenvironment suggests the hippocampus as a prime target for radiation-induced cognitive impairment. The brain renin-angiotensin system (RAS) has previously been implicated as a potent modulator of neurogenesis within the SGZ and selective RAS inhibitors have been implicated as mitigators of radiation brain injury. Here we investigate the angiotensin converting enzyme (ACE) inhibitor, ramipril, as a mitigator of radiation injury in this context.
Adult male Fisher 344 rats received WBI at doses of 10 Gy and 15 Gy. Ramipril was administered beginning 24 hours post-WBI and maintained continuously for 12 weeks.
Ramipril produced small but significant reductions in the deleterious effects of radiation on progenitor proliferation and neuronal differentiation in the rat dentate gyrus following 10 Gy-WBI, but was not effective following 15 Gy-WBI. Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats.
Our results indicate that chronic ACE inhibition with ramipril, initiated 24 hours post-irradiation, may reduce apoptosis among SGZ progenitors and/or inflammatory disruption of neurogenic signaling within SGZ microenvironment, and suggest that angiotensin II may participate in maintaining the basal rate of granule cell neurogenesis.
全脑照射（WBI）的亚致死剂量通常用于治疗，并经常导致晚期迟发性放射性损伤，表现为严重和不可逆的认知障碍。齿状回颗粒下区（SGZ）中的神经前体细胞是成年大脑中最敏感的细胞类型之一，已知参与海马可塑性和正常认知功能。这些祖细胞和神经元分化所需的特殊 SGZ 微环境是成年齿状回神经发生潜能的来源，并提供了不断供应的未成熟神经元，这些神经元随后可能迁移到相邻的颗粒细胞层成为成熟的颗粒细胞神经元。这些祖细胞和 SGZ 微环境的极端放射敏感性表明海马体是辐射引起认知障碍的主要靶标。脑肾素-血管紧张素系统（RAS）先前被认为是 SGZ 中神经发生的有力调节剂，选择性 RAS 抑制剂被认为是减轻辐射脑损伤的调节剂。在这里，我们研究了血管紧张素转换酶（ACE）抑制剂雷米普利在这种情况下作为辐射损伤的减轻剂。
成年雄性 Fisher 344 大鼠接受 10 Gy 和 15 Gy 的 WBI。雷米普利在 WBI 后 24 小时开始给药，并持续 12 周。
雷米普利在大鼠齿状回中，10 Gy-WBI 后，对辐射对祖细胞增殖和神经元分化的有害影响产生了微小但显著的降低，但在 15 Gy-WBI 后无效。雷米普利还降低了未照射对照大鼠 SGZ 中内源性神经发生的基础率。
我们的结果表明，雷米普利的慢性 ACE 抑制作用，在照射后 24 小时开始，可能会减少 SGZ 祖细胞中的细胞凋亡和/或 SGZ 微环境中神经发生信号的炎症破坏，并表明血管紧张素 II 可能参与维持颗粒细胞神经发生的基础率。
