Department of Neurosurgery, Henry Ford Health System, Detroit, MI 48202, USA.
J Neurooncol. 2011 Feb;101(3):449-56. doi: 10.1007/s11060-010-0282-x. Epub 2010 Jul 9.
Whole brain irradiation (WBI) is commonly administered therapeutically and is routinely associated with 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 SGZ 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 implicate them as potentially significant contributors to radiation-induced cognitive impairment. Previous reports suggest that statin drugs may be neuroprotective and may promote neurogenesis within the SGZ following both traumatic and ischemic brain injury. Here we investigate whether atorvastatin might similarly protect progenitors and/or preserve neurogenic potential within the SGZ when administered following radiation injury. We also investigate whether such mitigating effects might be enhanced by administering atorvastatin in combination with the angiotensin converting enzyme (ACE) inhibitor, ramipril, which has previously been shown to produce subtle mitigating effects in this context. Atorvastatin was administered to adult male Fisher 344 rats beginning 24 h post-WBI at doses of 10 and 15 Gy, and maintained daily until sacrifice at 12 weeks post-WBI. Combined atorvastatin and ramipril (atorvastatin + ramipril) were administered according to the same protocol following WBI doses of 10 Gy. Progenitor proliferation, neuronal differentiation, and microglial activation were assayed immunohistochemically. Our results indicate that chronic administration of atorvastatin is relatively ineffective as a mitigator of radiation injury in this context, whereas atorvastatin + ramipril appear to interact synergistically to potently and selectively mitigate radiation-induced disruption of neurogenic signaling within SGZ microenvironment.
全脑照射（WBI）通常作为治疗方法应用，并且通常与迟发性放射性损伤相关，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人脑中对辐射最敏感的细胞类型之一，已知它们参与海马可塑性和正常认知功能。这些前体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力的来源，并提供持续供应的未成熟神经元，然后迁移到相邻的颗粒细胞层成为成熟的颗粒细胞神经元。这些前体细胞和 SGZ 微环境的极端辐射敏感性暗示它们可能是辐射诱导认知障碍的重要贡献者。先前的报告表明，他汀类药物可能具有神经保护作用，并可能促进创伤性和缺血性脑损伤后 SGZ 中的神经发生。在这里，我们研究了阿托伐他汀在辐射损伤后给予是否可以类似地保护 SGZ 中的前体细胞和/或保留神经发生潜力。我们还研究了在这种情况下，联合给予阿托伐他汀和血管紧张素转换酶（ACE）抑制剂雷米普利是否可以增强这种缓解作用，雷米普利先前在这种情况下显示出轻微的缓解作用。阿托伐他汀在 WBI 后 24 小时开始以 10 和 15 Gy 的剂量给予成年雄性 Fisher 344 大鼠，并持续给予直至 WBI 后 12 周处死。根据相同的方案，在给予 10 Gy WBI 剂量后给予联合阿托伐他汀和雷米普利（阿托伐他汀+雷米普利）。通过免疫组织化学检测祖细胞增殖、神经元分化和小胶质细胞激活。我们的结果表明，在这种情况下，阿托伐他汀的慢性给药作为辐射损伤的缓解剂相对无效，而阿托伐他汀+雷米普利似乎协同作用，强烈且选择性地减轻 SGZ 微环境中辐射诱导的神经发生信号的破坏。
