Combined atorvastatin and ramipril mitigate radiation-induced impairment of dentate gyrus neurogenesis

Abstract

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.