Primary and metastatic brain cancers are commonly treated with partial or whole-brain irradiation (WBI). Twenty to fifty percent of patients that receive WBI develop progressive cognitive dysfunction caused by injury to irradiated normal brain tissue. The cellular and molecular mechanisms underlying radiation-induced normal brain tissue injury have not been fully elucidated. Neuroinflammation, in the form of microglial activation, and decreased hippocampal neurogenesis frequently occur in animal models before and concurrent with radiation related cognitive deficits. Pharmacological interventions that reduce neuroinflammation and/or promote neurogenesis may ameliorate WBI-induced cognitive deficits. Blockade of the renin-angiotensin system (RAS) is an attractive target since: (1) RAS blockade ameliorates radiation-induced injury to normal lung, kidney, and optic nerve tissue, (2) angiotensin II (Ang II) can act as a pro-inflammatory cytokine via its Ang II type 1 receptor (AT₁R), (3) the brain has its own intrinsic RAS, and (4) AT₁R blockade, by oral administration of the AT₁R antagonist L-158,809, ameliorated impairment in the novel object recognition task after fractionated WBI.

The work in this dissertation tested the hypothesis that blocking the intrinsic brain RAS with L-158,809 before, during, and after WBI would prevent radiation-induced neurobiological changes. The first study investigated whether L-158,809 treatment altered WBI-induced changes in hippocampal neuroinflammation and neurogenesis following a single dose of 10 Gy WBI. We found that L-158,809 treatment increased Ang II type 2 receptor expression in irradiated rats but had minimal, if any, effect on other analyzed markers of neuroinflammation and neurogenesis. Previous studies indicate that tissue responses to a single dose of radiation differ from responses to a fractionated dose; therefore, the second study evaluated whether L-158,809 treatment mediates its cognitive benefits via modulation of microglial population dynamics and/or the promotion of hippocampal proliferation and neurogenesis following a 40 Gy fractionated WBI dose. Our findings suggest the cognitive benefits of L-158,809 treatment before, during, and after fractionated WBI are not mediated through changes in the investigated indicators of cellular dynamics. Although cell population sizes in irradiated rats were not greatly altered by L-158,809 treatment, microglial function and the contribution of immature neurons to cognition may differ between these conditions.