Cognitive dysfunction develops in approximately 50% of patients who receive fractionated wholebrain 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.

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Blockers of the renin-angiotensin-aldosterone system (RAAS) ameliorate cognitive deficits and some aspects of brain injury after whole-brain irradiation. We investigated whether treatment with the angiotensin II type 1 receptor antagonist L-158,809 at a dose that protects cognitive function after fractionated whole-brain irradiation reduced radiation-induced neuroinflammation and changes in hippocampal neurogenesis, well-characterized effects that are associated with radiation-induced brain injury. Male F344 rats received L-158,809 before, during and after a single 10-Gy dose of radiation. Expression of cytokines, angiotensin II receptors and angiotensin-converting enzyme 2 was evaluated by real-time PCR 24 h, 1 week and 12 weeks after irradiation. At the latter times, microglial density and proliferating and activated microglia were analyzed in the dentate gyrus of the hippocampus. Cell proliferation and neurogenesis were also quantified in the dentate subgranular zone. L-158,809 treatment modestly increased mRNA expression for Ang II receptors and TNF-α but had no effect on radiation-induced effects on hippocampal microglia or neurogenesis. Thus, although L-158,809 ameliorates cognitive deficits after whole-brain irradiation, the drug did not mitigate the neuroinflammatory microglial response or rescue neurogenesis. Additional studies are required to elucidate other mechanisms of normal tissue injury that may be modulated by RAAS blockers.

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