Renin-angiotensin System Blockers and Modulation of Radiation-Induced Brain Injury

Radiation-induced brain injury remains a major cause of morbidity in cancer patients with primary or metastatic brain tumors. Approximately 200,000 individuals/year are treated with fractionated partial or whole-brain irradiation, and > half will survive long enough (≤6 months) to develop radiation-induced brain injury, including cognitive impairment. Although short-term treatments have shown efficacy, no long-term treatments or preventive approaches are presently available for modulating radiation-induced brain injury. Based on previous preclinical studies clearly demonstrating that renin-angiotensin system (RAS) blockers can modulate radiation-induced late effects in the kidney and lung, we and others hypothesized that RAS blockade would similarly modulate radiation-induced brain injury. Indeed, studies in the last 5 years have shown that both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor antagonists (AT1RAs) can prevent/ameliorate radiation-induced brain injury, including cognitive impairment, in the rat. The mechanistic basis for this RAS blocker-mediated effect remains the subject of ongoing investigations. Putative mechanisms include, i] blockade of Ang II/NADPH oxidase-mediated oxidative stress and neuroinflammation, and ii] a change in the balance of angiotensin (Ang) peptides from the pro-inflammatory and pro-oxidative Ang II to the anti-inflammatory and anti-oxidative Ang-(1-7). However, given that both ACEIs and AT1RAs are: 1] well-tolerated drugs routinely prescribed for hypertension, 2] exhibit some antitumor properties, and 3] can prevent/ameliorate radiationinduced brain injury, they appear to be ideal drugs for future clinical trials, offering the promise of improving the quality of life of brain tumor patients receiving brain irradiation.