Renin-angiotensin system blockers and modulation of radiation-induced brain injury

Abstract

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 (AT(1)RAs) 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 AT(1)RAs are 1] well-tolerated drugs routinely prescribed for hypertension, 2] exhibit some antitumor properties, and 3] can prevent/ameliorate radiation-induced 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.

Fig 1

Summary of various pathways and sources hypothesized to exist for the generation of Ang peptides. From left to right - An intracellular, renin-dependent pathway is well documented in paraventricular nucleus, nucleus of the solitary tract and rostroventrolateral medulla, that may mediate formation of both angiotensin (Ang) II and Ang-(1–7) involved in stress responses and regulation of arterial pressure. Ang-(1–12) is thought to be extracellular, contributing to hypertension and impairment of Baroreflex function in (mRen2)27 rats, but may not play a role in normal animals. Angiotensinogen of glial origin is the predominant source of the precursor protein in brain (~90%), but whether angiotensin peptide processing represents an intracellular or extracellular event is not known. ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; NEP, neprilysin; AT₁, Ang II type 1 receptor; Mas, Ang-(1–7) receptor.

Fig 2

Proposed signaling pathways involved in the opposing actions of Ang II versus Ang-(1–7). Generation of Ang II by converting enzyme (ACE) from Ang I dervided from either renin-dependent or independent [Ang-(1–12)] pathways. Ang II acts on AT₁ receptors to activate kinase pathways associated with increases in reactive oxygen species (ROS) and inflammation. ACE2 can cleave Ang II to form Ang-(1–7). Either mas activation via Ang-(1–7) or AT₂ activation via Ang II have been linked to protective prostanoids (PGs) or nitric oxide (NO) in addition to phosphatases know to counterbalance kinase activity.