About 500,000 new
cancer patients will develop
brain metastases in 2013. The primary treatment modality for these patients is partial or whole brain irradiation which leads to a progressive, irreversible
cognitive impairment. Although the exact mechanisms behind this radiation-induced
brain injury are unknown,
neuroinflammation in glial populations is hypothesized to play a role. Blockers of the renin-angiotensin system (RAS) prevent radiation-induced
cognitive impairment and modulate radiation-induced
neuroinflammation. Recent studies suggest that RAS blockers may reduce
inflammation by increasing endogenous concentrations of the anti-inflammatory heptapeptide
angiotensin-(1-7) [Ang-(1-7)]. Ang-(1-7) binds to the AT(1-7) receptor and inhibits MAP
kinase activity to prevent
inflammation. This study describes the inflammatory response to radiation in astrocytes characterized by radiation-induced increases in (i) IL-1β and
IL-6 gene expression; (ii) COX-2 and GFAP immunoreactivity; (iii) activation of
AP-1 and NF-κB
transcription factors; and (iv) PKCα,
MEK, and
ERK (MAP kinase) activation. Treatment with
U-0126, a
MEK inhibitor, demonstrates that this radiation-induced
inflammation in astrocytes is mediated through the MAP
kinase pathway. Ang-(1-7) inhibits radiation-induced
inflammation, increases in PKCα, and MAP
kinase pathway activation (phosphorylation of
MEK and ERK). Additionally Ang-(1-7) treatment leads to an increase in
dual specificity phosphatase 1 (DUSP1). Furthermore, treatment with
sodium vanadate (Na3VO4), a
phosphatase inhibitor, blocks Ang-(1-7) inhibition of radiation-induced
inflammation and MAP
kinase activation, suggesting that Ang-(1-7) alters
phosphatase activity to inhibit radiation-induced
inflammation. These data suggest that RAS blockers inhibit radiation-induced
inflammation and prevent radiation-induced
cognitive impairment not only by reducing Ang II but also by increasing Ang-(1-7) levels.