title: AT1 receptor antagonism does not influence early radiation-induced changes in microglial activation or neurogenesis in the normal rat brain.
abstract: 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.
authors.affiliation: Program in Neuroscience, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157-1010, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Conner
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Forbes
authors.forename: Won Hee
authors.initials: WH
authors.lastname: Lee
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Lee
authors.forename: David R
authors.initials: DR
authors.lastname: Riddle
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D016207:Cytokines / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004326:Drinking / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D055495:Neurogenesis / Q000187:drug effects* / Q000528:radiation effects*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; D044140:Receptor, Angiotensin, Type 1; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2