title: Effects of the AT1 receptor antagonist L-158,809 on microglia and neurogenesis after fractionated whole-brain irradiation.
abstract: Cognitive dysfunction develops in approximately 50% of patients who receive fractionated whole-brain 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.
authors.affiliation: Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1010, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Conner
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Payne
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Forbes
authors.forename: Mike E
authors.initials: ME
authors.lastname: Robbins
authors.forename: David R
authors.initials: DR
authors.lastname: Riddle
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000528:radiation effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D055495:Neurogenesis / Q000187:drug effects* / Q000528:radiation effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000528:radiation effects; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C070967:L 158809