The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment.
OBJECTIVE
We hypothesized that administration of the angiotensin type 1 (AT1) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment.


METHODS
Groups of 80 young adult male Fischer 344 x Brown Norway (F344xBN) rats, 12-14 weeks old, received either: (1) fractionated WBI; 40 Gy of gamma rays in 4 weeks, 2 fractions/week, (2) sham-irradiation; (3) WBI plus L-158,809 (20 mg/L drinking water) starting 3 days prior, during, and for 14, 28, or 54 weeks postirradiation; and (4) sham-irradiation plus L-158,809 for 14, 28, or 54 weeks postirradiation. An additional group of rats (n = 20) received L-158,809 before, during, and for 5 weeks postirradiation, after which they received normal drinking water up to 28 weeks postirradiation.


RESULTS
Administration of L-158,809 before, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks postirradiation. Moreover, giving L-158,809 before, during, and for only 5 weeks postirradiation ameliorated the significant cognitive impairment observed 26 weeks postirradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks postirradiation, respectively.


CONCLUSIONS
Administering L-158,809 before, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks postirradiation. These findings offer the promise of improving the quality of life for brain tumor patients.
Robbins
Mike E
ME
Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Payne
Valerie
V
Tommasi
Ellen
E
Diz
Debra I
DI
Hsu
Fang-Chi
FC
Brown
William R
WR
Wheeler
Kenneth T
KT
Olson
John
J
Zhao
Weiling
W
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D016371:Cranial Irradiation / Q000009:adverse effects*; D019583:Dose Fractionation, Radiation; D004353:Drug Evaluation, Preclinical; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D011833:Radiation Injuries, Experimental / Q000150:complications*; D051381:Rats; D011916:Rats, Inbred F344; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; C070967:L 158809