The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats

Cell Mol Neurobiol. 2020 Apr;40(3):407-420. doi: 10.1007/s10571-019-00744-x. Epub 2019 Oct 21.


Women who have bilateral oophorectomies prior to the age of natural menopause are at increased risk of developing mild cognitive decline, dementia, anxiety, and depressive type disorders. Clinical and animal studies indicate angiotensin type 1 receptor (AT1R) blockers (ARBs) have blood pressure (BP)-independent neuroprotective effects. To investigate the potential use of ARBs in normotensive women at increased risk of developing neurocognitive problems, we studied a rat model of bilateral oophorectomy. Long Evans rats were sham-operated (Sham) or ovariectomized (Ovx) at 3 months of age and immediately treated continuously with vehicle (Veh) or the ARB losartan (Los) for the duration of the experiment. In contrast to many hypertensive rat models, ovariectomy did not increase mean arterial pressure (MAP) in these normotensive rats. Ovariectomized rats spent less time in the open arms of the elevated plus maze (EPM) [(% total time): Veh, 34.1 ± 5.1 vs. Ovx, 18.7 ± 4.4; p < 0.05] and in the center of the open field (OF) [(s): Veh, 11.1 ± 1.7 vs. Ovx, 6.64 ± 1.1; p < 0.05]. They also had worse performance in the novel object recognition (NOR) test as evidenced by a reduction in the recognition index [Veh, 0.62 ± 0.04 vs. Ovx, 0.45 ± 0.03; p < 0.05]. These adverse effects of ovariectomy were prevented by Los. Losartan also reduced plasma corticosterone in Ovx rats compared to Veh treatment [(ng/mL): Ovx-Veh, 238 ± 20 vs. Ovx-Los, 119 ± 42; p < 0.05]. Ovariectomy increased AT1R mRNA expression in the CA3 region of the hippocampus (Hc) [(copies x 106/µg RNA): Sham-Veh, 7.15 ± 0.87 vs. Ovx-Veh, 9.86 ± 1.7; p < 0.05]. These findings suggest the neuroprotective effects of this ARB in normotensive Ovx rats involve reduction of plasma corticosterone and blockade of increased AT1R activity in the hippocampus. These data suggest ARBs have therapeutic potential for normotensive women at increased risk of developing cognitive and behavioral dysfunction due to bilateral oophorectomy prior to the natural age of menopause.

Keywords: Cognition; Memory; Postmenopausal; Premature ovarian failure.

MeSH terms

  • Angiotensin Receptor Antagonists / pharmacology*
  • Angiotensin Receptor Antagonists / therapeutic use
  • Animals
  • Anxiety / etiology
  • Anxiety / prevention & control*
  • Behavior, Animal / drug effects
  • Blood Pressure / drug effects
  • Body Weight / drug effects
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / prevention & control*
  • Female
  • Food Preferences / drug effects
  • Losartan / pharmacology*
  • Losartan / therapeutic use
  • Maze Learning / drug effects
  • Memory / drug effects
  • Ovariectomy / adverse effects
  • Rats
  • Rats, Long-Evans
  • Receptor, Angiotensin, Type 1 / metabolism
  • Recognition, Psychology / drug effects
  • Uterus / drug effects
  • Uterus / pathology


  • Angiotensin Receptor Antagonists
  • Receptor, Angiotensin, Type 1
  • Losartan