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

Abstract

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 (AT 1 R) 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 AT 1 R mRNA expression in the CA3 region of the hippocampus (Hc) [(copies x 10 6 /µg RNA): Sham-Veh, 7.15 ± 0.87 vs. 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 AT 1 R 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.

Facilitation of TRKB activation by the angiotensin II receptor type-2 (AT2R) agonist C21

“…Taken together, these outcomes raise the question whether the observed effects also apply to other drugs acting on RAS. The AT1R antagonist losartan was able to relieve ovariectomy-induced increase in anxiety-like behavior in the elevated plus-maze, and cognitive impairment in the novel object recognition test, and decreased the levels of plasma corticosterone [42]. Telmisartan, another AT1R antagonist, reduced the consequences of stress on cognitive impairment, and inhibited the activity of the HPA axis [43].…”

The Role of Estrogen in Anxiety-Like Behavior and Memory of Middle-Aged Female Rats

“…There is some evidence indicating that ovariectomy in youngadult females has anxiogenic effect (16)(17)(18)(19)(20). However, there is little data on the effect of ovariectomy on anxiety in middleaged rats (44).…”

“…A large number of studies have shown that ovariectomy may induce cognitive dysfunction in young ( 13 – 16 ) and also in middle-aged rats ( 29 , 30 , 43 ), while estrogens may improve learning and memory performance following ovariectomy in both, young ( 15 , 24 , 59 – 61 ) and middle-aged females ( 21 – 23 , 25 , 29 , 31 ). However, OVX females in our experiment exhibited mild memory impairment only, and the estradiol-treated group did not outperform vehicle-treated OVX rats.…”

“…In animal experiments, the bilateral removal of ovariesovariectomy-is the most used tool to mirror the postmenopausal state of women (12). It has been shown that ovariectomy causes impaired learning and memory indicated by longer latency time to find a platform and less time spent in the target zone in the Morris water maze, and by lower recognition index in the novel object recognition and object placement tasks (13)(14)(15)(16). Similarly, there are numerous data showing anxiogenic effect of ovariectomy in several tests, such as open field, elevated plus maze or light-dark box (16)(17)(18)(19)(20).…”

“…It has been shown that ovariectomy causes impaired learning and memory indicated by longer latency time to find a platform and less time spent in the target zone in the Morris water maze, and by lower recognition index in the novel object recognition and object placement tasks (13)(14)(15)(16). Similarly, there are numerous data showing anxiogenic effect of ovariectomy in several tests, such as open field, elevated plus maze or light-dark box (16)(17)(18)(19)(20). On the other hand, estradiol replacement in the surgical model of menopause may improve cognitive functions and decrease anxiety-like behavior in rodents (14,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”