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

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 (B...

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Autores principales: Campos, Glenda V., de Souza, Aline M. A., Ji, Hong, West, Crystal A., Wu, Xie, Lee, Dexter L., Aguilar, Brittany L., Forcelli, Patrick A., de Menezes, Rodrigo C., Sandberg, Kathryn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056686/
https://www.ncbi.nlm.nih.gov/pubmed/31637567
http://dx.doi.org/10.1007/s10571-019-00744-x
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author Campos, Glenda V.
de Souza, Aline M. A.
Ji, Hong
West, Crystal A.
Wu, Xie
Lee, Dexter L.
Aguilar, Brittany L.
Forcelli, Patrick A.
de Menezes, Rodrigo C.
Sandberg, Kathryn
author_facet Campos, Glenda V.
de Souza, Aline M. A.
Ji, Hong
West, Crystal A.
Wu, Xie
Lee, Dexter L.
Aguilar, Brittany L.
Forcelli, Patrick A.
de Menezes, Rodrigo C.
Sandberg, Kathryn
author_sort Campos, Glenda V.
collection PubMed
description 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. 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 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.
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spelling pubmed-70566862020-03-16 The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats Campos, Glenda V. de Souza, Aline M. A. Ji, Hong West, Crystal A. Wu, Xie Lee, Dexter L. Aguilar, Brittany L. Forcelli, Patrick A. de Menezes, Rodrigo C. Sandberg, Kathryn Cell Mol Neurobiol Original Research 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. 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 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. Springer US 2019-10-21 2020 /pmc/articles/PMC7056686/ /pubmed/31637567 http://dx.doi.org/10.1007/s10571-019-00744-x Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
Campos, Glenda V.
de Souza, Aline M. A.
Ji, Hong
West, Crystal A.
Wu, Xie
Lee, Dexter L.
Aguilar, Brittany L.
Forcelli, Patrick A.
de Menezes, Rodrigo C.
Sandberg, Kathryn
The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats
title The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats
title_full The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats
title_fullStr The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats
title_full_unstemmed The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats
title_short The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats
title_sort angiotensin type 1 receptor antagonist losartan prevents ovariectomy-induced cognitive dysfunction and anxiety-like behavior in long evans rats
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056686/
https://www.ncbi.nlm.nih.gov/pubmed/31637567
http://dx.doi.org/10.1007/s10571-019-00744-x
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