TY - JOUR
T1 - Intranasal 17β-estradiol modulates spatial learning and memory in a rat model of surgical menopause
AU - Prakapenka, Alesia V.
AU - Peña, Veronica L.
AU - Strouse, Isabel
AU - Northup-Smith, Steven
AU - Schrier, Ally
AU - Ahmed, Kinza
AU - Bimonte-Nelson, Heather A.
AU - Sirianni, Rachael W.
N1 - Funding Information:
Acknowledgments: The authors would like to acknowledge the National Institutes of Health, National Science Foundation, Barrow Neurological Institute (BNI), Arizona State University (ASU)-BNI Interdepartmental Neuroscience Program, ASU Department of Psychology, and the ARCS Foundation for their support. We thank Janet Neisewander and her laboratory team for the use of her laboratory space to conduct work with tritiated E2 as well as the ASU veterinary staff, especially Dale DeNardo, Seth Nydam, and Jacquelyn Kilbourne, for aiding us in developing the intranasal administration technique. We also thank Stephanie V. Koebele for expert assistance on the project and Shalini Vijayaraghavan for technical assistance with the open field task.
Funding Information:
Funding: AVP was funded by the National Science Foundation Graduate Research Fellowship (DGE-1311230). HAB-N was funded by the National Institute on Aging (NIA-R01AG028084), state of Arizona, Arizona Department of Health Services (ADHS14-052688), National Institutes of Health (NIH) Alzheimer’s Disease Core Center (P30AG019610), Arizona State University Office of Knowledge Enterprise Development, College of Liberal Arts and Sciences, and Department of Psychology. RWS was funded by the Barrow Neurological Institute and the University of Texas Health Science Center at Houston.
Funding Information:
AVP was funded by the National Science Foundation Graduate Research Fellowship (DGE-1311230). HAB-N was funded by the National Institute on Aging (NIA-R01AG028084), state of Arizona, Arizona Department of Health Services (ADHS14-052688), National Institutes of Health (NIH) Alzheimer?s Disease Core Center (P30AG019610), Arizona State University Office of Knowledge Enterprise Development, College of Liberal Arts and Sciences, and Department of Psychology. RWS was funded by the Barrow Neurological Institute and the University of Texas Health Science Center at Houston.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/12
Y1 - 2020/12
N2 - Exogenously administered 17β-estradiol (E2) can improve spatial learning and memory, although E2 also exerts undesired effects on peripheral organs. Clinically, E2 has been solubilized in cyclodextrin for intranasal administration, which enhances brain-specific delivery. Prior work shows that the cyclodextrin structure impacts region-specific brain distribution of intranasally administered small molecules. Here, we investigated (1) cyclodextrin type-specific modulation of intranasal E2 brain distribution, and (2) cognitive and peripheral tissue effects of intranasal E2 in middle-aged ovariectomized rats. First, brain and peripheral organ distribution of intranasally administered, tritiated E2 was measured for E2 solubilized freely or in one of four cyclodextrin formulations. The E2-cyclodextrin formulation with greatest E2 uptake in cognitive brain regions versus uterine horns was then compared to free E2 on learning, memory, and uterine measures. Free E2 improved spatial reference memory, whereas E2-cyclodextrin impaired spatial working memory compared to their respective controls. Both E2 formulations increased uterine horn weights relative to controls, with E2-cyclodextrin resulting in the greatest uterine horn weight, suggesting increased uterine stimulation. Thus, intranasal administration of freely solubilized E2 is a strategic delivery tool that can yield a cognitively beneficial impact of the hormone alongside decreased peripheral effects compared to intranasal administration of cyclodextrin solubilized E2.
AB - Exogenously administered 17β-estradiol (E2) can improve spatial learning and memory, although E2 also exerts undesired effects on peripheral organs. Clinically, E2 has been solubilized in cyclodextrin for intranasal administration, which enhances brain-specific delivery. Prior work shows that the cyclodextrin structure impacts region-specific brain distribution of intranasally administered small molecules. Here, we investigated (1) cyclodextrin type-specific modulation of intranasal E2 brain distribution, and (2) cognitive and peripheral tissue effects of intranasal E2 in middle-aged ovariectomized rats. First, brain and peripheral organ distribution of intranasally administered, tritiated E2 was measured for E2 solubilized freely or in one of four cyclodextrin formulations. The E2-cyclodextrin formulation with greatest E2 uptake in cognitive brain regions versus uterine horns was then compared to free E2 on learning, memory, and uterine measures. Free E2 improved spatial reference memory, whereas E2-cyclodextrin impaired spatial working memory compared to their respective controls. Both E2 formulations increased uterine horn weights relative to controls, with E2-cyclodextrin resulting in the greatest uterine horn weight, suggesting increased uterine stimulation. Thus, intranasal administration of freely solubilized E2 is a strategic delivery tool that can yield a cognitively beneficial impact of the hormone alongside decreased peripheral effects compared to intranasal administration of cyclodextrin solubilized E2.
KW - Cyclodextrin
KW - Delivery
KW - Estrogen
KW - Intranasal
KW - Learning
KW - Memory
KW - Menopause
UR - http://www.scopus.com/inward/record.url?scp=85098285903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098285903&partnerID=8YFLogxK
U2 - 10.3390/pharmaceutics12121225
DO - 10.3390/pharmaceutics12121225
M3 - Article
AN - SCOPUS:85098285903
SN - 1999-4923
VL - 12
SP - 1
EP - 22
JO - Pharmaceutics
JF - Pharmaceutics
IS - 12
M1 - 1225
ER -