Intranasal 17β-Estradiol Modulates Spatial Learning and Memory in a Rat Model of Surgical Menopause

Abstract

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.

Keywords: cyclodextrin; delivery; estrogen; intranasal; learning; memory; menopause.

Figure 1

General timeline for Studies 1 and 2.

Figure 2

Tritiated E2 distribution in frontal cortex, cingulate cortex, olfactory bulbs, and trigeminal nerves 0.5, 2, and 6 h following intranasal administration as a function of CD type [53].

Figure 3

Tritiated E2 distribution in dorsal hippocampus, amygdala, and hypothalamus 0.5, 2, and 6 h following intranasal administration as a function of CD type [53].

Figure 4

Tritiated E2 concentration in the dorsal hippocampus and frontal cortex 0.5 h following intranasal administration of Treatments A–E. All data are represented as mean ± s.e.m. * p < 0.05.

Figure 5

Tritiated E2 concentration in dorsal hippocampus, frontal cortex, uterine horns, and whole blood across time after intranasal administration of Treatment A and Treatment C. (a) Tritiated E2 concentration in dorsal hippocampus, frontal cortex, and uterine horns 0.5, 2, and 6 h following intranasal administration of Treatment A and Treatment C; (b) tritiated E2 concentration in uterine horns and whole blood 0.5, 2, and 6 h following intranasal administration of Treatment A and Treatment C. All data are represented as mean ± s.e.m.

Figure 5

Tritiated E2 concentration in dorsal hippocampus, frontal cortex, uterine horns, and whole blood across time after intranasal administration of Treatment A and Treatment C. (a) Tritiated E2 concentration in dorsal hippocampus, frontal cortex, and uterine horns 0.5, 2, and 6 h following intranasal administration of Treatment A and Treatment C; (b) tritiated E2 concentration in uterine horns and whole blood 0.5, 2, and 6 h following intranasal administration of Treatment A and Treatment C. All data are represented as mean ± s.e.m.

Figure 6

Rat body weight throughout the duration of Study 2. (a) Weekly body weight across the study, depicting changes in rat weight with Ovx, treatment initiation, and behavior initiation; (b) treatment effects on body weight in the weeks before treatment initiation, weeks 1–4, and the weeks after treatment initiation, weeks 5–10. All data are represented as mean ± s.e.m. * p < 0.05.

Figure 6

Rat body weight throughout the duration of Study 2. (a) Weekly body weight across the study, depicting changes in rat weight with Ovx, treatment initiation, and behavior initiation; (b) treatment effects on body weight in the weeks before treatment initiation, weeks 1–4, and the weeks after treatment initiation, weeks 5–10. All data are represented as mean ± s.e.m. * p < 0.05.

Figure 7

Reference memory (RM) errors made on the acquisition phase (days 2–7) of the WRAM. (a) Main effect of Estrogen on RM errors; (b) two group comparisons for further interpretation of the main effect of Estrogen on RM performance. All data are represented as mean ± s.e.m. * p < 0.05, ** p < 0.01.

Figure 8

Working memory incorrect (WMI) errors made on the asymptotic phase (days 8–12) of the WRAM. (a) The Estrogen × Vehicle interaction for WMI errors; (b) the Trial × Estrogen × Vehicle interaction for WMI errors as well as the Estrogen × Vehicle interaction for Trial 4 only, the highest working memory load trial; (c) two group comparisons for further interpretation of the Estrogen × Vehicle interaction; (d) two group comparisons for further interpretation of the Trial × Estrogen × Vehicle interaction. All data are represented as mean ± s.e.m. * p < 0.05, ** p < 0.01, ^# p < 0.1.

Figure 9

Uterine horn weights across treatment groups. All data are represented as mean ± s.e.m. ** p < 0.01, **** p < 0.0001.