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.

Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?

“…These data suggest that neuroactive polypeptides may be targeted in specific brain regions by choosing the appropriate CD in nasal formulations [ 65 ]. Similarly, 17β-estradiol (E2), proposed to improve spatial learning and memory, appears influenced by CD in targeting specific brain regions upon nasal administration [ 66 ].…”

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough

“…The results of the aforementioned studies suggest that utilising this particular mode of administration may result in improvements of verbal memory and executive function, alongside a decrease in the advancement of the disease (Shiraishi et al, 2024). Another study suggests the use of intranasal estradiol spray as a means of delivering estrogen locally, with the objective of enhancing cognitive functions by targeting specific brain regions (Prakapenka et al, 2020). Another study shows that combination of therapies, specifically the combination of estrogen plus progesterone or estrogen plus cholinesterase inhibitors, can improve the motor and non-motor functions induced by estrogen depletion (Tan et al, 2024).…”