Hyaluronic Acid-Conjugated 17β-Estradiol Provide More Effectively to Alleviate Estropause-Induced Cognitive Deficits in Rats

Women are at higher risk of cognitive impairment and Alzheimer’s disease (AD) after menopause when the estrous cycle becomes irregular and begins to taper off. Numerous studies have shown that estrogen deficiency, especially estradiol (E2), has been shown to play a key role in this phenomenon. Recently, a novel polymeric drug, hyaluronic acid-17β-Estradiol conjugate (HA-E2), has been developed which has the ability to cross the blood-brain barrier (BBB), facilitate a longer E2 release profile and lower risk of estrogen supplement related side effects. In this study, we used an ovariohysterectomy (OHE) rat model of postmenopausal cognitive deficits and explore whether HA-E2 treatment can improve the cholinergic septo-hippocampal innervation system, synaptic transmission in the hippocampal pyramidal neuron and cognitive impairment. Our results show that OHE rats after HA-E2 administration have increased expression of choline acetyltransferase (ChAT) in the medial septal nucleus (MS nucleus) and the hippocampus, increased spine density in hippocampal pyramidal neurons, and improved spatial learning and memory. Therefore, HA-E2 has great potential as a new novel class of drugs for estrogen-deficiency-induced cognitive impairment and AD.