Osthole Ameliorates Estrogen Deficiency-Induced Cognitive Impairment in Female Mice

Abstract

Loss of endogenous estrogen and dysregulation of the estrogen receptor signaling pathways are associated with an increase in risk for cognitive deficit and depression in women after menopause. Estrogen therapy for menopause increases the risk of breast and ovarian cancers, and stroke. Therefore, it is critical to find an alternate treatment for menopausal women. Osthole (OST), a coumarin, has been reported to have neuroprotective effects. This study examined whether OST improves ovariectomy (OVX)-induced cognitive impairment, and alleviates anxiety- and depression-like behaviors induced by OVX in mice. Adult female C57BL/6J mice were ovariectomized and then treated with OST at a dose of 30 mg/kg for 14 days. At the end of the treatment period, behavioral tests were used to evaluate spatial learning and memory, recognition memory, anxiety- and depression-like behaviors. A cohort of the mice were sacrificed after 14 days of OST treatment and their hippocampi were collected for measurement of the proteins of interest using western blot. OVX-induced alteration in the levels of proteins was accompanied by cognitive deficit, anxiety- and depression-like behaviors. OST treatment improved cognitive deficit, alleviated anxiety- and depression-like behaviors induced by OVX, and reversed OVX-induced alterations in the levels of synaptic proteins and ERα, BDNF, TrKB, p-CREB, p-Akt and Rac1 in the hippocampus. Therefore, reversal of OVX-induced decrease in the levels of hippocampal proteins by OST might contribute to the effects of OST on improving cognitive deficit and alleviating anxiety- and depression-like behaviors induced by OVX.

Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity

“…Analogs of coumarins showing pharmacological activities have been described [49]. Coumarin and its derivatives demonstrate their potential in treating AD through several mechanisms such as inhibiting AChE [50] and β-secretase [51], preventing misfolded Aβ aggregation [21], upregulating CREB and anti-oxidative pathways [22,23], and promoting BDNF-TRKB and CREB signaling [24,25]. Here, we found the potential of new coumarin derivatives ZN014 and ZN015 for AD treatment by reducing Aβ aggregation, ROS, caspase-1, and AChE as well as promoting neurite outgrowth (Figures 2 and 3) and TRKB signaling (Figure 4).…”

“…Coumarin derivative imperatorin also activates BDNF and CREB signaling to improve learning and memory deficits in prenatally stressed rats [24]. In addition, osthole lessens cognitive impairment in estrogen-deficiency mice by rescuing the reduction of BDNF and TRKB, as well as phosphorylation of CREB, in the hippocampus [25]. Here, we report the potential of two newly synthetic coumarins, ZN014 and ZN015, to reduce Aβ aggregations and oxidative stress as well as to enhance the TRKB signaling pathway in SH-SY5Y neuroblastoma cell models for AD.…”

Improvement of Cognitive Function in Ovariectomized Rats by Human Neural Stem Cells Overexpressing Choline Acetyltransferase via Secretion of NGF and BDNF

“…In particular, it induces apoptosis, neuronal loss, and cognitive dysfunction in the hippocampus [ 30 ]. Therefore, several studies have focused on developing therapeutic strategies, such as hormone replacement, and understanding their mechanisms [ 31 , 32 , 33 ]. In this study, estradiol treatment increased the expression of the cholinergic system for ACh synthesis.…”

Osthole: An up-to-date review of its anticancer potential and mechanisms of action

“…Z. et al, 2020 ). Osthole treatment was shown to improve cognitive deficit and alleviate anxiety- and depression-like behaviors induced by ovariectomy, the standard surgical treatment for ovarian cancer ( Adu-Nti et al, 2021 ).…”