Abstract
BackgroundDangguijakyak-san (DJS) is an herbal formulation that has been clinically applicable for treating postmenopausal symptoms and neurological disorders. It is reported that hippocampal estrogen attenuates memory impairment via neuroprotection and synaptogenesis. However, the effect of DJS on hippocampal estrogen synthesis remains unknown. In this study, we explored the effect of DJS and its neuroprotective mechanism against memory impairment in ovariectomized (OVX) mice, with respect to hippocampal estrogen stimulation.MethodsCell cultures were prepared from the hippocampi of 18-day-old embryos from timed pregnant Sprague–Dawley rats. The hippocampi were dissected, collected, dissociated, and plated in 60-mm dishes. The cells were treated with DJS for 48 h and the supernatant was collected to determine estrogen levels. Female ICR mice (8-weeks-old) were housed for 1 week and ovariectomy was performed to remove the influence of ovary-synthesized estrogens. Following a 2-week post-surgical recovery period, the mice were administrated with DJS (50 and 100 mg/kg/day, p.o.) or 17β-estradiol (200 μg/kg/day, i.p.) once daily for 21 days. Hippocampal and serum estrogen levels were determined using enzyme-linked immunosorbent assay kit. Memory behavioral tests, western blot, and immunohistochemical analyses were performed to evaluate the neuroprotective effects of DJS in this model.ResultsDJS treatment promoted estrogen synthesis in primary hippocampal cells and the hippocampus of OVX mice, resulting in the amelioration of OVX-induced memory impairment. Hippocampal estrogen stimulated by DJS treatment contributed to the activation of cAMP response element-binding protein and synaptic protein in OVX mice.ConclusionDJS may attenuate memory deficits in postmenopausal women via hippocampal estrogen synthesis.
Highlights
Dangguijakyak-san (DJS) is an herbal formulation that has been clinically applicable for treating postmenopausal symptoms and neurological disorders
In this study, we explored whether the memory improvement effect of DJS is due to hippocampal estrogen synthesis and its related mechanisms focusing on synapse consolidation by assessing the expression of phosphorylated cyclic-AMP response element-binding protein (CREB), SYN, and Postsynaptic density protein-95 (PSD-95) in an OVX model
DJS stimulates hippocampal estrogen synthesis both in the primary cells and in the mouse hippocampus Increasing evidence indicates that hippocampus-derived estrogen contributes to promoting synaptic plasticity and neuroprotective actions rather than estrogen synthesized from gonads [37]
Summary
Dangguijakyak-san (DJS) is an herbal formulation that has been clinically applicable for treating postmenopausal symptoms and neurological disorders. It is reported that hippocampal estrogen attenuates memory impairment via neuroprotection and synaptogenesis. The effect of DJS on hippocampal estrogen synthesis remains unknown. We explored the effect of DJS and its neuroprotective mechanism against memory impairment in ovariectomized (OVX) mice, with respect to hippocampal estrogen stimulation. Estrogen regulates the expression of essential extracellular-signal-regulated kinase (ERK)/cyclic-AMP response element-binding protein (CREB) signaling in long-term hippocampal memory in neurons [8–11] and synaptic protein, including synaptophysin (SYN) and postsynaptic density protein-95 (PSD95) [12–14]. It was reported that estrogen is synthesized from cholesterol and androgen precursor [18, 19] by neurons and glia in numerous brain regions including the hippocampus, hypothalamus, and cerebral cortex [20–22]. Stimulating estrogen synthesis in the hippocampus will be a new strategy for attenuating memory impairment due to ovary dysfunction status at the postmenopausal stage
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