estradiol-3-benzoate and Learning-Disabilities

A decline in estradiol (E2)-mediated cognitive benefits denotes a critical window for the therapeutic effects of E2, but the mechanism for closing of the critical window is unknown. We hypothesized that upregulating the expression of estrogen receptor α (ERα) or estrogen receptor β (ERβ) in the hippocampus of aged animals would restore the therapeutic potential of E2 treatments and rejuvenate E2-induced hippocampal plasticity. Female rats (15 months) were ovariectomized, and, 14 weeks later, adeno-associated viral vectors were used to express ERα, ERβ, or green fluorescent protein (GFP) in the CA1 region of the dorsal hippocampus. Animals were subsequently treated for 5 weeks with cyclic injections of 17β-estradiol-3-benzoate (EB, 10 μg) or oil vehicle. Spatial memory was examined 48 h after EB/oil treatment. EB treatment in the GFP (GFP + EB) and ERβ (ERβ + EB) groups failed to improve episodic spatial memory relative to oil-treated animals, indicating closing of the critical window. Expression of ERβ failed to improve cognition and was associated with a modest learning impairment. Cognitive benefits were specific to animals expressing ERα that received EB treatment (ERα + EB), such that memory was improved relative to ERα + oil and GFP + EB. Similarly, ERα + EB animals exhibited enhanced NMDAR-mediated synaptic transmission compared with the ERα + oil and GFP + EB groups. This is the first demonstration that the window for E2-mediated benefits on cognition and hippocampal E2 responsiveness can be reinstated by increased expression of ERα.. Estradiol is neuroprotective, promotes synaptic plasticity in the hippocampus, and protects against cognitive decline associated with aging and neurodegenerative diseases. However, animal models and clinical studies indicate a critical window for the therapeutic treatment such that the beneficial effects are lost with advanced age and/or with extended hormone deprivation. We used gene therapy to upregulate expression of the estrogen receptors ERα and ERβ and demonstrate that the window for estradiol's beneficial effects on memory and hippocampal synaptic function can be reinstated by enhancing the expression of ERα. Our findings suggest that the activity of ERα controls the therapeutic window by regulating synaptic plasticity mechanisms involved in memory.

Topics: Animals; Contraceptive Agents; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Female; Gene Expression Regulation; HEK293 Cells; Hippocampus; Humans; Learning Disabilities; Maze Learning; Nerve Tissue Proteins; Ovariectomy; Quinoxalines; Rats; Rats, Inbred F344; Spatial Memory; Time Factors; Transduction, Genetic

Estrogen deficiency is associated with cognitive impairment. Hormone replacement therapy (HRT) has proven to be effective in preventing and reversing the memory and learning deficiencies. However, conventional estrogenic treatment could increase the risks of breast cancer and venous thromboembolism. Tenuigenin (TEN) is putatively believed as the active component extracted from a Chinese herb Polygala tenuifolia root. Although TEN has been shown to enhance learning and memory in healthy mice, it remains unknown whether or not TEN could ameliorate learning and memory impairments. In the present study, mice were divided into four groups: sham-operated (sham), ovariectomized (OVX), OVX+estradiol benzoate (EB) and OVX+TEN groups. Step-through passive avoidance and Y-maze tests were used to assess learning and memory abilities, and the number of nitric oxide synthase (NOS) positive neurons and the synaptic measurement of hippocampal CA1 area were examined. The results showed that TEN was given orally to OVX mice, leading to the improvement of learning and memory in step-through passive avoidance and Y-maze tests. TEN could reduce the loss of NOS positive neurons and prevent the synaptic morphological changes induced by ovariectomy. Our results suggest that TEN may exert a potential therapeutic value for menopause cognitive dysfunction.

Topics: Animals; Avoidance Learning; CA1 Region, Hippocampal; Cognition Disorders; Drugs, Chinese Herbal; Estradiol; Female; Learning Disabilities; Maze Learning; Memory Disorders; Mice; NADPH Dehydrogenase; Ovariectomy; Psychomotor Performance; Synapses