Neuroprotective Effects Of Estrogen Research Articles

The impact of VPS35 D620N mutation on alternative autophagy and its reversal by estrogen in Parkinson's disease

VPS35 plays a key role in neurodegenerative processes in Alzheimer’s disease and Parkinson’s disease (PD). Many genetic studies have shown a close relationship between autophagy and PD pathophysiology, and specifically, the PD-causing D620N mutation in VPS35 has been shown to impair autophagy. However, the molecular mechanisms underlying neuronal cell death and impaired autophagy in PD are debated. Notably, increasing evidence suggests that Rab9-dependent “alternative” autophagy, which is driven by a different molecular mechanism that driving ATG5-dependent “conventional” autophagy, also contributes to neurodegenerative process. In this study, we investigated the relationship between alternative autophagy and VPS35 D620N mutant-related PD pathogenesis. We isolated iPSCs from the blood mononuclear cell population of two PD patients carrying the VPS35 D620N mutant. In addition, we used CRISPR-Cas9 to generate SH-SY5Y cells carrying the D620N variant of VPS35. We first revealed that the number of autophagic vacuoles was significantly decreased in ATG5-knockout Mouse Embryonic Fibroblast or ATG5-knockdown patient-derived dopaminergic neurons carrying the VPS35 D620N mutant compared with that of the wild type VPS35 control cells. Furthermore, estrogen, which activates alternative autophagy pathways, increased the number of autophagic vacuoles in ATG5-knockdown VPS35 D620N mutant dopaminergic neurons. Estrogen induces Rab9 phosphorylation, mediated through Ulk1 phosphorylation, ultimately regulating alternative autophagy. Moreover, estrogen reduced the apoptosis rate of VPS35 D620N neurons, and this effect of estrogen was diminished under alternative autophagy knockdown conditions. In conclusion, alternative autophagy might be important for maintaining neuronal homeostasis and may be associated with the neuroprotective effect of estrogen in PD with VPS35 D620N.

Menopausal transition in multiple sclerosis: relationship with disease activity and brain volume measurements.

Recent evidence has shown a significant association between menopause and multiple sclerosis (MS) progression. This study investigated the possible role of menopause in influencing MS from clinical and neuroradiological perspectives. Notably, the possible association between menopause and brain atrophy has been evaluated. This study included women with MS whose ages ranged from 45 to 55 years. Demographic and clinical characteristics were collected, and the reproductive phase was defined as non-menopausal or menopausal based on the final menstrual period. Thus, MS activity over the past year was reported as the annualised relapse rate (ARR), and MRI activity (defined as new T2 lesions and/or the presence of gadolinium-enhancing lesions at the last MRI assessment in comparison with the MRI performed within the previous 12 months) were compared between non-menopausal women (non-MW) and menopausal women (MW). Volume measurements of the whole brain (WB), white matter (WM), grey matter (GM), and cortical GM were estimated using the SIENAX software, and the possible relationship with menopausal status was assessed by regression analysis. The study included 147 women with MS. Eighty-four (57.1%) were MW, with a mean age of 48.5 ± 4.3 years at menopause onset and a mean duration of menopause of 4.1 ± 1.1 years. When compared for ARR, MW reported a lower rate than the non-MW (ARR of 0.29 ± 0.4 vs. 0.52 ± 0.5; p < 0.01). MRI activity was observed in 13.1% of MW and 20.6% of non-MW (p = 0.03). Lower cortical GM volumes (578.1 ± 40.4 mL in MW vs. 596.9 ± 35.8 mL in non-MW; p < 0.01) have also been reported. Finally, multivariate analysis showed a significant association of lower ARR (p = 0.001) and cortical GM volume (p = 0.002) with menopausal status after correction for chronological age and other variables. Menopause may be an adverse prognostic factor of MS. Our preliminary results suggest that menopause may facilitate cortical GM atrophy, probably due to a decline in the neuroprotective effects of estrogen, with negative effects on MS evolution.

Exploring a Possible Interplay between Schizophrenia, Oxytocin, and Estrogens: A Narrative Review

Schizophrenia is characterized by symptoms of psychosis and sociocognitive deficits. Considering oxytocin's antipsychotic and prosocial properties, numerous clinical, and preclinical studies have explored the neuropeptide's therapeutic efficacy. Sex differences in the clinical course of schizophrenia, as well as in oxytocin-mediated behaviors, indicate the involvement of gonadal steroid hormones. The current narrative review aimed to explore empirical evidence on the interplay between schizophrenia psychopathology and oxytocin's therapeutic potential in consideration of female gonadal steroid interactions, with a focus on estrogens. The review was conducted using the PubMed and PsychINFO databases and conforms to the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. The results suggest a potential synergistic effect of the combined antipsychotic effect of oxytocin and neuroprotective effect of estrogen on schizophrenia. Consideration of typical menstrual cycle-related hormonal changes is warranted and further research is needed to confirm this assumption.

Neuroprotective Effects of Estrogen Through BDNF-Transient Receptor Potential Channels 6 Signaling Pathway in the Hippocampus in a Rat Model of Perimenopausal Depression.

Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 μg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 μg/24 μl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.

Abstract EP67: Early Menopause Is Linked To Increased Risk Of Presenile Dementia Before Age 65 Years

Introduction: Evidence on the association between age at menopause and risk of dementia has been inconsistent. Some studies observed that later menopause was related to lower risk of dementia, while others reported no association, or even came to the opposite. Estradiol plays an important role in a wide range of neurological functions in brain, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative diseases, and accelerate the progression of dementia. Hypothesis: Based on the neuroprotective effects of estrogen, we hypothesized that earlier menopause might be related to higher risk of and earlier onset of dementia, compared with menopause at normal age or later. Methods: We used cohort data from UK Biobank and a total of 153 291 postmenopausal women were included. Age at menopause was categorized as &lt;40 (premature), 40-44 (early), 45-49, 50-51 (reference), 52-55, and &gt;55 years. The main outcome was all-cause dementia, a comprehensive outcome including Alzheimer's disease (AD), vascular dementia (VD) and dementia classified elsewhere. We used Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) on the association between menopausal age and all-cause dementia. We also stratified the age when dementia was diagnosed into ≤65 years and &gt;65 years to explore the association between age at menopause and timing of experiencing dementia. All HRs were adjusted for age at last follow-up, race, education level, BMI, cigarette smoking, alcohol drinking, cardiovascular disease status, diabetes status, income, leisure activities and physical activities. We also used restricted cubic splines to analyze the dose-response relationship between menopausal age and dementia. Results: Among the 153 291 women, there were 1688 woman suffering from all-cause dementia. The average follow-up time was 11.7 years. Compared with menopausal age of 50-51 years, the HRs (95% CI) with dementia in women with menopausal age &lt;40, 40-44, 45-49, 52-55 and &gt;55 years were 1.53 (1.22-1.91), 1.07 (0.89-1.28), 1.08 (0.94-1.25), 0.81 (0.70-0.94), and 0.91 (0.78-1.06) respectively. Restricted cubic spline also showed an inverse dose-response relationship between them. In addition, compared to women with menopausal age of 50-51 years, women with early menopause (&lt;45 years) had elevated risk of experiencing all-caused dementia before age 65 years (1.31, 1.07-1.72; P &lt;0.001). Conclusions: Compared to women with menopausal age of 50-51 years, women with premature menopause (&lt;40 years) had around 35% higher risk of having all-cause dementia, and women with early menopause (&lt;45 years) were 1.3 times more likely to experience presenile dementia before age 65 years. Women with early menopause may need a close monitoring of their cognitive decline in clinical practice.

Sex-specific differences in cognitive functions and synaptic dysfunction in an Alzheimer's disease mouse model.

Women have higher burden of Alzheimer's disease (AD) compared to men. Although neuroprotective effect of estrogen is well established, the underlying pathogenic mechanisms explaining the higher burden of AD in women remains unknown. Therefore, we attempted to investigate the sex-specific differences through the progression of AD in familial AD mouse model. Synaptic dysfunction is considered to occur prior to the appearance of the pathophysiological and behavioural symptoms of AD. Akt1-mTOR signaling has a critical role at the synapse in AD. Here, we investigated behavioural and synaptic deficits in female AD mice of different age and compared it male mice of similar age in order to study the progression of AD in mouse models. Recall memory test was assessed by contextual fear conditioning (cFC). We isolated synaptosomes prepared from brain cortices of WT and APP/PS1 mice at different ages. Synaptosomes were resolved on SDS-PAGE and immunoblotted against respective antibodies. WT and APP/PS1 female mice underwent an ovariectomy and sham surgery. After ovariectomy and behavioural assessment we prepared synaptoneurosomes from hippocampus and performed 35 [S] methionine incorporation assay. APP/PS1 female mice protected from cFC recall deficits and activity dependent synaptic protein translation until 8 months of age. However, these mice started showing cFC recall deficits and activity dependent synaptic protein translation after 8 months of age unlike APP/PS1 male mice wherein these deficits were observed very early (2-4 months). Ovariectomized APP/PS1 female mice induced cFC recall deficits and activity dependent protein translation at 4 months of age which is similar to young APP/PS1 male mice. Synaptosomal pAkt1, pGSK3β, pmTOR, p70S6K, p4E-BP1 levels were significantly increased at 4 months but when they entered into menopause (at 8 months of age) these protein levels were significantly decreased in APP/PS1 female mice. We conclude that the appearance of recall deficits and loss of synaptosomal Akt1-mTOR signaling occurred in females only as they aged and attained menopause. Our findings indicate that the neuroprotective effects of estrogen may play an important role in protecting from b-amyloid induced toxicity at the synapse.

Effects of L-dopa on expression of prolactin and synaptotagmin IV in 17-estradiol-induced prolactinomas of ovariectomized hemiparkinsonian rats

ABSTRACTParkinson’s disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. Dopamine precursor levodopa (L-dopa) is used as the first-line treatment for PD. Evidence suggests neuroprotective effects of estrogens in PD. Since both 17b-estradiol (E2) and L-dopa act as regulators of prolactin (PRL) secretion from the pituitary gland, we investigated their effect on the expression of PRL in prolactinomas that developed in ovariectomized hemiparkinsonian rats treated with E2. We also investigated the effect of E2 and L-dopa on the expression of synaptotagmin IV (Syt IV), an immediate early gene whose product is abundant in the pituitary gland and was found to be highly co-expressed with PRL in lactotrophs (>90%). The hemiparkinsonian rat model was obtained by unilateral lesioning of dopaminergic nigrostriatal neurons. Rats received silastic tubing implants with E2 and were treated with L-dopa. Enzyme-linked immunosorbent assay and immunohistochemistry were used to assess the serum concentrations of PRL and E2 and expression of PRL and Syt IV in the tissue of adenohypophysis, respectively. We found that high levels of serum E2 were associated with the upregulation of Syt IV and PRL in PRL-ir cells, while treatment with L-dopa decreased the size of prolactinomas and downregulated Syt IV but had no effect on PRL expression or serum concentrations.

Neuroprotective Effects of Estrogen on Beta‐Amyloid Induced Neurotoxicity in Murine Hypothalamic Cells

Alzheimer’s disease (AD) is a neurodegenerative affliction marked by significant cognitive decline and eventual dementia. The two most notable pathological hallmarks of AD include beta‐amyloid plaques, formed from the extracellular aggregation and deposition of beta‐amyloid fibrils, and the intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles in the brain. Previous research has suggested a possible neuroprotective property of estrogen, the female sex hormone, in AD. Despite the implications of a hypothalamic role in the early pathophysiology of AD, such as disturbances in sleep and emotional affect, scant literature exists outside of cortical and hippocampal AD research. This study is designed to replicate AD models using a control cell line, SH‐SY5Y human neuroblastoma cells, and an experimental cell line, N38 murine hypothalamic cells in culture, by incubating these cells with oligomerized human beta‐amyloid 42 (Aβ42). Each cell line is then treated with estrogen in order to observe the hormone’s efficacy as a neuroprotective agent. Cell viability, cytotoxicity and proliferation were measured in order to determine estrogen’s neuroprotective potential, using a variety of bioassays such as MTT and LDH. Preliminary results show lower mitochondrial activity and higher rates of cell lysis when treated with physiologically relevant concentrations of estrogen and low beta‐amyloid concentrations in the SH‐SY5Y cell line. In addition, the low concentration of Aβ42 (10μmol) appeared to have neuroproliferative effects on the SH‐SY5Y cells as opposed to its expected neurotoxicity. Conversely, N38 cells treated with estrogen at dosages higher than physiologically relevant concentrations, were found to have higher mitochondrial activity than cells treated with only Aβ42 after 24 hours, indicating a possible neuroprotective effect of estrogen at high concentrations on the hypothalamic cell line. Cell lysis and cytotoxicity of Aβ42 in N38 cells will be tested in order to further elucidate the pathology of the hypothalamus in AD, as well as estrogen’s potential neuroprotective effect on this unexplored brain region.Support or Funding InformationBiology Department, Adelphi University, Garden City, New York. Department of Biological Sciences, New York City College of Technology/CUNY, New York, NY.

Does Estrogen Act as a Neuroprotective Agent on In Vitro‐Induced β‐Amyloid Plaques in N38 Hypothalamic Neuronal Cells?

A key characteristic of Alzheimer's disease (AD) is the deposition of beta‐amyloid fibrils in extracellular plaques, as well as the intracellular accumulation of tau in neurofibrillary tangles in the brain. This study is designed to induce plaques on N38 hypothalamic neuronal cells under in vitro conditions using synthetic beta‐amyloid and subsequently to treat with estrogen as a neuroprotective reagent. The cell viability, toxicity and proliferation were determined using different bioassays like cell count, Congo red, MTT and lactate dehydrogenase assay. Results indicate a significant loss in cell death, amyloidosis, mitochondrial dysfunction and increased cytotoxicity in cells treated with beta‐amyloid and neuroprotection when exposed to estrogen. Further, in order to understand the mechanism by which neuronal death by plaque formation and neuroprotection by estrogen western blotting was performed to determine the changes associated with biomarker Tau protein. Taking together the biochemical and molecular data, the neuroprotective effect of estrogen on beta amyloid plaque formation will be analyzed.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Protective Effects of G Protein-Coupled Estrogen Receptor 1 (GPER1) on β-Amyloid-Induced Neurotoxicity: Implications for Alzheimer’s Disease

Alzheimer’s disease (AD) is a problematic disease that has shown a significant increase in patient numbers worldwide. AD is identified pathologically by the accumulation of the toxic amyloid beta (Aβ) protein, neurofibrillary tangles and neuropil threads in postmortem brains of AD patients. Women are more prone to AD either due to their increased life expectancy or the decline in Estrogen hormone levels around menopause. Estrogens play a physiologically important role in the brain, but there is debate about the association between estrogen and Ad. The neuroprotective effects of estrogens are possibly mediated by estrogen receptors (ERs), which include classical nuclear estrogen receptors (ERα and ERβ) and nonclassical ER (G protein-coupled estrogen receptor 1, GPER1(GPR30)). The effect of GPER1 on Aβ-induced neurotoxicity is unclear. Here we studied the effect of GPER1 receptor agonists G-1 on rat neuronal cells. Rat neuronal cells were incubated with Aβ1–42, either alone or in combination with GPER1 agonist G-1 (10−7, 10−8 and 10−9 M). Cell viability was determined by MTT assays and apoptotic effects induced by Aβ1–42 were measured by Cell Death Detection kit. Oxidative stress parameters, including nitric oxide (NO) levels and total oxidant status (TOS) were measured by spectrophotometry. Approximately half of the cell death was observed with 10−6 M Aβ1–42 incubation for 48 hours. This is the first study that explores the effect of activation of GPER1 by its agonist G-1 on neuroprotection against Aβ1–42-toxicity in rat neuronal cells. GPER1 activation significantly reduced on rat neuronal cells. Aβ1–42 induced cell death was significantly reduced by co-incubating with G-1. Our results suggest that G-1 treatment protects neurons from Aβ1–42 induced neurotoxicity by changing the oxidative parameters on rat neuronal cells.

Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ER\u03b2 activation

BackgroundRecent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior.MethodsExperiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERβ knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing.ResultsEight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERβ expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERβ activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERβ and its target genes by demethylation of DNA and histone on the ERβ promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior.ConclusionsWe conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application.

Neuroprotective effects of estrogen on Alzheimer induced SH‐SY5Y neuroblastoma cells and N38 hypothalamic neuronal cells

Alzheimer's disease is a neurodegenerative disease characterized by neuronal cell damage and death, neurofibrillary tangle formation and cerebral plaques formed by beta amyloid peptides. Previous studies have shown that the hippocampus, a region of brain related to cognition and memory is mainly affected by Alzheimer's disease. This study is designed to induce Alzheimer's disease by treating SH‐SY5Y neuroblastoma cells and N38 hypothalamic neuronal cells with synthetic beta‐amyloid plaques under in vitro conditions. In the current study, we wanted to determine whether hypothalamus; a region involved in feeding, sleep, reproduction and energy balance is affected similarly as well. Hypothalamic cells were treated with beta‐amyloid1‐42 to induce neurofibrillary tangles and plaque formation. The cell viability, toxicity and proliferation were determined using different bioassays like cell count, MTT and lactate dehydrogenase assay. Preliminary results indicated a significant loss in mitochondrial function when exposed to beta‐amyloid. Cell damage and cellular toxicity were further analyzed by lactate dehydrogenase (LDH). Further, western blotting was done to determine the changes associated with biomarkers like P53 and Tau protein. Taking together the biochemical and molecular data the neuroprotective effect of estrogen on beta amyloid plaque formation will be analyzed.Support or Funding InformationAdelphi UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Female Sex Steroids Administration on Pathophysiologic Mechanisms in Traumatic Brain Injury.

Secondary brain damage following initial brain damage in traumatic brain injury (TBI) is a major cause of adverse outcomes. There are many gaps in TBI research and a lack of therapy to limit debilitating outcomes in TBI or enhance the neurogenesis, despite pre-clinical and clinical research performed in TBI. Females show harmful outcomes against brain damage including TBI less than males, independent of different TBI occurrence. A significant reduction in secondary brain damage and improvement in neurologic outcome post-TBI has been reported following the use of progesterone and estrogen in many experimental studies. Although useful features of sex steroids including progesterone have been identified in TBI clinical trials I and II, clinical trials III have been unsuccessful. This review article focuses on evidence of secondary injury mechanisms and neuroprotective effects of estrogen and progesterone in TBI. Understanding these mechanisms may enable researchers to achieve greater success in TBI clinical studies. It seems that the design of clinical studies should be revised due to translation loss of animal studies to clinical studies. The heterogeneous and complex nature of TBI, the endogenous levels of sex hormones at the time of taking these hormones, the therapeutic window of the drug, the dosage of the drug, the selection of appropriate targets in evaluation, the determination of responsive population, gender and age based on animal studies should be considered in the design of TBI human studies in future.

Role of estrogen and levodopa in 1-methyl-4-pheny-l-1, 2, 3, 6-tetrahydropyridine (mptp)-induced cognitive deficit in Parkinsonian ovariectomized mice model: A comparative study

Parkinson’s disease (PD) is one of the most common neurodegenerative disease found in the aging population. Currently, many studies are being conducted to find a suitable and effective cure for PD, with an emphasis on the use of herbal plants.In this study, the neuroprotective effects of estrogen was evaluated in the 1-methyl-4-phe-nyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD with cognitive deficit and compared to Levodopa (LD), a well reported neuroprotective agent used for treating PD. Twenty-four Swiss albino mice were randomly divided into four groups: Control, MPTP, MPTP+LD and MPTP+estrogen. The behavioral recovery in both LD and estrogen treated mice were investigated using the rotarod, foot printing, narrow beam walking test and hanging tests. Non-motor behavioral recovery in both LD and estrogen treated were investigated using the Y-maze and Morris water maze. Furthermore, we performed the biochemical test i.e. catalase, lipid and nitrite in prefrontal cortex as well as nigrostriatal region of mouse brain. We also performed the acetylcholine esterase activity in prefrontal cortex and nigrostriatal region of mice brain. The recovery of dopamine neurons in the substantia nigra (SN) region was estimated by immunostaining of tyrosine hydroxylase (TH).Estrogen treatment restored all the deficits induced by MPTP more effectively than levodopa. Estrogen treatment recovered the number of TH-positive cells in both the SN region. Treatment with Estrogen significantly increased the levels of catalase, decreased the level of lipid and nitite in both region SN as well as prefrontal cortex region. Notably, the effect of estrogen was greater than that elicited by levodopa. Acetylcholine esterase activity was significantly increased in MPTP and it was found to be decreased by the treatment of estrogen as well as levodopa, although decrease in the activity was highly significant in estrogen treated group.Our result suggested that estrogen treatment significantly reduced the MPTP induced neurotoxicity as evident by decrease in oxidative damage, physiological abnormalities and immunohistochemical changes in the Parkinsonian mouse with cognitive deficit as compared to levodopa treatment.

Alleviation of ischaemia-reperfusion injury by endogenous estrogen involves maintaining Bcl-2 expression via the ERα signalling pathway

The neuroprotective effects of estrogen against cerebral ischaemia have been confirmed by multiple basic and clinical studies. However, most of these studies used exogenous estrogen administered via different injection methods, and the neuroprotective effects of endogenous estrogen produced by ovaries during different phases of estrous cycle and the underlying mechanisms involved have rarely been explored. In this study, we first identified the stage of estrous cycle via vaginal smears and then measured serum estradiol levels at each phase via radioimmunoassay. We found that the estradiol level was highest in the proestrous and lowest in the diestrous. However, ovariectomy or treatment with the aromatase inhibitor letrozole significantly decreased estradiol levels compared to that of rats in diestrous. Western blotting showed that ovariectomy or letrozole treatment significantly decreased ERα and Bcl-2 protein expression and dramatically increased Bax protein expression compared with the rats in diestrous or proestrous. Rats also underwent 2h of ischaemia via middle cerebral artery occlusion followed by a 24-h reperfusion. Ovariectomy or letrozole treatment significantly decreased the neurological scores and the number of intact neurons detected via Nissl staining and dramatically increased the infarct volume detected via TTC staining and the extent of apoptosis detected via TUNEL staining and Western blotting for cleaved-caspase 3 protein expression. These results demonstrate that endogenous estrogen alleviates ischaemia-reperfusion injury by maintaining Bcl-2 expression via ERα signalling pathway and highlight the neuroprotective effects of endogenous estrogen during different stages of the estrous cycle, providing preliminary information on the underlying mechanism of this process.

Neuroprotective effects of estrogen in CNS injuries: insights from animal models.

Among the estrogens that are biosynthesized in the human body, 17β-estradiol (estradiol or E2) is the most common and the best estrogen for neuroprotection in animal models of the central nervous system (CNS) injuries such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic brain injury (IBI). These CNS injuries are not only serious health problems, but also enormous economic burden on the patients, their families, and the society at large. Studies from animal models of these CNS injuries provide insights into the multiple neuroprotective mechanisms of E2 and also suggest the possibility of translating the therapeutic efficacy of E2 in the treatment SCI, TBI, and IBI in humans in the near future. The pathophysiology of these injuries includes loss of motor function in the limbs, arms and their extremities, cognitive deficit, and many other serious consequences including life-threatening paralysis, infection, and even death. The potential application of E2 therapy to treat the CNS injuries may become a trend as the results are showing significant therapeutic benefits of E2 for neuroprotection when administered into the animal models of SCI, TBI, and IBI. This article describes the plausible mechanisms how E2 works with or without the involvement of estrogen receptors and provides an overview of the known neuroprotective effects of E2 in these three CNS injuries in different animal models. Because activation of estrogen receptors has profound implications in maintaining and also affecting normal physiology, there are notable impediments in translating E2 therapy to the clinics for neuroprotection in CNS injuries in humans. While E2 may not yet be the sole molecule for the treatment of CNS injuries due to the controversies surrounding it, the neuroprotective effects of its metabolite and derivative or combination of E2 with another therapeutic agent are showing significant impacts in animal models that can potentially shape the new treatment strategies for these CNS injuries in humans.

Outlook on the neuroprotective effect of estrogen.

Outlook on the neuroprotective effect of estrogen.

SELECTIVE ER-B ACTIVATION MITIGATES COGNITIVE IMPAIRMENT IN TYPE 2 DIABETIC OVARIECTOMIZED RATS

Type 2 diabetes mellitus is common in postmenopausal women and is a major risk factor for cognitive loss. Neuroprotective effects of estrogen appear to be absent in women with diabetes, may be due to, differential expression as well as activation of ER-α and β during disease conditions. This study attempts to characterize the specific estrogen receptor which could be selectively targeted to mitigate memory impairment in postmenopausal diabetic situation. Young female wistar rats aged 3-4 months (150-200g) were divided in nine groups (n=6-8). To induce postmenopausal diabetic stage, rats were bilaterally ovariectomized, and after 1 week of ovariectomy, HFD was given for 2 weeks, followed by a single injection of STZ (35 mg/kg/i.p.) and rats were continued on HFD diet for another 8 weeks. Rats were administered with 10 μg/kg/s.c. of a nonselective estrogen receptor agonist, 17-β estradiol (17βE2), selective ER-α agonist (4, 4’, 4’’-(4-propyl-[1H] pyrazole-1, 3, 5-triyl) tris phenol (PPT) and selective ER-β agonist, 2, 3-bis (4-hydroxyphenyl)-propionitrile (DPN) for eight weeks after STZ injection. Marked impairment in memory [increased transfer latency and pathlength (4 fold) and decreased time spent in target quadrant (3 fold)] coupled with a marked decrease in brain derived neurotrophic factors (BDNF) (3 fold) and increase in acetylcholinesterase activity (2.5 fold) were observed in ovariectomized type 2-diabetic rats as compared to sham rats. However, partial change in all these parameters were observed in ovariectomized or diabetic rats as compared to sham rats. Treatment with DPN and 17-βE2 markedly while PPT treatment partially prevented transfer latency, BDNF and acetylcholinesterase activity changes induced in ovariectomized diabetic rats. To assess feminizing action of all the agents, we also assessed serum estradiol levels and uterine weights. 17-βE2 reversed ovariectomy-induced decrease in serum estradiol levels and uterine weights but PPT and DPN treatment did not show any effect. Our data suggests that ER-β could be an important pharmacological target, to mimic the beneficial effect of estradiol in memory impairment, especially in postmenopausal diabetes.

Tamoxifen versus aromatase inhibitors for the adjuvant treatment of breast cancer in older women: A feasibility study to examine differences in cognitive outcomes.

TPS626Background: Tamoxifen (TAM) and aromatase inhibitors (AIs) are the mainstay endocrine therapies (ETs) for the treatment of hormone-receptor-positive (HR+) breast cancer (BC). While these ETs dramatically improve BC outcomes by reducing estrogen activity, increased awareness of the neuroprotective effects of estrogen on cognition has led to concerns regarding potential adverse cognitive effects. Cognitive concerns are heightened by the fact BC is more common among older women, who are already at greater risk of cognitive impairment (CI). While the anti-estrogen properties of TAM and AIs are unique, their differential effect on cognition remains unknown. Our overarching objective is to compare the cognitive effects of TAM and AIs in older women; however, before undertaking the large multicenter study needed to meet this goal, we are conducting a feasibility study to i) establish metrics on participation, retention, and ET adherence, and ii) inform sample size calculation for the future multicenter stu...

GPER1 mediates estrogen-induced neuroprotection against oxygen-glucose deprivation in the primary hippocampal neurons

It is well-known that the neuroprotective effects of estrogen have potential in the prevention and amelioration of ischemic and degenerative neurological disorders, while the underlying mechanisms for estrogen actions are undefined. As an important mediator for the non-genomic functions of estrogen, GPER1 (G Protein-coupled Estrogen Receptor 1) has been suggested to involve in the beneficial roles of estrogen in neural cells. Here our studies on primary hippocampal neurons have focused on GPER1 in an in vitro model of ischemia using oxygen-glucose deprivation (OGD). GPER1 expression in the primary hippocampal neurons was stimulated by the OGD treatments. Both E2 (estradiol) and E2-BSA (membrane impermeable estradiol by covalent conjugation of bovine serum albumin) attenuated OGD-induced cell death in primary cultures of hippocampal neurons. Importantly, this membrane-mediated estrogen function requires GPER1 protein. Knocking down of GPER1 diminished, while overexpression of GPER1 potentiated, the protective roles of E2/E2-BSA following OGD. Additionally, the downstream mechanisms employed by membrane-associated estrogen signaling were found to include PI3K/Akt-dependent Ask1 inhibition in the primary hippocampal neurons. Overall, these research results could enhance our understanding of the neuroprotective actions for estrogen, and provide a new therapeutic target for improving stroke outcome and ameliorating degenerative neurological diseases.