c Impairment of astrocytic glutamate transporter (GLT-1; EAAT2) function is associated with multiple neurodegenerative diseases, including Parkinson's disease (PD) and manganism, the latter being induced by chronic exposure to high levels of manganese (Mn). Mn decreases EAAT2 promoter activity and mRNA and protein levels, but the molecular mechanism of Mn-induced EAAT2 repression at the transcriptional level has yet to be elucidated. We reveal that transcription factor Yin Yang 1 (YY1) is critical in repressing EAAT2 and mediates the effects of negative regulators, such as Mn and tumor necrosis factor alpha (TNF-␣), on EAAT2. YY1 overexpression in astrocytes reduced EAAT2 promoter activity, while YY1 knockdown or mutation of the YY1 consensus site of the EAAT2 promoter increased its promoter activity and attenuated the Mn-induced repression of EAAT2. Mn increased YY1 promoter activity and mRNA and protein levels via NF-B activation. This led to increased YY1 binding to the EAAT2 promoter region. Epigenetically, histone deacetylase (HDAC) classes I and II served as corepressors of YY1, and, accordingly, HDAC inhibitors increased EAAT2 promoter activity and reversed the Mn-induced repression of EAAT2 promoter activity. Taken together, our findings suggest that YY1, with HDACs as corepressors, is a critical negative transcriptional regulator of EAAT2 and mediates Mn-induced EAAT2 repression.

The G protein-coupled estrogen receptor GPR30 contributes to the neuroprotective effects of 17β-estradiol (E2); however, the mechanisms associated with this protection have yet to be elucidated. Given that E2 increases astrocytic expression of glutamate transporter-1 (GLT-1), which would prevent excitotoxic-induced neuronal death, we proposed that GPR30 mediates E2 action on GLT-1 expression. To investigate this hypothesis, we examined the effects of G1, a selective agonist of GPR30, and GPR30 siRNA on astrocytic GLT-1 expression, as well as glutamate uptake in rat primary astrocytes, and explored potential signaling pathways linking GPR30 to GLT-1. G1 increased GLT-1 protein and mRNA levels, subject to regulation by both MAPK and PI3K signaling. Inhibition of TGF-α receptor suppressed the G1-induced increase in GLT-1 expression. Silencing GPR30 reduced the expression of both GLT-1 and TGF-α and abrogated the G1-induced increase in GLT-1 expression. Moreover, the G1-induced increase in GLT-1 protein expression was abolished by a protein kinase A inhibitor and an NF-κB inhibitor. G1 also enhanced cAMP response element-binding protein (CREB), as well as both NF-κB p50 and NF-κB p65 binding to the GLT-1 promoter. Finally, to model dysfunction of glutamate transporters, manganese was used, and G1 was found to attenuate manganese-induced impairment in GLT-1 protein expression and glutamate uptake. Taken together, the present data demonstrate that activation of GPR30 increases GLT-1 expression via multiple pathways, suggesting that GPR30 is worthwhile as a potential target to be explored for developing therapeutics of excitotoxic neuronal injury.

Background: Tamoxifen (TX), a selective estrogen receptor modulator, enhances glutamate transporter (GLT-1) expression in astrocytes. Results: TX up-regulated GLT-1 expression via the CREB and NF-B pathways. Conclusion: TX enhanced GLT-1 expression at the transcriptional level. Significance: Understanding the mechanisms of TX action on GLT-1 will contribute to the development of neuroprotectants against excitotoxicity.

No abstract

Background To maintain cerebral blood flow (CBF), cerebral blood vessels dilate and contract in response to blood supply through cerebrovascular reactivity (CR). Purpose Cardiovascular (CV) disease is associated with increased stroke risk, but which risk factors specifically impact CR is unknown. Study Type Prospective longitudinal. Subjects Fifty‐three subjects undergoing carotid endarterectomy or stenting. Field Strength/Sequence 3T, 3D pseudo‐continuous arterial spin labeling (PCASL) ASL, and T1 3D fast spoiled gradient echo (FSPGR). Assessment We evaluated group differences in CBF changes for multiple cardiovascular risk factors in patients undergoing carotid revascularization surgery. Statistical Tests PRE (baseline), POST (48‐hour postop), and 6MO (6 months postop) whole‐brain CBF measurements, as 129 CBF maps from 53 subjects were modeled as within‐subject analysis of variance (ANOVA). To identify CV risk factors associated with CBF change, the CBF change from PRE to POST, POST to 6MO, and PRE to 6MO were modeled as multiple linear regression with each CV risk factor as an independent variable. Statistical models were performed controlling for age on a voxel‐by‐voxel basis using SPM8. Significant clusters were reported if familywise error (FWE)‐corrected cluster‐level was P < 0.05, while the voxel‐level significance threshold was set for P < 0.001. Results The entire group showed significant (cluster‐level P < 0.001) CBF increase from PRE to POST, decrease from POST to 6MO, and no significant difference (all voxels with P > 0.001) from PRE to 6MO. Of multiple CV risk factors evaluated, only elevated systolic blood pressure (SBP, P = 0.001), chronic renal insufficiency (CRI, P = 0.026), and history of prior stroke (CVA, P < 0.001) predicted lower increases in CBF PRE to POST. Over POST to 6MO, obesity predicted lower (P > 0.001) and cholesterol greater CBF decrease (P > 0.001). Data Conclusion The CV risk factors of higher SBP, CRI, CVA, BMI, and cholesterol may indicate altered CR, and may warrant different stroke risk mitigation and special consideration for CBF change evaluation. Level of Evidence: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;51:734–747.

No abstract

Empathy of the caregiver can influence both the caregiver’s performance and the receiver’s enhanced life. The aim of this study is to examine whether Simulation-based Empathy Enhancement program for the Carer of the Elderly (SEE-C) is effective in increasing care receivers’ session satisfaction and positive emotional change. We developed SEE-C by modifying the Dementia Live(TM) program and adding with a brief mindfulness. The effect on counselling was assessed using the Session Evaluation Questionnaire (SEQ), which is self-report tool asking the client about their experience with the session just ended. A total of 100 older adults living alone were interviewed by caregivers who experienced SEE-C (n=12) and by non-experienced (n=12). Participants in this study were randomly assigned to each of the two caregiver groups, and were interviewed about demographics, health and emotional status, and lifestyle using the same protocols. Analysis of covariance was conducted, controlling variables of age of subjects and caregivers’ months of career, which were found to differ significantly between the two groups. Among the four subcategories of SEQ, the experimental group reported significantly higher scores than the control group in three subcategories of session-depth (F(1, 96)=9.647, P=.002), session-smoothness (F(1, 96)=13.699, p<.001), emotion-positive (F(1, 96)=18.056, p<.001), with the exception of emotion-alertness (F(1, 96)=0.366, p=.546). These results suggest that SEE-C could have a positive impact on interviewing the elderly in terms of improving the capacity of the interviewer and raising the satisfaction of the interviewee.

No abstract