Ifenprodil Improves Long-Term Neurologic Deficits Through Antagonizing Glutamate-Induced Excitotoxicity After Experimental Subarachnoid Hemorrhage.

Excessive glutamate leading to excitotoxicity worsens brain damage after SAH and contributes to long-term neurological deficits. The drug ifenprodil is a non-competitive antagonist of GluN1-GluN2B N-methyl-d-aspartate (NMDA) receptor, which mediates excitotoxic damage in vitro and in vivo. Here, we show that cerebrospinal fluid (CSF) glutamate level within 48 h was significantly elevated in aSAH patients who later developed poor outcome. In rat SAH model, ifenprodil can improve long-term sensorimotor and spatial learning deficits. Ifenprodil attenuates experimental SAH-induced neuronal death of basal cortex and hippocampal CA1 area, cellular and mitochondrial Ca2+ overload of basal cortex, blood-brain barrier (BBB) damage, and cerebral edema of early brain injury. Using in vitro models, ifenprodil declines the high-concentration glutamate-mediated intracellular Ca2+ increase and cell apoptosis in primary cortical neurons, reduces the high-concentration glutamate-elevated endothelial permeability in human brain microvascular endothelial cell (HBMEC). Altogether, our results suggest ifenprodil improves long-term neurologic deficits through antagonizing glutamate-induced excitotoxicity.

Educational Attainment and Ischemic Stroke: A Mendelian Randomization Study.

Observational studies have evaluated the potential association of socioeconomic factors such as higher education with the risk of stroke but reported controversial findings. The objective of our study was to evaluate the potential causal association between higher education and the risk of stroke. Here, we performed a Mendelian randomization analysis to evaluate the potential association of educational attainment with ischemic stroke (IS) using large-scale GWAS datasets from the Social Science Genetic Association Consortium (SSGAC, 293,723 individuals), UK Biobank (111,349 individuals), and METASTROKE consortium (74,393 individuals). We selected three Mendelian randomization methods including inverse-variance-weighted meta-analysis (IVW), weighted median regression, and MR-Egger regression. IVW showed that each additional 3.6-year increase in years of schooling was significantly associated with a reduced IS risk (OR = 0.54, 95% CI: 0.41-0.71, and p = 1.16 × 10-5). Importantly, the estimates from weighted median (OR = 0.49, 95% CI: 0.33-0.73, and p = 1.00 × 10-3) and MR-Egger estimate (OR = 0.18, 95% CI: 0.06-0.60, and p = 5.00 × 10-3) were consistent with the IVW estimate in terms of direction and magnitude. In summary, we provide genetic evidence that high education could reduce IS risk.

Stroke and Alzheimer's Disease: A Mendelian Randomization Study.

Stroke and Alzheimer's disease (AD) are common neurological diseases. Several exiting studies indicated that late onset-AD and ischemic stroke have shared genetic links. Different kinds of stroke have different mechanisms. However, it remains unclear whether there is a causal relationship between different types of strokes, including any stroke (AS), any ischemic stroke (AIS), large-artery atherosclerotic stroke (LAS), and cardio-embolic stroke (CES), and AD. Herein, we conducted several Mendelian randomization (MR) studies to explore genetically causal link of different kinds of strokes and AD. The results for inverse-variance weighted (IVW) meta-analysis (ß = -0.039, OR = 0.9618, and P-value = 0.750) and weighted median regression (WMR) (ß = -0.156, OR = 0.8556, and P-value = 0.274) demonstrated that AS is not causally associated with AD risk. The result of MR-Egger regression (ß = -1.312, P-value = 0.098) and intercept term (P-value = 0.105) illustrated no pleiotropy in this MR study. According to the results for IVW (P-value = 0.305, ß = -0.103, and OR = 0.9021) and WMR (P-value = 0.487, ß = -0.092, and OR = 0.9121) in the MR study between AIS and AD, there is no causal association between AIS and AD risk. In addition, the MR-Egger regression (P-value = 0.290 and ß = -0.512) and intercept term (P-value = 0.387) showed no potential pleiotropy. LAS is not causally associated with AD risk according to the MR results (IVW: P-value = 0.568, ß = 0.037, and OR = 1.0377; WMR: P-value = 0.793, ß = -0.022, and OR = 0.9782). Additionally, the results of MR-Egger regression (P-value = 0.122 and ß = -1.220) and intercept term (P-value = 0.110) showed no potential pleiotropy. Our results [IVW: P-value = 0.245, ß = -0.064, and OR = 0.938; WMR: P-value = 0.331, ß = -0.057, and OR = 0.9446; MR-Egger: P-value = 0.673 and ß = -0.062, and intercept term (P-value = 0.985)] further demonstrated there is no causal link between CES and AD and no pleiotropy in this MR study. In conclusion, different types of stroke, including AS, AIS, LAS, and CES, would not be causally associated with AD risk.

Impact of Serum Calcium Levels on Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Altered calcium homeostasis is hypothesized to underlie Alzheimer's disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. OBJECTIVE: To develop effective therapies, we should establish the causal link between serum calcium levels and AD. METHODS: Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. RESULTS: IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35-0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. CONCLUSION: In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.