Impaired rich-club connectivity in childhood absence epilepsy.

Introduction: Childhood absence epilepsy (CAE) is a well-known pediatric epilepsy syndrome. Recent evidence has shown the presence of a disrupted structural brain network in CAE. However, little is known about the rich-club topology. This study aimed to explore the rich-club alterations in CAE and their association with clinical characteristics. Methods: Diffusion tensor imaging (DTI) datasets were acquired in a sample of 30 CAE patients and 31 healthy controls. A structural network was derived from DTI data for each participant using probabilistic tractography. Then, the rich-club organization was examined, and the network connections were divided into rich-club connections, feeder connections, and local connections. Results: Our results confirmed a less dense whole-brain structural network in CAE with lower network strength and global efficiency. In addition, the optimal organization of small-worldness was also damaged. A small number of highly connected and central brain regions were identified to form the rich-club organization in both patients and controls. However, patients exhibited a significantly reduced rich-club connectivity, while the other class of feeder and local connections was relatively spared. Moreover, the lower levels of rich-club connectivity strength were statistically correlated with disease duration. Discussion: Our reports suggest that CAE is characterized by abnormal connectivity concentrated to rich-club organizations and might contribute to understanding the pathophysiological mechanism of CAE.

Use of Diterpene Ginkgolides Meglumine Injection to Regulate Plasma Levels of PAI-1 and t-PA in Patients With Acute Atherosclerotic Cerebral Infarction.

BACKGROUND: To: (i) explore the effect of diterpene ginkgolides meglumine injection (DGMI) on neurological deficit symptoms in acute atherosclerotic cerebral infarction (AACI) patients; (ii) measure the level of plasma plasminogen activator inhibitor (PAI)-1 and tissue plasminogen activator (t-PA). METHODS: Eighty AACI patients were divided equally and randomly into the DGMI group and control group. In addition to basic treatment, the DGMI group was treated with DGMI (25 mg/d) for 14 days. The control group had basic treatment without DGMI. Before and after treatment, the degree of neurological deficit was assessed, thromboelastography undertaken, and plasma levels of PAI-1 and t-PA measured. RESULTS: The National Institutes of Health Stroke Scale score of patients in the DGMI group after treatment was lower than that in the control group, and the Barthel Index was higher than that in the control group ( P <0.05). Thromboelastography revealed that, in the DGMI group, the R value and K value after treatment were higher than before treatment, the angle and maximum amplitude value were lower than before treatment, and both were significant ( P <0.05). Compared with the control group, the plasma PAI-1 level of patients in the DGMI group was lower than that in the control group, and the t-PA level was higher than that in the control group ( P <0.05) after 14 days of treatment. CONCLUSIONS: DGMI may affect the activity of the blood coagulation and fibrinolysis system by regulating the plasma level of PAI-1 and t-PA, and improving neurological deficit symptoms. DGMI is important for improving the prognosis of patients with AACI.

Targeting the TLR4/NF-κB pathway in ß-amyloid-stimulated microglial cells: A possible mechanism that oxysophoridine exerts anti-oxidative and anti-inflammatory effects in an in vitro model of Alzheimer's disease.

ß-amyloid (Aß) accumulation is a major neuropathological characteristic of Alzheimer's disease (AD) and serves as an inflammatory stimulus for microglial cells. Oxysophoridine has multiple pharmacological effects, including anti-inflammatory and anti-oxidative activities. In view of this, the current study aimed to investigate the effects of oxysophoridine on Aß-induced activation of microglial BV-2 cells. Cell Counting Kit-8 assay showed that oxysophoridine concentration-dependently attenuated Aß-induced viability reduction of BV-2 cells. Aß stimulation reduced the activities of glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) and elevated malondialdehyde (MDA) content in BV-2 cells, but these effects were attenuated by oxysophoridine. Oxysophoridine abolished Aß-induced increase of mRNA expression, secretion, and protein expression of tumor necrosis factor-α (TNF-α) and interleukin 1ß (IL-1ß) in BV-2 cells. Additionally, western blot suggested that oxysophoridine inhibited Aß-induced activation of the toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) pathways in BV-2 cells. Inhibition of the TLR4/NF-κB pathway by TAK-242 enhanced the effects of oxysophoridine on Aß-induced viability reduction, oxidative stress, and inflammation in BV-2 cells. Taken together, oxysophoridine suppressed Aß-induced oxidative stress and inflammation in BV-2 cells by inhibition of the TLR4/NF-κB pathway.

Prognostic Value of Plasma Trimethylamine N-Oxide Levels in Patients with Acute Ischemic Stroke.

Trimethylamine N-oxide (TMAO) has emerged as a newly identified gut microbiota-dependent metabolite contributing to a variety of diseases, such as diabetes, atherosclerosis, and cardiovascular diseases. The aim of our study was to determine whether a relatively high TMAO level is associated with an increased risk of poor outcome in ischemic stroke patients. From June 2018 to December 2018, we prospectively recruited acute ischemic stroke patients diagnosed within 24 h of symptom onset. The plasma TMAO level was measured at admission for all patients. Functional outcome was evaluated at 3 months after the stroke using the modified Rankin Scale (mRS) and then dichotomized as favorable (mRS 0-2) or unfavorable (mRS 3-6). A multivariate logistic regression analysis was conducted to evaluate the association between TMAO concentration and poor functional outcome and mortality at 3 months. Of the 225 acute ischemic stroke patients included in the analysis, the median TMAO concentration was 3.8 µM (interquartile range, 1.9-4.8 µM). At 3 months after admission, poor functional outcome was observed in 116 patients (51.6%), and 51 patients had died (22.7%). After adjusting for potential confounders, patients with TMAO levels in the highest quartile were more likely to have higher risks of poor functional outcome [compared with the lowest quartile, odds ratio (OR) 3.63; 95% confidence interval (CI) 1.34-9.82; P = 0.011] and mortality (OR 4.27; 95% CI 1.07-17.07; P = 0.040). Our data suggest that a high plasma TMAO level upon admission may predict unfavorable clinical outcomes in acute ischemic stroke patients.

Role of plasminogen activator inhibitor-1 in the diagnosis and prognosis of patients with Parkinson's disease.

Parkinson's disease is a neurodegenerative disease that frequently results in memory disorders, cognitive decline and dementia. Previous studies have reported that plasminogen activator inhibitor-1 (PAI-1) serves an important role in cardiovascular disease risk, adiposity, insulin resistance and inflammation. However, the role of PAI-1 in diagnosis and prognosis of patients with Parkinson's disease following deep brain stimulation (DBS) has not reported, to the best of our knowledge. Therefore, the purpose of the present study was to investigate the clinical significance of PAI-1 in patients with Parkinson's disease. Plasma PAI-1 levels were measured in 102 patients with Parkinson's disease who underwent DBS. It was demonstrated that plasma PAI-1 levels were significantly increased in patients with Parkinson's disease compared with healthy individuals (P<0.01). Patients with Parkinson's disease received DBS presented significantly improved cognitive competence compared with controls (P<0.01). DBS significantly decreased plasma PAI-1 levels in patients with Parkinson's disease compared with controls (P<0.05). It was also observed that plasma PAI-1 levels were significantly negatively associated with cognitive function for patients with Parkinson's disease (P<0.01). In conclusion, these findings demonstrated that the degree of Parkinson's disease severity is positively associated with circulating levels of plasma PAI-1 levels, which suggests that PAI-1 may be a potential diagnostic and prognostic marker for patients with Parkinson's disease.

The protective effect of 2-(2-benzonfu-ranyl)-2-imidazoline against oxygen-glucose deprivation in cultured rat cortical astrocytes.

Astrocytes play a pivotal role in neuronal survival in the setting of post-ischemic brain inflammation, but the astrocyte-derived mediators of ischemic brain injury remain to be defined. 2-(2-Benzofu-ranyl)-2-imidazoline (2-BFI) is a newly discovered ligand for high-affinity imidazoline I2 receptors (I2Rs) mainly located on the mitochondrial outer membrane in astrocytes. We previously reported that in a rat model of cerebral ischemia-reperfusion injury, 2-BFI limits infarct volume, reduces neurological impairment scores, and inhibits neuronal apoptosis in the ischemic penumbra. This study was performed to clarify the underlying mechanism in an astrocyte oxygen-glucose deprivation (OGD) model. The results show that 2-BFI reduces lipid peroxidation and inhibits mitochondria apoptotic pathways.

2-(2-benzofuranyl)-2-imidazoline (2-BFI) improved the impairments in AD rat models by inhibiting oxidative stress, inflammation and apoptosis.

Alzheimer's Disease (AD) is one of the commonest neural degeneration in aging population, and has become a global health challenge. 2-(2-benzofuranyl)-2-imidazoline (2-BFI) was reported to effectively improved the damage of patients with neuropathological disorders. In the present study, we investigated the effect of 2-BFI on the improvement of antioxidative, inflammation, and apoptosis in AD rats. Sprague-Dawley rats (2 months old, n=40) were used in this study and after injection of Aß1-42 into hippocampal CA1 (Cornu Ammonis) region, the rats were given high, moderate and low dose of 2-BFI though intraperitoneal (i.p.) injection. Then spatial memory and navigation ability were analyzed by Morrize Water Maze. For the molecular testing, chemical colorimetry, ELISA and immunoblotting were performed to measure the activities of antioxidative enzymes, the abundance of immune cytokines and expression of apoptotic proteins, respectively. Hematoxylin and Eosin staining was used to analyze the pathological changes. We observed that 2-BFI significantly ameliorated the learning and memory abilities in rat models with AD by dosage treatment, as demonstrated by the shorten learning latency and greater times of travel across the platform quadrant. Additionally, reactive oxygen species (ROS) and malondialdehyde (MDA), were decreased after treatment of 2-BFI with dosage dependency, while the activities of superoxidase dismutase (SOD) and (GPX) Glutathione peroxidase were in turn enhanced, suggesting that 2-BFI could protect the antioxidative enzymes and reduce the oxidative stress in the hippocampus. Moreover, the expression of inflammatory factors including TNF-a and IL-1ß were decreased after 2-BFI treatment. Additionally, the neuronal apoptosis was also attenuated, as shown by Western blot results. Taken together, the cognitive impairment in AD rats could be significantly improved by 2-BFI in a dose-dependent manner through suppressing oxidants accumulation, inhibiting of inflammatory response, as well as enhancing the neural viability.

2-(-2-benzofuranyl)-2-imidazoline induces Bcl-2 expression and provides neuroprotection against transient cerebral ischemia in rats.

Stroke is the third leading cause of death and disability in North America and is becoming the most frequent cause of death in the rapid developing China. Protecting neurons in order to minimize brain damage represents an effective approach towards stroke therapeutics. Our recent study demonstrated that 2-(-2-benzofuranyl)-2-imidazoline (2-BFI), a ligand for imidazoline I(2) receptors, is potently neuroprotective against stroke, possibly through transiently antagonizing NMDA receptor activities. In this study, we further investigated the characteristics and mechanisms of 2-BFI-mediated neuroprotection using a rat stroke model of transient occlusion of the middle cerebral artery. Here, we show that 2-BFI was most effective at the dose of 3mg/kg in vivo, with significantly reduced brain infarct size and improved neurological deficits. Lower doses of 2-BFI at 1.5mg/kg, or higher dose of 2-BFI at 6 mg/kg, were either not effective, or toxic to the brain, respectively. Treating stroke rats with 3mg/kg 2-BFI significantly reduced the number of TUNEL positive cells and preserved the integrity of subcellular structures such as nuclear membranes and mitochondria as shown under the electron microscope, confirming neuroprotection. Most interestingly, 2-BFI-treated brains exhibited significant expression of Bcl-2, a gene with a known function in neuroprotection. Taken together, these studies not only demonstrated that 2-BFI at 3mg/kg was effective in neuroprotection, but also, for the first time, showed that 2-BFI provided neuroprotection through up-regulating the neuroprotective gene Bcl-2. 2-BFI can be further developed as a therapeutic drug for stroke treatment.