Donepezil Attenuates Obesity-Associated Oxidative Stress and Central Inflammation and Improves Memory Deficit in Mice Fed a High-Fat Diet.

BACKGROUND/AIMS: Obesity is associated with chronic inflammation and cognitive decline, and is considered a major risk factor for neurodegeneration. Meanwhile, neuroinflammation is important in the pathogenesis and progression of neurodegenerative diseases. METHODS: In this study, we tested the hypothesis that donepezil would attenuate central inflammation and oxidative damage and improve memory deficit in high-fat diet (HFD)-fed mice. After 16 weeks on a HFD, C57BL/6J mice were given either donepezil (3 mg/kg, i.p.) or saline for 4 weeks in parallel to a control diet (CD) group. Thereafter, the step-through test was used to assess learning and memory function. RESULTS: In the brain of HFD-fed mice, levels of the proinflammatory cytokines interleukin 16 and tumor necrosis factor α were reduced by donepezil treatment. Similarly, HFD-induced protein levels of advanced glycation end-products and oxidative stress in the brain were significantly decreased by donepezil treatment. CONCLUSION: Our results indicate that donepezil may reverse obesity-related central inflammation and oxidative damage and improve memory deficit in HFD-fed mice.

Copper(II)-catalyzed C5 and C7 halogenation of quinolines using sodium halides under mild conditions.

A simple and mild protocol for copper catalyzed halogenation of quinoline at C5 and C7 positions was developed, affording the desired remote C-H activation products in moderate to good yields. This reaction proceeds with low-cost sodium halides (NaX, X = Cl, Br, I) and features excellent substrate tolerance. A series of control experiments were carried out to illustrate a single-electron-transfer process which plays a vital role in the halogenation.

A prospective cohort study of prognosis for newly diagnosed epilepsy in east China.

BACKGROUND: Limited data are available on the outcome of antiepileptic drug treatment response in patients of Chinese Han ethnicity with newly diagnosed epilepsy. We sought to explore the prognosis with antiepileptic drug treatment and to identify the predictors of poor drug control of seizures in these patients. METHODS: For at least 2 years, we prospectively followed up a cohort of patients with newly diagnosed epilepsy and analyzed the response to each antiepileptic drug. Cumulative risk for seizure relapse after initial remission achieved was estimated. The patients were divided into two groups (poor and good control) and compared for clinical characteristics. RESULTS: A total of 180 patients were included. Early remission was reached in 125 (69.44%) patients, 19 (10.56%) patients entered late remission, while 36 (20%) patients failed to achieve remission. The relapse rates were 19.5% at 2 years and 31.9% at 3 years of the follow-up. The response rates of the first throughout the fourth treatment regimens were 60.0%, 16.1%, 2.8%, and 0.6%, respectively. Multiple seizure types and changes in seizure type during treatment were significantly (p = 0.013 and 0.047, respectively) associated with a poor control. CONCLUSIONS: The prognosis of the majority of patients with newly diagnosed epilepsy is good and the clinical pattern of epilepsy during treatment is complex. The chances of seizure control declines with each subsequent treatment regimen. The prognosis for patients with multiple seizure types and seizure type changes during treatment is unfavorable.

Curative Effect of Prebiotics/Probiotics-Assisted Ketogenic Diet on Children with Refractory Epilepsy.

Objective: The aim is to study the curative effect of prebiotics/probiotics-assisted ketogenic diet (KD) on children with refractory epilepsy. Methods: A retrospective analysis was performed on the clinical data of 80 children with refractory epilepsy treated in the hospital between December 2018 and December 2020. According to different treatment methods, they were divided into the KD group (36 cases, KD) and combination group (44 cases, prebiotics/probiotics assisted KD). All were followed up for 1 year. The curative effect, electroencephalogram findings, levels of neurotransmitters, quality of life scores, cognitive function (verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ)), and incidence of adverse reactions were compared between the two groups. Results: At the last follow-up, the effective rate of the combination group was higher than that of the KD group (95.45% vs 80.56%) (P < 0.05). After 1 year of treatment, video electroencephalogram findings in both groups were improved, and the response rate of the combination group was higher than that of the KD group (97.73% vs 83.33%) (P < 0.05). After 1 year of treatment, levels of VIQ and PIQ in both groups were increased, which were higher in the combination group than the KD group (P < 0.05). After 1 year of treatment, the level of 5-hydroxytryptamine (5-HT) in both groups was increased, which was higher in the combination group than the KD group (P < 0.05). After 1 year of treatment, quality of life scores in both groups were increased, which was higher in the combination group than the KD group (P < 0.05). The incidence of adverse reactions in the combination group was lower than that in the KD group (13.64% vs 36.11%) (P < 0.05). Conclusion: The curative effect of prebiotics/probiotics-assisted KD is better on children with refractory epilepsy, which can effectively improve electroencephalogram and quality of life, increase neurotransmitters and cognitive levels, with good safety.

Effects of brain IKKß gene silencing by small interfering RNA on P-glycoprotein expression and brain damage in the rat kainic acid-induced seizure model.

Multidrug resistance mediated by over-expression of P-glycoprotein (P-gp) in brain is an important mechanism accounting for the drug-therapy failure in epilepsy. Over-expression of P-gp in epilepsy rat brain may be regulated by inflammation and nuclear factor-kappa B (NF-κB) activation. Inhibitory κ B kinase subunit ß (IKKß) is an up-stream molecular controlling NF-κB activation. With the small interfering RNA (siRNA) technique and kainic acid (KA)-induced rat epileptic seizure model, the present study was aimed to further evaluate the role of NF-κB inhibition, via blocking IKKß gene transcription, in the epileptic brain P-gp over-expression, seizure susceptibility, and post-seizure brain damage. siRNA targeting IKKß was administered to rats via intracerebroventricular injection before seizure induction by KA microinjection; scrambled siRNA was used as control. Brain mRNA and protein levels of IKKß and P-gp were detected by RT-PCR and immunohistochemistry. NF-κB activity was measured by electrophoretic mobility shift assay. Latency to grade III or V seizure onset was recorded, brain damage was evaluated by neuronal cell counting and epileptiform activity was monitored by electroencephalography. IKKß siRNA pre-treatment inhibited NF-κB activation and abolished P-gp over-expression in KA-induced epileptic rat brain, accompanied by decreased seizure susceptibility. These findings suggested that epileptogenic-induced P-gp over-expression could be regulated by IKKß through the NF-κB pathway.

Predictors for relapse after antiepileptic drug withdrawal in seizure-free patients with epilepsy.

The objective of this study was to evaluate the timing of medication withdrawal and other clinical factors as potential predictors of seizure relapse after antiepileptic drug (AED) withdrawal in patients with epilepsy. A total of 99 patients who were seizure free for more than 2 years were recruited from the Neurology Clinics of Nanjing Brain Hospital between 2001 and 2009, and were followed prospectively for at least 2 years or until seizure relapse. Kaplan-Meier survival analysis was used for calculating recurrence rates. Univariate and multivariate analyses for recurrence risk factors were performed using the Cox proportional hazards model. Thirteen patients were excluded due to loss of follow-up or incomplete seizure records. Epileptiform electroencephalography (EEG) abnormality within the first year after AED withdrawal (hazard ratio [HR] = 4.810, 95% confidence interval [CI] = 2.220-10.420) was found on multivariate analysis to be a predictor of seizure recurrence. Early AED withdrawal after a seizure-free period of 2-3 years did not significantly increase the risk of recurrence (HR = 0.999, 95% CI = 0.969-1.029) as compared with delayed AED withdrawal (patients who were seizure-free for more than 3 years). AED can be withdrawn in patients who have been seizure-free for more than 2 years. As epileptiform EEG abnormality within the first year after AED withdrawal predicts seizure relapse, it is necessary to perform EEG for patients during the first year after AED withdrawal.

A meta-analysis of pro-inflammatory cytokines in the plasma of epileptic patients with recent seizure.

This review was to assess the concentration changing trends of various cytokines in plasma of epilepsy patients after recent seizure, as well as to assess the differences between temporal lobe epilepsy (TLE) and extra-TLE (XLE) patients. We performed a meta-analysis of studies measuring cytokine concentration in plasma of patients suffering from epilepsy after recent seizure, by searches of the English literature in Pubmed and Embase databases (to July 1st 2010) and a manual search of references. A random-effects model was used to do accumulative analysis for the included studies by RevMan 5.0 software. Eight studies were included and analyzed. We found the plasma concentrations of interleukin-6 (IL-6) within 72h after seizure were significantly increased in epileptic patients compared with control subjects (211 epilepsy patients vs. 564 controls, overall weighted mean difference 1.27pg/ml, 95% confidence interval 0.72-1.82, P<0.0001). There were no significant differences for IL-1 beta and, IL-1 receptor antagonist (IL-1RA) between the two groups. The concentration changes of IL-6 and IL-1RA were not significantly different between TLE patients and XLE patients. The result of this meta-analysis revealed significantly higher concentrations of the pro-inflammatory cytokines IL-6 in epileptic seizure patients compared with control subjects. Further rigorous studies are needed to clarify the precise role of cytokines in epilepsy.

Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats.

BACKGROUND: Ischemic postconditioning (IPOC), or relief of ischemia in a stuttered manner, has emerged as an innovative treatment strategy to reduce programmed cell death, attenuate ischemic injuries, and improve neurological outcomes. However, the mechanisms involved have not been completely elucidated. Recent studies indicate that autophagy is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. This study aims to determine the role of autophagy in IPOC-induced neuroprotection against focal cerebral ischemia in rats. METHODOLOGY/PRINCIPAL FINDINGS: A focal cerebral ischemic model with permanent middle cerebral artery (MCA) occlusion plus transient common carotid artery (CCA) occlusion was established. The autophagosomes and the expressions of LC3/Beclin 1/p62 were evaluated for their contribution to the activation of autophagy. We found that autophagy was markedly induced with the upregulation of LC3/Beclin 1 and downregulation of p62 in the penumbra at various time intervals following ischemia. IPOC, performed at the onset of reperfusion, reduced infarct size, mitigated brain edema, inhibited the induction of LC3/Beclin 1 and reversed the reduction of p62 simultaneously. Rapamycin, an inducer of autophagy, partially reversed all the aforementioned effects induced by IPOC. Conversely, autophagy inhibitor 3-methyladenine (3-MA) attenuated the ischemic insults, inhibited the activation of autophagy, and elevated the expression of anti-apoptotic protein Bcl-2, to an extent comparable to IPOC. CONCLUSIONS/SIGNIFICANCE: The present study suggests that inhibition of the autophagic pathway plays a key role in IPOC-induced neuroprotection against focal cerebral ischemia. Thus, pharmacological inhibition of autophagy may provide a novel therapeutic strategy for the treatment of stroke.