ABSTRACT
Background: The 4-hydroxysesamin (4-HS, a di-tetrahydrofuran lignin) is a modified sesamin that was prepared in the laboratory. This preclinical study was designed to preliminarily investigate the neuroprotective properties of 4-HS. Methods: In vitro, neuronal injury and inflammation were simulated by oxygen-glucose deprivation and lipopolysaccharide (LPS) exposure in mouse hippocampal neuronal HT22 cell line, and treated with 4-HS and/or metformin (MET, MAPK pathway activator for exploring mechanism). CCK-8, flow cytometry, and enzyme-linked immunosorbent assay were performed to evaluate cell viability, apoptosis, and inflammation. Apoptosis- and pathway-related proteins were detected by Western blotting. Middle cerebral artery occlusion (MCAO) was constructed as a stroke model and treated with 4-HS for in vivo confirmation. Histological staining was used for in vivo evaluation of 4-HS properties. Results: The 4-HS showed similar anti-inflammatory activity to sesamin but did not affect the cell viability of HT22 cells. In vitro, 4-HS improved the cell viability, ameliorated neuronal apoptosis, along with the reversion of apoptotic proteins (Bax, cleaved-caspase 3/9, Bcl-2) expression and inflammatory cytokines (IL-6, TNF-α, IL-10) in LPS-treated HT22 cells. The 4-HS suppressed the phosphorylation of ERK, JNK, and p38 but the addition of MET reversed 4-HS-induced changes of phenotype and protein expression in LPS-treated cells. In vivo, 4-HS showed apparent improvement in cerebral infarction, brain tissue morphology, neuronal architecture, apoptosis, and inflammation of MCAO mice, and also showed inhibiting effects on the phosphorylation of ERK, JNK, and p38, confirming in vivo results. Conclusion: In this first pre-clinical study on 4-HS, we preliminarily demonstrated the neuroprotective properties of 4-HS both in cell and animal models, and proposed that the underlying mechanism might be associated with the MAPK pathway.
ABSTRACT
OBJECTIVE: To explore effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with restless legs syndrome (RLS). METHODS: In total, 18 patients with primary RLS were divided into rTMS group and sham stimulation group. The rTMS treatment group received 15-Hz high-frequency rTMS to stimulate the leg motor representative area of the frontal cortex for 14 days, and the sham stimulation group received 15 Hz high-frequency rTMS sham stimulation in primary motor cortex for 14 days. RESULTS: After rTMS, RLS severity scale score, Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Scale (HAMA), as well as Hamilton Depression Rating Scale 24 (HAMD24) in rTMS treatment group were significantly lower than before treatment; 1 month and 2 months after treatment, the score remained at low level. Meanwhile, no significant changes have been observed in the aforementioned index before rTMS stimulation for the sham stimulation group after 14 days or after 1 month and 2 months. In addition, the results of correlation analysis suggested for all the 18 patients with RLS, there was a positive correlation between PSQI score and HAMA as well as HAMD24 scores before and after rTMS stimulation. In addition, the RLS severity score was also positively correlated with PSQI, HAMA, and HAMD24 scores. CONCLUSIONS: High-frequency rTMS stimulation reduces the frequency and severity of RLS; improves the quality of sleep, anxiety, as well as depression of the patients; and the curative effect can be sustained for 2 months. High-frequency rTMS may be used as an alternative treatment option for improving the quality of life of patients with RLS.
Subject(s)
Restless Legs Syndrome , Transcranial Magnetic Stimulation , Humans , Restless Legs Syndrome/therapy , Pilot Projects , Male , Female , Transcranial Magnetic Stimulation/methods , Middle Aged , Treatment Outcome , Adult , Aged , Motor Cortex/physiopathology , Severity of Illness IndexABSTRACT
Epilepsy (EP) is a complex brain disorder showing a lot of unknows reasons. Recent studies showed that gut microbiota can influence epilepsy via the brain-gut axis. Nevertheless, the mechanism by which gut microbiota affects adult epilepsy still remains unclear. In this study, fecal and serum samples were obtained from patients with epilepsy and normal controls. Using an integrated analysis, sequencing was performed by macrogenomics and high-throughput targeted metabolomics with various bioinformatics approaches. The macrogenomic sequencing revealed significant changes in microbial structure in patients suffering from epilepsy. For example, at the phylum level, the relative abundance of Actinobacteria, Bacteroidetes and Proteobacteria showed an increase in the patients with epilepsy, whereas that of Firmicutes decreased. In addition, the patients with epilepsy had significantly differential metabolite profiles compared to normal controls, and five clusters with 21 metabolites, mainly containing the upregulation of some fatty acids and downregulation of some amino acids. Tryptophan (AUC = 91.81, p < 0.0001), kynurenine (AUC = 79.09, p < 0.01) and 7Z,10Z,13Z,16Z-Docosatetraenoic acid (AUC = 80.95, p < 0.01) may be used as potential diagnostic markers for epilepsy. Differential serum metabolites have effects on tryptophan metabolism, iron death and other pathways. Furthermore, a multiomic joint analysis observed a statistically significant correlation between the differential flora and the differential serum metabolites. In our findings, a macrogenomic analysis revealed the presence of dysregulated intestinal flora species and function in adult epileptic patients. Deeper metabolomic analyses revealed differences in serum metabolites between patients with epilepsy and healthy populations. Meanwhile, the multiomic combination showed connection between the gut microbes and circulating metabolites in the EP patients, which may be potential therapeutic targets.
ABSTRACT
OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSDs) are blindness-causing neuritis; their pathogenesis is still not fully elucidated. Although it has been determined that Bruton tyrosine kinase (BTK) and NF-κB are associated with NMOSD, the changes that occur in different periods remain unknown. The study aimed to demonstrate the changes in the BTK/NF-κB pathway and related chemokines in different stages of NMOSDs. METHODS: A total of 32 patients with NMOSD were selected as the experimental group, and 32 healthy volunteers were included in the control group. In this study, the BTK/NF-κB pathway and related chemokines in the cerebrospinal fluid and peripheral blood samples of patients with NMOSD were analyzed in the acute or remission phase. RESULTS: BTK, NF-κB, PI3K, IKK, CXCL2, and CXCL12 levels in the NMOSD group in the acute or remission phase were significantly higher than those in the control group (p < 0.05). CONCLUSION: The BTK/NF-κB pathway plays a vital role in the progression of NMOSD pathology. Our results shed light on its important role as a therapeutic target for NMOSD.
Subject(s)
Neuromyelitis Optica , Agammaglobulinaemia Tyrosine Kinase , Cytokines , Humans , NF-kappa B , Neuromyelitis Optica/cerebrospinal fluid , Signal TransductionABSTRACT
BACKGROUND: For the past 20 years, many hypertension guidelines have strongly recommended the practical use of ambulatory blood pressure monitoring (ABPM) to the diagnosis and management of hypertension. However, whether different sleep conditions during ABPM will affect blood pressure (BP) fluctuations and lead to inaccurate measurement results is a concern of clinicians. METHOD: This was a prospective cohort study in the real-world setting. The participants were recruited between June 2018 and June 2019 in Hebei Province, China. There are three types of sleep during ABPM: undisturbed sleep, disturbed sleep and severely disturbed sleep. The people were divided into three groups according to their sleep types during ABPM. The primary outcome is 24-h mean BP, circadian rhythm of BP and variation coefficient of 24-h BP. Comparisons between groups are tested by Kruskal-Wallis H test. RESULTS: In total 1154 people completed the study. There was no significant difference in 24-h mean BP and circadian rhythm of BP among the three groups. There are statistically significant differences among the three groups in the variation coefficient of 24-h BP for the general population and noninsomnia population. There was no significant difference in mean BP, circadian rhythm of BP and variation coefficient of BP among the three groups for the insomnia people. CONCLUSION: Regardless of the insomniac or noninsomniac population, sleep conditions during ABPM do not affect BP value and BP rhythm. For noninsomniac people, the sleep situation during ABPM may affect the BP variation coefficient.
Subject(s)
Hypertension , Sleep Initiation and Maintenance Disorders , Blood Pressure/physiology , Blood Pressure Monitoring, Ambulatory/methods , Circadian Rhythm/physiology , Humans , Hypertension/diagnosis , Prospective Studies , SleepABSTRACT
Oxidative stress plays an important role in the neuronal damage induced by epilepsy. The present study assessed the possible neuroprotective effects of astaxanthin (ATX) on neuronal damage, in hippocampal CA3 neurons following amygdala kindling. Male Sprague-Dawley rats were chronically kindled in the amygdala and ATX or equal volume of vehicle was given by intraperitoneally. Twenty-four hours after the last stimulation, the rats were sacrificed by decapitation. Histopathological changes and the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and reduced glutathione (GSH) were measured, cytosolic cytochrome c (CytC) and caspase-3 activities in the hippocampus were also recorded. We found extensive neuronal damage in the CA3 region in the kindling group, which was preceded by increases of ROS level and MDA concentration and was followed by caspase-3 activation and an increase in cytosolic CytC. Treatment with ATX markedly attenuated the neuronal damage. In addition, ATX significantly decreased ROS and MDA concentrations and increased GSH levels. Moreover, ATX suppressed the translation of CytC release and caspase-3 activation in hippocampus. Together, these results suggest that ATX protects against neuronal loss due to epilepsy in the rat hippocampus by attenuating oxidative damage, lipid peroxidation and inhibiting the mitochondrion-related apoptotic pathway.
Subject(s)
Hippocampus/drug effects , Kindling, Neurologic/drug effects , Neurons/drug effects , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Animals , Caspase 3/metabolism , Cytochromes c/metabolism , Enzyme Activation , Hippocampus/cytology , Hippocampus/metabolism , Male , Neurons/cytology , Protein Transport , Rats, Sprague-Dawley , Xanthophylls/pharmacologyABSTRACT
Maternal seizure has adverse effects on brain histology as well as on learning and memory ability in progeny. An enriched environment (EE) is known to promote structural changes in the brain and improve cognitive and motor deficits following a variety of brain injuries. Whether EE treatment in early postnatal periods could restore cognitive impairment induced by prenatal maternal seizure is unknown. Adult female Sprague-Dawley rats were randomly separated into two groups and were injected intraperitoneally either saline or pentylenetetrazol (PTZ) for 30 days. Then the fully kindled rats and control animals were allowed to mate. PTZ administration was continued until delivery, while the control group received saline at the same time. After weaning at postnatal day 22, one-half of the male offspring in the control and in the prenatal maternal group were given the environmental enrichment treatment through all the experiments until they were tested. Morris water maze testing was performed at 8 weeks of age. Western blot and synaptic ultrastructure analysis were then performed. We found that EE treatment reversed spatial learning deficits induced by prenatal maternal seizure. An EE also reversed the changes in synaptic ultrastructure following prenatal maternal seizure. In addition, prenatal maternal seizure significantly decreased phosphorylation states of cAMP response element binding (CREB) in the hippocampus, whereas EE reversed this reduced expression. These findings suggest that EE treatment on early postnatal periods could be a potential therapy for improving cognitive deficits induced by prenatal maternal seizure.
Subject(s)
Cognition Disorders/etiology , Cognition Disorders/therapy , Environment , Epilepsy/physiopathology , Prenatal Exposure Delayed Effects/physiopathology , Animals , Animals, Newborn , Brain-Derived Neurotrophic Factor/metabolism , CREB-Binding Protein/metabolism , Cell Count , Cognition Disorders/pathology , Convulsants/toxicity , Epilepsy/chemically induced , Epilepsy/mortality , Epilepsy/pathology , Female , Hippocampus/pathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Male , Maze Learning/physiology , Microscopy, Electron, Transmission , Pentylenetetrazole/toxicity , Pregnancy , Random Allocation , Rats , Rats, Sprague-Dawley , Synapses/drug effects , Synapses/pathology , Synapses/ultrastructure , Time FactorsABSTRACT
Cognitive dysfunction is commonly observed in epileptic patients. It has been shown that not only epilepsy but also antiepileptic drugs could induce cognitive impairment. Thus, there is an urgent need for drugs that can suppress seizures without causing cognitive deficit. Recent studies have shown that oxidative stress is involved in the pathophysiology of epilepsy, and many antioxidants have an antiepileptic property. Epigallocatechin-3-gallate (EGCG), a catechin polyphenols component, is found to be an effective antioxidant. The purpose of this study was to assess the effect of EGCG against seizures, seizure-induced oxidative stress and cognitive impairment in pentylenetetrazole-induced kindling. Male Sprague-Dawley rats were injected intraperitoneally with a dose of 35 mg/kg of pentylenetetrazole (PTZ) once every alternate day for 13 injections. EGCG was administered daily in two doses (25mg/kg and 50mg/kg) intraperitoneally along with alternate-day PTZ. Morris water maze test was carried out 24h after the last injection of PTZ, and the oxidative stress parameters (malondialdehyde and glutathione) were assessed after the completion of the behavioral test. The results showed that EGCG dose-dependently suppressed the progression of kindling. EGCG also ameliorated the cognitive impairment and oxidative stress induced by PTZ kindling. These observations suggest that EGCG may be a potential agent for the treatment of epilepsy as well as a preventive agent against cognitive impairment induced by seizure.