Effects of Dexamethasone on Remodeling of the Hippocampal Synaptic Filamentous Actin Cytoskeleton in a Model of Pilocarpine-induced Status Epilepticus.

The filamentous actin (F-actin) cytoskeleton is progressively damaged after status epilepticus (SE), which is related to delayed neuronal death, aberrant recurrent circuits and epileptogenesis. Glucocorticoids regulate dendritic spine remodeling by acting on glucocorticoid receptors and the dynamics of the F-actin cytoskeleton. Our previous study showed that administration of dexamethasone (DEX) in the latent period of the pilocarpine epileptic model reduces damage to the hippocampal filamentous actin cytoskeleton and the loss of hippocampal neurons and aids in maintaining the synaptic structures, but it is not sufficient to stop epileptogenesis. In this work, we focused on the role of glucocorticoids in regulating the hippocampal F-actin cytoskeleton during SE. We examined the abundance of synaptic F-actin, analyzed the hippocampal F-actin/G-actin (F/G) ratio and pCofilin, and evaluated the number of hippocampal neurons and pre/postsynaptic markers in pilocarpine-induced status epilepticus mice with or without administration of dexamethasone (DEX). We found that the latency of Stage 3 seizures increased, the mortality decreased, the damage to the synaptic F-actin cytoskeleton in the hippocampal subfields was significantly attenuated, and a greater number of postsynaptic structures were retained in the hippocampal subfields after treatment with DEX. These results indicate that treatment with dexamethasone stabilizes the synaptic F-actin cytoskeleton and reduces the damage to the brain due to SE. This approach is expected to be beneficial in alleviating delayed neuron damage and the process of epileptogenesis.

Role of the immunogenic and tolerogenic subsets of dendritic cells in multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disorder in the central nervous system (CNS) characterized by inflammation and demyelination as well as axonal and neuronal degeneration. So far effective therapies to reverse the disease are still lacking; most therapeutic drugs can only ameliorate the symptoms or reduce the frequency of relapse. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are key players in both mediating immune responses and inducing immune tolerance. Increasing evidence indicates that DCs contribute to the pathogenesis of MS and might provide an avenue for therapeutic intervention. Here, we summarize the immunogenic and tolerogenic roles of DCs in MS and review medicinal drugs that may affect functions of DCs and have been applied in clinic for MS treatment. We also describe potential therapeutic molecules that can target DCs by inducing anti-inflammatory cytokines and inhibiting proinflammatory cytokines in MS.

The association between oxcarbazepine-induced maculopapular eruption and HLA-B alleles in a northern Han Chinese population.

BACKGROUND: We investigated the association between oxcarbazepine (OXC)-induced maculopapular eruption (MPE) and HLA-B alleles in a northern Han Chinese population, and conducted an analysis of clinical risk factors for OXC-MPE. METHODS: Forty-two northern Han Chinese patients who had been treated with OXC in Changchun, China were genotyped. Among them were 14 cases with OXC-induced MPE; the remaining 28 were OXC-tolerant. The HLA-B allele frequencies of the normal control group were found in the Allele Frequency Net Database. Polymerase chain reaction-sequence specific primer( PCR-SSP )was used for HLA-B*1502 testing and direct sequencing for four-digit genotype determination. RESULTS: Four-digit allele sequencing showed that there was no statistically significant difference in the frequency of the HLA-B*1502 allele between the OXC-MPE and OXC-tolerant controls (3.6% versus 7.5%, OR = 0.38, 95% CI = 0.04-3.40, P = 0.65), as well as between OXC-MPE and normal controls (3.6% versus 2.4%, OR = 1.54, 95% CI = 0.20-11.73, P = 0.49). However, a significant difference in the frequency of HLA-B*3802 alleles was found between the MPE group and normal controls (10.7% versus 1.9%, OR = 6.329, 95% CI = 1.783-22.460, P = 0.018). There was no significant difference in terms of age, gender, or final OXC dose between the OXC-MPE and OXC-tolerant groups. CONCLUSIONS: There was no significant association between OXC-MPE and HLA-B*1502 in the northern Han Chinese population in our study. Instead, HLA-B*3802 was found to be a potential risk factor for OXC-MPE.

Association between epileptiform discharges and the sleep cycle in 200 epileptic patients.

OBJECTIVE: The poor sleep quality of epileptic patients may be partly due to the occurrence epileptiform discharges (EDs). We observed the number of interictal discharges in each sleep stage and explored the associations between EDs and sleep phases in epileptic patients. METHODS: Two hundred epileptic patients and 182 healthy volunteers were enrolled in the current study. For all subjects, video electroencephalography (EEG) monitoring and 24-hr night polysomnography were conducted to detect EDs and analyze the sleep structures. RESULTS: EDs were detected in 91% of epileptic patients with the most frequent cases from the temporal lobe. The EDs detected during waking, sleeping, or both waking and nonrapid eye movement (NREM) sleep stages 1-2 accounted for 7.1%, 19.2%, and 25.3% of the total patients, respectively. EDs were rare during NREM stages 3-4 with 1.1% of total patients mainly in the central-temporal lobe. The total sleep time and time spent in REM were similar between the epileptic patients and healthy volunteers. However, epileptic patients spent a significantly longer mean sleep time in NREM stages 1-2 (293.91 ± 27.57 min vs. 223.17 ±15.28; p = .000) and less in NREM stages 3-4 (50.11 ± 12.12 min vs. 133.96 ± 10.77; p = .000) than healthy volunteers. Furthermore, asymmetric sleep spindles and fragmentary sleep structure as well as high inversion frequency were found in 26.7% and 43.3% of epileptic patients, respectively. CONCLUSION: Combination of long-term video EEG with polysomnography is a useful method to analyze associations between EDs and the sleep-wake cycle. This strategy can also help identify the nature of sleep disorders in epileptic patients, which may improve the treatment efficacy.

Dexamethasone ameliorates the damage of hippocampal filamentous actin cytoskeleton but is not sufficient to cease epileptogenesis in pilocarpine induced epileptic mice.

Rogressive deconstruction of filament actin (F-actin) in hippocampal neurons in the epileptic brain have been associated with epileptogenesis. Previous clinical studies suggest that glucocorticoids treatment plays beneficial roles in refractory epilepsy. Glucocorticoids treatment affects dendritic spine morphology by regulating local glucocorticoid receptors and F-actin cytoskeleton dynamics. However, how glucocorticoids regulate epileptogenesis by controlling F-actin cytoskeleton is not clear yet. Here we study the function of glucocorticoids in epileptogenesis by examining F-actin abundance, hippocampal neuron number, and synaptic markers in pilocarpine-induced epileptic mice in the presence or absence of dexamethasone (DEX) treatment. We found that spontaneous seizure duration was significantly reduced; F-actin damage in hippocampal subfields was remarkably attenuated; loss of pyramidal cells was dramatically decreased; more intact synaptic structures indicated by pre- and postsynaptic markers were preserved in multiple hippocampal regions after DEX treatment. However, the number of ZNT3 positive particles in the molecular layer in the hippocampus of pilocarpine epileptic mice was not altered after DEX treatment. Although not sufficient to cease epileptogenesis, our results suggest that dexamethasone treatment ameliorates the damage of epileptic brain by stabilizing F-actin cytoskeleton in the pilocarpine epileptic mice.

Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer's disease rats.

As a part of Alzheimer's disease (AD) development the mammalian target of rapamycin (mTOR) has been reported to play a crucial role in regulating cognition and can be used as a neuronal marker. Neuro-inflammation is also a cause of the pathophysiological process in AD. Thus, we examined the protein expression levels of mTOR and its downstream pathways as well as pro-inflammatory cytokines (PICs) in the brain of AD rats. We further examined the effects of blocking mTOR on PICs, namely IL-1ß, IL-6 and TNF-α. Our results showed that the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1) and p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in the hippocampus of AD rats compared with controls. Blocking mTOR by using rapamycin selectively enhanced activities of IL-6 and TNF-α signaling pathways, which was accompanied with an increase of Caspase-3, indicating cellular apoptosis and worsened learning performance. In conclusion, our data for the first time revealed specific signaling pathways engaged in the development of AD, including a regulatory role by the activation of mTOR in PIC mechanisms. Stimulation of mTOR is likely to play a beneficial role in modulating neurological deficits in AD.Targeting one or more of these signaling molecules may present with new opportunities for treatment and clinical management of AD.

Deterioration of palatal myoclonus after acute thalamic hemorrhage.

BACKGROUND: Palatal myoclonus (PM) is the hallmark of hypertrophic olivary degeneration (HOD); however, little is known regarding the association of thalamic lesions and PM. Case presentation: Here, we report a case of deteriorative PM after an acute small ventrolateral thalamic hemorrhage in a female Chinese patient with HOD. The sudden and severe deterioration of PM was preceded by at least 10 days of an occasionally occurring PM, which was related to an acute cerebellar hemorrhage 8 months earlier. A computed tomography scan upon admission showed a small intracerebral hematoma in the left ventrolateral thalamus, and a magnetic resonance imaging scan revealed the typical signs of HOD as well as a remote lesion in the dentate nucleus. Symptoms of PM were controlled by carbamazepine and clonazepam. CONCLUSION: These findings indicated that the damaged dentatothalamic tract might be due to a unique pathogenic mechanism involving a lesion of the ventrolateral thalamus and Guillain-Mollaret triangle.

Successful treatment of paraquat poisoning by Xuebijing, an injection concocted from multiple Chinese medicinal herbs: a case report.

BACKGROUND AND OBJECTIVES: 1,1'-Dimethyl-4,4'-bipyridinium dichloride (Paraquat) poisoning remains a significant global health problem. Despite noteworthy research and clinical efforts worldwide in the last few decades, little improvement has been made in reducing fatality from Paraquat poisoning with conventional treatment strategies. We herein report a case of successful management of Paraquat poisoning by Xuebijing, a newly developed injection concocted from multiple traditional Chinese medicinal herbs. SETTINGS/LOCATION, SUBJECTS, AND INTERVENTIONS: A 25-year-old male patient was brought to the Emergency Department at the First Affiliated Hospital of Jilin University in Changchun, China approximately 23 hours after ingestion of approximately 50 mL of 20% (w/v) Paraquat in a suicide attempt. On admission, the patient presented with clinical symptoms as well as significantly abnormal results in the liver and kidney function tests that were typical of severe Paraquat poisoning. Following the routine emergency procedures for pesticide poisoning to minimize the poison exposure and relieve the poisoning symptoms, an intravenous drip of Xuebijing together with dexamethasone was given daily to the patient until discharge 10 days after admission. The patient was followed up for 15 months after discharge, during which monthly chest radiography was performed. Treatment outcomes: At the time of discharge, the patient had recovered well: His symptoms of poisoning in the mouth and gastrointestinal tract were all diminishing; his liver and kidney functions were recovering with the major test parameters improving; his chest radiograph was clear, showing no signs of pulmonary fibrosis. During the postdischarge follow-up period, the monthly chest radiographs were all normal. CONCLUSIONS: This case report suggests that Xuebijing has great potential as a novel effective alternative to the conventional management of Paraquat poisoning. This potential needs to be further evaluated in a substantially larger number of clinical cases in the future.