Xin Tian

The efficacy and safety of brivaracetam at different doses for partial-onset epilepsy: a meta-analysis of placebo-controlled studies.

Objective: This meta-analysis systematically assessed the efficacy and safety of different doses of brivaracetam (BRV) compared with placebo as adjunctive therapy for adults with partial-onset epilepsy. Methods: Electronic and clinical trials databases were searched for randomized controlled trials of BRV published up to May 2015. We assessed the risk of bias of the included studies using the Cochrane Risk of Bias tool. The outcomes of interest included 50% responder rates, seizure freedom, the incidence of withdrawal and treatment-emergent adverse events (TEAEs). Results: Five trials met the inclusion criteria. Compared with placebo, 20, 50, 100 and 150 mg/day BRV was associated with significantly higher 50% responder rates. In addition, the effect of 50 mg BRV on seizure freedom was significantly different than that of placebo. Both fatigue and nasopharyngitis were significantly associated with 20 mg BRV, whereas fatigue and irritability were associated with 50 mg BRV. Somnolence was associated with 150 mg BRV. No significant differences were observed for the other common TEAEs. Conclusion: The use of BRV at doses > 5 mg/day resulted in statistically significant reduction in seizure frequency in respect to the 50% responder rate. BRV was reasonably tolerated by patients. These findings warrant confirmation in future studies.

Risk factors for lung infection in stroke patients: a meta-analysis of observational studies.

Background: The aims of this meta-analysis were to evaluate the risk factors associated with lung infections in stroke patients and to provide evidence for prevention decisions. Methods: We searched the Embase, PubMed, EBSCO and Web of Science databases to collect studies from January 2000 to July 2015. Results: The meta-analysis identified 23 risk factors for lung infections in stroke patients, and the top 5, ranked by order according to odds ratio values (95% confidence interval), were as follows: multiple vertebrobasilar stroke, 22.99 (4.04, 130.83); National Institutes of Health Stroke Scale score >15 points, 14.63 (8.54, 25.08); mechanical ventilation, 10.20 (7.15, 14.57); nasogastric tube use, 9.87 (6.21, 15.70); and dysphagia, 7.50 (2.60, 21.65). Conclusion: Preventive measures should be taken against these risk factors to reduce the incidence of lung infection.

Adverse Effects of Immunoglobulin Therapy

Immunoglobulin has been widely used in a variety of diseases, including primary and secondary immunodeficiency diseases, neuromuscular diseases, and Kawasaki disease. Although a large number of clinical trials have demonstrated that immunoglobulin is effective and well tolerated, various adverse effects have been reported. The majority of these events, such as flushing, headache, malaise, fever, chills, fatigue and lethargy, are transient and mild. However, some rare side effects, including renal impairment, thrombosis, arrhythmia, aseptic meningitis, hemolytic anemia, and transfusion-related acute lung injury (TRALI), are serious. These adverse effects are associated with specific immunoglobulin preparations and individual differences. Performing an early assessment of risk factors, infusing at a slow rate, premedicating, and switching from intravenous immunoglobulin (IVIG) to subcutaneous immunoglobulin (SCIG) can minimize these adverse effects. Adverse effects are rarely disabling or fatal, treatment mainly involves supportive measures, and the majority of affected patients have a good prognosis.

A novel scoring system to predict the outcomes of adult patients with hypoxic-ischemic encephalopathy

ABSTRACT Background: Adult patients with hypoxic-ischemic encephalopathy (HIE) often incur large costs, but their outcomes are poor. Currently, there is lack of a comprehensive quantitative approach to predict patient prognoses. Methods: A total of 73 adult patients with HIE participated in this prospective, observational study. Clinical assessments, laboratory tests, and electrophysiological examinations were conducted within 3 days after HIE occurred. Logistic regression model was used to identify independent factors associated with patient outcomes. Results: After a 6-month follow-up, 44 (61.1%) patients survived, 28 (38.9%) patients died, and one patient was lost to follow-up. The level of blood calcium and lactate, the presence of electroencephalography reactivity, and Glasgow Coma Scale (GCS) score were significantly associated with the patient’s outcome. Based on the regression coefficients from logistic regression analysis, we constructed a scoring system (CEGL; C: calcium, E: EEG reactivity, G: GCS, L: lactate) to predict the possibility of a patient’s death. The area under the receiver operating characteristic curve was 0.91 (P < 0.001, 95% CI [0.87–0.95]) with a specificity of 97.7% and a positive predictive value of 97.4%. Conclusion: CEGL score can provide clinicians useful information for assessment of patient prognosis within 6 months after HIE.

CNTNAP4 Impacts Epilepsy Through GABAA Receptors Regulation: Evidence From Temporal Lobe Epilepsy Patients and Mouse Models

Abstract Epilepsy is a serious neurological condition characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Here, we demonstrated that the expression of contactin‐associated protein‐like 4 (CNTNAP4) was decreased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. Lentivirus‐mediated knock‐down of CNTNAP4 in the hippocampus increased mice susceptibility to epilepsy. Conversely, lentivirus‐mediated overexpression of CNTNAP4 decreased epileptic behavior in mice. CNTNAP4 affected neuronal excitability and inhibitory synaptic transmission via postsynaptic receptors in Mg2+‐free epilepsy cell model. Down‐regulation or overexpression of CNTNAP4 in the hippocampus influenced the expression of gamma‐aminobutyric acid A receptor &bgr;2/3 (GABAAR&bgr;2/3) membrane protein, without affecting total GABAAR&bgr;2/3 protein concentration in epileptic mice. Protein interactions between CNTNAP4, GABAAR&bgr;2/3 and gamma‐aminobutyric acid receptor‐associated protein (GABARAP) were observed in the hippocampus of epileptic mice. These findings suggest CNTNAP4 may be involved in the occurrence and development of epilepsy through the regulation of GABAAR function, and may be a promising target for the development of epilepsy treatment.

Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1

Background/Aims: The imbalance between excitation and inhibition is a defining feature of epilepsy. GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII, a cGMP-dependent protein kinase, regulates the GluA1 levels at the plasma membrane. Methods: To explore the role of cGKII in epilepsy, we investigated the expression of cGKII in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model and then performed behavioral, histological, and electrophysiological analyses by applying either a cGKII agonist or inhibitor in the hippocampus of the animal model. Results: cGKII expression was upregulated in the epileptogenic brain tissues of both humans and rats. Pharmacological activation or inhibition of cGKII induced changes in epileptic behaviors in vivo and epileptic discharges in vitro. Further studies indicated that cGKII activation disrupted the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulated epileptic seizures by phosphorylating GluA1 at Ser845 to modulate the expression and function of GluA1 in the postsynaptic membrane. Conclusion: These results suggest that cGKII plays a key role in seizure activity and could be a potential therapeutic target for epilepsy.

POSH participates in epileptogenesis by increasing the surface expression of the NMDA receptor: a promising therapeutic target for epilepsy.

ABSTRACT Objectives: Plenty of SH3 (POSH) was originally found to be a key regulator of neuronal apoptosis, axon outgrowth, and neuronal migration. However, the role of POSH in epilepsy has not been reported. Methods: We investigated the expression of POSH in patients with intractable temporal epilepsy (TLE) and in a kainic acid (KA)-induced mouse model, and then we performed behavioral, electrophysiological and biochemical analyses after the lentivirus (LV)-mediated knockdown or overexpression of POSH in the KA-induced model. Results: POSH overexpression shortened the latency of seizure onset, increased the frequency of spontaneous recurrent seizures, and increased the frequency of electrical epileptic discharges, while POSH knockdown had contrasting effects. Whole-cell patch-clamp recordings confirmed that POSH overexpression and knockdown were associated with increased and decreased miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents, respectively. Finally, co-immunoprecipitation showed that POSH and NMDA receptor subunit 1 (NMDAR1) precipitated with each other, and western blot analysis revealed that the surface expression of NMDAR1 was altered in the hippocampus of epileptic mice. Conclusion: These results show that POSH plays a critical role in the progression of epileptic seizures via NMDAR trafficking and suggest that the protein is a novel target for the treatment of human epilepsy.

FRMPD2: a novel GluN2A-interacting scaffold protein in synaptic excitatory transmission

The scaffold proteins FRMPD2 is localized at the basolateral membranes of polarized epithelial cells and associated with tight junction formation. But the expression and function of FRMPD2 in vivo remain unknown. Here, we found that postsynaptic FRMPD2 effectively alters the neuronal excitability by regulating NMDARs-component excitatory synaptic transmission in adult hippocampus. FRMPD2 anchors the NMDAR subunit GluN2A at the synapses without changing the total NMDAR expression. By using of Co-IP, Pull Down and SPR, the second PDZ (PDZ2) domain of FRMPD2 direct and binds to the C-terminus of GluN2A. Moreover, Ferm domain of FRMPD2 directly interacts with actin filaments and modifies excitatory synapse morphogenesis, further strengthen neuronal excitatory transmission. In particular, FRMPD2 mediates the behavioral and field potential phenotypes of epilepsy, a brain disorder of excitatory/inhibitory imbalance. Our study discover that a novel scaffold protein FRMPD2 regulates synaptic excitatory in a PDZ2 domain- and Ferm domain-dependent manner in adult hippocampus.

GPR40 modulates epileptic seizure and NMDA receptor function

GPR40 modulates epileptic seizure and NMDA receptor function through the regulation of NR2A and NR2B surface expression. Epilepsy is a common neurological disease, and approximately 30% of patients do not respond adequately to antiepileptic drug treatment. Recent studies suggest that G protein–coupled receptor 40 (GPR40) is expressed in the central nervous system and is involved in the regulation of neurological function. However, the impact of GPR40 on epileptic seizures remains unclear. In this study, we first reported that GPR40 expression was increased in epileptic brains. In the kainic acid–induced epilepsy model, GPR40 activation after status epilepticus alleviated epileptic activity, whereas GPR40 inhibition showed the opposite effect. In the pentylenetetrazole-induced kindling model, susceptibility to epilepsy was reduced with GPR40 activation and increased with GPR40 inhibition. Whole-cell patch-clamp recordings demonstrated that GPR40 affected N-methyl-d-aspartate (NMDA) receptor–mediated synaptic transmission. Moreover, GPR40 regulated NR2A and NR2B expression on the surface of neurons. In addition, endocytosis of NMDA receptors and binding of GPR40 with NR2A and NR2B can be regulated by GPR40. Together, our findings indicate that GPR40 modulates epileptic seizures, providing a novel antiepileptic target.

Overexpression of miRNA-137 in the brain suppresses seizure activity and neuronal excitability: A new potential therapeutic strategy for epilepsy.

ABSTRACT miRNA‐137 is an extremely abundant miRNA in the central nervous system and is thought to be closely related to synaptic plasticity. Here, we report a previously unrecognized role of miRNA‐137 in epilepsy. The expression of miRNA‐137 was decreased both in patients with temporal lobe epilepsy (TLE) and in two different mouse models of epilepsy. Overexpression of miRNA‐137 induced by an intrahippocampal injection of a specific agomir prolonged the latency to spontaneous recurrent seizures (SRSs) and reduced seizure severity in a mouse model of pilocarpine‐induced epilepsy. Elevated levels of miRNA‐137 also prolonged the latency to full kindling and reduced the seizure severity in a mouse model of pentylenetetrazol (PTZ)‐kindled epilepsy. Suppression of miRNA‐137 levels decreased the latency to the first SRS or the latency to full kindling and increased the seizure severity in both epileptic mouse models. Whole‐cell patch‐clamp recordings showed that overexpression of miRNA‐137 reduced the excitability of pyramidal neurons in the hippocampal CA3a region in a Mg2+‐free‐induced brain slice model of epileptiform activity. This effect may have been achieved by the regulation of the frequency of miniature inhibitory postsynaptic currents (mIPSCs) and presynaptic inhibitory neurotransmitter release. These results suggest that elevated levels of miRNA‐137 may exert an antiepileptic effect via a presynaptic neurotransmission mechanism. These data may provide a new potential target and therapeutic strategy for treating epilepsy in the future. HIGHLIGHTSThe expression of miRNA‐137 was decreased both in patients with TLE and in two different epileptic mouse models.In vivo miRNA‐137 interventions altered the latency and severity of seizures in two mouse models of epilepsy.miRNA‐137 might regulate the frequency of mIPSCs by governing the release of presynaptic inhibitory neurotransmitters.