Executive function impairment is associated with low serum vitamin D levels in children with epilepsy.

PURPOSE: Executive function (EF) impairment and vitamin D deficiency are common clinical features among children with epilepsy (CWE). Recently, vitamin D has become a potential modification factor that affects cognitive status in individuals with neurological disorders. In this study, we investigated the association between EF status and vitamin D levels in patients with CWE. METHODS: In total, 79 CWE patients and 39 healthy controls (HCs) were recruited in this study. Each participant's EF was assessed using the Behavior Rating Inventory of Executive Function-Parent form (Brief-P), and the serum level of 25-OH vitamin D was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Compared with those in the HC group, the CWE group had higher T scores of Brief-P scale, including global executive composite (GEC) (51.01(45.12, 60.69) vs. 44.08(39.24, 49.96), p＜0.001), behavioral regulation index (BRI) (51.29(45.67, 59.13) vs. 45.67(40.06, 51.29), p＜0.001), metacognition index (MI) (51.83(46.77, 59.43) vs. 46.13(40.44, 51.83), p＜0.001), and lower serum vitamin D (14.85(10.24,23.2) vs. 22.5(16.91,30), p＜0.001) levels. After adjustment for covariates, multivariate linear regression models suggested that for every 1 ng/ml increase in vitamin D, the GEC, BRI, and MI would decrease by 0.52 (Coeff = -0.48; 95 % CI = -0.69, -0.26; p = 0.000), 0.45 (Coeff = -0.45; 95 % CI = -0.69, -0.20; p = 0.000), and 0.47 (Coeff = -0.45; 95 % CI = -0.67, -0.22; p = 0.000), respectively. CONCLUSION: There may be an association between decreased vitamin D levels and EF impairment in CWE. Future research should consider longitudinal variations in EF related to improving vitamin D deficiency.

Novel compound heterozygous variants in the CSPP1 gene causes Joubert syndrome: case report and literature review of the CSPP1 gene's pathogenic mechanism.

Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental condition characterized by congenital mid-hindbrain abnormalities and a variety of clinical manifestations. This article describes a case of Joubert syndrome type 21 with microcephaly, seizures, developmental delay and language regression, caused by a CSPP1 gene variant and examines the contributing variables. This paper advances the understanding of JS by summarizing the literature and offering detection patterns for practitioners with clinical suspicions of JS.

How is the P2X7 receptor signaling pathway involved in epileptogenesis?

Epilepsy, a condition characterized by spontaneous recurrent epileptic seizures, is among the most prevalent neurological disorders. This disorder is estimated to affect approximately 70 million people worldwide. Although antiseizure medications are considered the first-line treatments for epilepsy, most of the available antiepileptic drugs are not effective in nearly one-third of patients. This calls for the development of more effective drugs. Evidence from animal models and epilepsy patients suggests that strategies that interfere with the P2X7 receptor by binding to adenosine triphosphate (ATP) are potential treatments for this patient population. This review describes the role of the P2X7 receptor signaling pathways in epileptogenesis. We highlight the genes, purinergic signaling, Pannexin1, glutamatergic signaling, adenosine kinase, calcium signaling, and inflammatory response factors involved in the process, and conclude with a synopsis of these key connections. By unraveling the intricate interplay between P2X7 receptors and epileptogenesis, this review provides ideas for designing potent clinical therapies that will revolutionize both prevention and treatment for epileptic patients.

MCC950 alleviates seizure severity and angiogenesis by inhibiting NLRP3/ IL-1ß signaling pathway-mediated pyroptosis in mouse model of epilepsy.

Epilepsy is one of the most common serious chronic brain disorders, affecting up to 70 million people worldwide. Vascular disruption, including blood-brain barrier impairment and pathological angiogenesis, exacerbates its occurrence. However, its underlying mechanisms remain elusive. MCC950 is a specific small-molecule inhibitor that selectively blocks NLRP3 inflammatory vesicle activation across the blood-brain barrier, limits downstream IL-1ß maturation and release, and exerts therapeutic effects across multiple diseases. In the present study, an epilepsy model was established by intraperitoneal administration of Kainic acid to adult male C57BL/6J wild-type mice. The results revealed that the epilepsy susceptibility of MCC950-treated mice was decreased, and neural damage following seizure episodes was reduced. In addition, immunofluorescence staining, RT-qPCR, and Western blot demonstrated that MCC950 inhibited the expression of the NLRP3 inflammasome and its related proteins in microglia, whereas microangiogenesis was found to be increased in the cerebral cortex and hippocampus of epileptic mice, and these effects could be reversed by MCC950. Furthermore, neurobehavioral impairment was observed in the epileptic mouse model, and MCC950 similarly alleviated the aforementioned pathological process. To the best of our knowledge, this is the first study to establish that pathological microangiogenesis is associated with NLRP3/IL-1ß signaling pathway activation in a Kainic acid-induced epilepsy mouse model and that MCC950 administration attenuates the above-mentioned pathological changes and exerts neuroprotective effects. Therefore, MCC950 is a promising therapeutic agent for the treatment of epilepsy.

Comorbidity of epilepsy and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis.

Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are common neurological and neuropsychiatric disorders, respectively, that can exist as comorbidities. However, the degree of comorbidity between both disorders has never been quantified based on a systematic review with meta-analysis. We performed a systematic search of the literature in Embase, PubMed, PsychINFO and the Cochrane Library on June 20, 2022. In a meta-analysis of 63 studies with a total sample size of 1,073,188 individuals (172,206 with epilepsy and 900,982 with ADHD) from 17 countries, the pooled prevalence of ADHD in epilepsy was 22.3% (95% CI 20.3-24.4%). The highest pooled prevalence was 12.7% (95% CI 9-17.1%) for ADHD-I subtype, whereas the pooled prevalence of epilepsy in ADHD was 3.4% (95% CI 2.53-4.21%). However, substantial heterogeneity in comorbidity rates was observed and partially attributed to the following factors: sample size, sample specification, geographical variations and diagnostic methods. Our study highlights the need for increased awareness of this diagnostic co-occurrence, and research is warranted to elucidate the underlying pathophysiological mechanisms.

Altered hippocampal GR/KCC2 signaling mediates susceptibility to convulsion in male offspring following dexamethasone exposure during pregnancy in rats.

Epidemiological research suggests that convulsions may have an intrauterine developmental origin related to the application of dexamethasone, an artificially synthesized glucocorticoid. Here, using a rat animal model of prenatal dexamethasone exposure (PDE) we confirm that PDE can cause susceptibility to convulsions in male offspring and explore the epigenetic programming mechanism underlying this effect related to intrauterine type 2 K+-Cl- cotransporter (KCC2). Wistar rats were injected with dexamethasone (0.2 mg/kg/d) subcutaneously during the gestational days (GD) 9-20 and part of the offspring was given lithium pilocarpine (LiPC) at postnatal week 10. Our results showed that male offspring of the PDE+LiPC group exhibited convulsions susceptibility, as well as increased hippocampal gamma-aminobutyric acid (GABA) and intracellular chloride ions level and decreased GABA receptor expression. The offspring also showed a decrease of hippocampal KCC2 H3K14ac levels and KCC2 expression. PDE male fetal rats (GD20) showed similar changes to male offspring after birth and exhibited an increased expression of glucocorticoid receptor (GR) and histone deacetylase type 2 (HDAC2). We observed effects consistent with those observed in PDE fetal rats following in vitro dexamethasone treatment of the fetal rat hippocampal neuron H19-7 cell line, and the effects could be reversed by treatment with a GR inhibitor (RU486) or HDAC2 inhibitor (romidepsin). Taken together, this study confirmed that PDE causes a reduction of H3K14ac levels in the KCC2 promoter region caused by activation of fetal hippocampal GR-HDAC2-KCC2 signaling. We proposed that this abnormal epigenetic modification is the mechanism underlying offspring convulsions susceptibility. CATEGORIES: Mechanism of toxicity.

A Treatable Genetic Disease Caused by CAD Mutation.

Type 50 early infantile epileptic encephalopathy, or EIEE-50 for short, is an autosomal recessive genetic disorder resulting from CAD mutations. So far, little has been reported on the disease. In this article, we will discuss the case of a male infant who is 8 years and 5 months old. A whole-exome sequencing of the boy revealed CAD compound heterozygous mutations. He suffered from global developmental delay and regression, refractory epilepsy, and anemia. After his diagnosis, we used uridine treatment and gained encouraging results. In this article, we will analyze our case studies in the context of the literature, so as to improve pediatricians' understanding of the disease.

NLRP3 Inflammasome Activation Enhances ADK Expression to Accelerate Epilepsy in Mice.

Epilepsy (SE) is a common and serious neurological disease. NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome participates in the pathogenesis of SE, while its underlying mechanism is still unclear. Here, we attempted to explore the mechanism of action of NLRP3 inflammasome in SE. SE mouse model was constructed by administration of kainic acid (KA). Astrocytes were treated with KA to mimic SE cell model. MCC950 (NLRP3 inhibitor) and Z-YVAD-FMK (Caspase-1 inhibitor) were used to treat astrocytes to inhibit the activity of NLRP3 and Caspase-1. Nissl staining was performed to examine the morphology of neuron. Western blot, enzyme-linked immunosorbent assay and immunofluorescence staining were performed to assess protein expression. SE mouse model exhibited an increase of neuronal loss, and an up-regulation of Cleaved-Caspase-1, IL-1ß and IL-18 in hippocampus. The levels of GFAP+ADK+ cells were significantly increased in SE mice. MCC950 or Z-YVAD-FMK abolished these impacts conferred by KA in SE mice. Moreover, KA treatment enhanced the expression of NLRP3, Cleaved-Caspase-1, IL-1ß and IL-18 in astrocytes, which was rescued by knockdown of NLRP3 or Caspase-1. Additionally, CREB, p-CREB, REST were up-regulated, and SP1 was down-regulated in the KA-treated SE mice and KA-treated astrocytes. Inhibition of NLRP3 or Caspase-1 rescued these proteins expression in KA-treated astrocytes. CREB or REST silencing reduced adenosine kinase (ADK) expression, while SP1 knockdown enhanced ADK expression in KA-treated astrocytes. In conclusion, NLRP3 inflammasome activation enhances ADK expression to accelerate SE in mice through regulating CREB/REST/SP1 signaling pathway. Thus, inhibition of NLRP3 inflammasome may be a treatment for SE.

Inhibition of microRNA-23b prevents polymicrobial sepsis-induced cardiac dysfunction by modulating TGIF1 and PTEN.

Cardiovascular dysfunction is a major complication associated with sepsis induced mortality. Cardiac fibrosis plays a critical role in sepsis induced cardiac dysfunction. The mechanisms of the activation of cardiac fibrosis is unclarified. In this study, we found that microRNA-23b (miR-23b) was up-regulated in heart tissue during cecal ligation and puncture (CLP)-induced sepsis and transfection of miR-23b inhibitor improved survival in late sepsis. Inhibition of miR-23b in the myocardium protected against cardiac output and enhanced left ventricular systolic function. miR-23b inhibitor also alleviated cardiac fibrosis in late sepsis. MiR-23b mediates the activation of TGF-ß1/Smad2/3 signaling to promote the differentiation of cardiac fibroblasts through suppression of 5'TG3'-interacting factor 1 (TGIF1). MiR-23b also induces AKT/N-Cadherin signaling to contribute to the deposition of extracellular matrix by inhibiting phosphatase and tensin homologue (PTEN). TGIF1 and PTEN were confirmed as the targets of miR-23b in vitro by Dual-Glo Luciferase assay. miR-23b inhibitor blocked the activation of adhesive molecules and restored the imbalance of pro-fibrotic and anti-fibrotic factors. These data provide direct evidence that miR-23b is a critical contributor to the activation of cardiac fibrosis to mediate the development of myocardial dysfunction in late sepsis. Blockade of miR-23b expression may be an effective approach for prevention sepsis-induced cardiac dysfunction.

Inhibition of MicroRNA-23b Attenuates Immunosuppression During Late Sepsis Through NIK, TRAF1, and XIAP.

Background: microRNA-23b (miR-23b) is a multiple functional miRNA. We hypothesize that miR-23b plays a role in the pathogenesis of sepsis. Our study investigated the effect of miR-23b on sepsis-induced immunosuppression. Methods: Mice were treated with miR-23b inhibitors by tail vein injection 2 days after cecal ligation puncture (CLP)-induced sepsis. Apoptosis in spleens and apoptotic signals were investigated, and survival was monitored. T-cell immunoreactivities were examined during late sepsis. Nuclear factor κB (NF-κB)-inducing kinase (NIK), tumor necrosis factor (TNF)-receptor associated factor 1 (TRAF1), and X-linked inhibitor of apoptosis protein (XIAP), the putative targets of miR-23b, were identified by a dual-luciferase reporter assay. Results: miR-23b expression is upregulated and sustained during sepsis. The activation of the TLR4/TLR9/p38 MAPK/STAT3 signal pathway contributes to the production of miR-23b in CLP-induced sepsis. miR-23b inhibitor decreased the number of spleen cells positive by terminal deoxynucleotidyl transferase dUTP nick-end labeling and improved survival. miR-23b inhibitor restored the immunoreactivity by alleviating the development of T-cell exhaustion and producing smaller amounts of immunosuppressive interleukin 10 and interleukin 4 during late sepsis. We demonstrated that miR-23b mediated immunosuppression during late sepsis by inhibiting the noncanonical NF-κB signal and promoting the proapoptotic signal pathway by targeting NIK, TRAF1, and XIAP. Conclusions: Inhibition of miR-23b reduces late-sepsis-induced immunosuppression and improves survival. miR-23b might be a target for immunosuppression.

TGF-ß1/Smad2/3/Foxp3 signaling is required for chronic stress-induced immune suppression.

Depending on the duration and severity, psychological tension and physical stress can enhance or suppress the immune system in both humans and animals. Although it has been established that chronic stress exerts a significant suppressive effect on immune function, the mechanisms by which affects immune responses remain elusive. By employing an in vivo murine system, we revealed that TGF-ß1/Smad2/3/Foxp3 axis was remarkably activated following chronic stress. Furthermore, TLR9 and p38 MAPK played a critical role in the activation of TGF-ß1/Smad2/3/Foxp3 signaling cascade. Moreover, inhibition of TGF-ß1/Smad2/3/Foxp3 or p38 significantly attenuated chronic stress-induced lymphocyte apoptosis and apoptosis-related proteins, as well as the differentiation of T regulatory cells in spleen. Interestingly, disequilibrium of pro-inflammatory and anti-inflammatory cytokines balance caused by chronic stress was also rescued by blocking TGF-ß1/Smad2/3/Foxp3 axis. These findings yield insight into a novel mechanism by which chronic stress modulates immune functions and identifies new targets for the development of novel anti-immune suppressant medications.

Hematopoietic stem progenitor cells prevent chronic stress-induced lymphocyte apoptosis.

Physical or psychological chronic stress can suppress the immune system. However, the mechanisms remain to be elucidated. We investigated the effect of hematopoietic stem-progenitor cells (HSPCs) on chronic stress-induced the alterations of immune responses. We demonstrate that HSPCs prevents stress-induced lymphocyte apoptosis. Moreover, we also demonstrate that the protective effect of HSPCs on stress-induced lymphocyte reduction exerts by steroid hormones. Furthermore, we reveal that chronic stress-induced T cell-mediated immune responses contributes to the protective effect of HSPCs. These results indicate that HPSCs might offer a novel therapeutic strategy against the deleterious effects of chronic stress on the immune system.

MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and ß-arrestin 2.

Cardiac dysfunction is correlated with detrimental prognosis of sepsis and contributes to a high risk of mortality. After an initial hyperinflammatory reaction, most patients enter a protracted state of immunosuppression (late sepsis) that alters both innate and adaptive immunity. The changes of cardiac function in late sepsis are not yet known. MicroRNA-155 (miR-155) is previously found to play important roles in both regulations of immune activation and cardiac function. In this study, C57BL/6 mice were operated to develop into early and late sepsis phases, and miR-155 mimic was injected through the tail vein 48 h after cecal ligation and puncture (CLP). The effect of miR-155 on CLP-induced cardiac dysfunction was explored in late sepsis. We found that increased expression of miR-155 in the myocardium protected against cardiac dysfunction in late sepsis evidenced by attenuating sepsis-reduced cardiac output and enhancing left ventricular systolic function. We also observed that miR-155 markedly reduced the infiltration of macrophages and neutrophils into the myocardium and attenuated the inflammatory response via suppression of JNK signaling pathway. Moreover, overexpression of ß-arrestin 2 (Arrb2) exacerbated the mice mortality and immunosuppression in late sepsis. Furthermore, transfection of miR-155 mimic reduced Arrb2 expression, and then restored immunocompetence and improved survival in late septic mice. We conclude that increased miR-155 expression through systemic administration of miR-155 mimic attenuates cardiac dysfunction and improves late sepsis survival by targeting JNK associated inflammatory signaling and Arrb2 mediated immunosuppression.

The Role and Effects of ANXA1 in Temporal Lobe Epilepsy: A Protection Mechanism?

BACKGROUND The endogenous protein annexin A1 (ANXA1) is an anti-inflammatory mediator in the brain that is thought to contribute to the progression of many neurological conditions. However, its exact role in temporal lobe epilepsy (TLE) remains unclear. We hypothesized that ANXA1 exerts negative actions on TLE by alleviating inflammatory damage in neurons. To identify the potential mechanism of TLE by assessing ANXA1 expression in TLE rats. MATERIAL AND METHODS TLE was induced in rats (n=70) via an intraperitoneal injection of lithium chloride (LiCl) and pilocarpine (PILO). The control group (n=10) received an injection of the equivalent amount of saline. ANXA1 expression was detected via immunohistochemistry and Western blotting. RESULTS Successful establishment of the TLE model in rats resulted in epileptic seizures. ANXA1 was immunohistochemically detected as brownish yellow particles in the dentate gyrus and the CA1 region of the door zone; this expression was predominantly localized to the cytoplasm of glia rather than neurons. ANXA1 expression was stronger in TLE rats compared with the control group. ANXA1 expression in TLE was also assessed via Western blotting, and compared between groups at various time points. ANXA1 expression was significantly increased in the acute (the first 24 h) and chronic (after 1 month) phases (P<0.001) but significantly decreased during the recovery phase (72 h, 1 week, and 2 weeks) (P<0.001). These findings suggest that ANXA1 expression is correlated with TLE activity. CONCLUSIONS Our data suggest that ANXA1 plays an important role in TLE by alleviating inflammatory damage and protecting neurons.

SAA1 gene variants and childhood obesity in China.

BACKGROUND: Obesity increases the risk for insulin resistance and metabolic syndrome in both adults and children. SAA is a member of apolipoprotein and plays an important role in maintaining glucose and lipid homeostasis. The purpose of this study was to assess SAA1 allelic variants with obesity in young school-age children. METHODS: A total of 520 consecutive children ages 5-15 years were recruited. Children were divided based on BMI z score into Obese (OB; BMI z score ≥1.65; n = 253) and non-obese (NOB; n = 267). Four SNPs of the human SAA1 gene (rs12218, rs4638289, rs7131332 and rs11603089) were genotyped by use of polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Compared to NOB, circulating SAA levels were increased in OB, as were LDL-C, TG and TC concentration. Obese children showed increased frequency of rs12218 and rs4638289 polymorphism compared to control children. There were no differences between OB and NOB for the other 2 polymorphisms. Only the rs4638289 polymorphism showed significant contributions to higher SAA plasma levels. CONCLUSIONS: SAA1 genetic polymorphism was associated with obesity in Chinese children.

Astrocyte activation and memory impairment in the repetitive febrile seizures model.

Frequently repetitive febrile seizures (FRFS) in immature brain could impair long-term memory without obvious pathological alteration. Although astrocyte activation has been implicated in many seizure models, it has never been examined in febrile seizure models. We investigated astrocyte activation states after FRFS in postnatal-10-day (P10) rats by western blot and immunohistochemical analysis of GFAP and S100beta, two protein markers for activated astrocytes, at three time points (P25, P35, P45). The levels of GFAP and S100beta increased significantly at all the time examined. Furthermore, we administered propentofylline, an astrocyte modulator, to verify the relationship between the activated astrocytes and memory injury. After propentofylline treatment for 10 consecutive days following P10 frequently repetitive FS, rats exhibited improved performances in Morris water maze at P36 and inhibitory avoidance task at P45, along with markedly suppressed overexpression of GFAP and S100beta. This research suggests that modulation of astrocyte activation might be a potential therapeutic target to improve memory outcomes after frequently repetitive febrile seizures.

Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats.

OBJECTIVE: To examine modulations caused by cyclooxygenase-2 (COX-2) inhibitors on altered microenvironments and overbalanced neurotransmitters in pilocarpine-induced epileptic status rats and to investigate possible mechanisms. METHODS: Celecoxib (a COX-2 inhibitor) was administered 45 min prior to pilocarpine administration. The effects of COX-2 inhibitors on mIPSCs (miniature GABAergic inhibitory postsynaptic currents) of CA3 pyramidal cells in the hippocampus were recorded. Expressions of COX-2, c-Fos, newly generated neurons, and activated microgliosis were analyzed by immunohistochemistry, and expressions of alpha-subunit of gamma-amino butyric acid (GABA(A)) receptors and mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activity were detected by Western blotting. RESULTS: Pretreatment with celecoxib showed protection against pilocarpine-induced seizures. Celecoxib prevented microglia activation in the hilus and inhibited the abnormal neurogenesis and astrogliosis in the hippocampus by inhibiting MAPK/ERK activity and c-Fos transcription. Celecoxib also up-regulated the expression of GABA(A) receptors. NS-398 (N-2-cyclohexyloxy-4-nitrophenyl-methanesulfonamide), another COX-2 inhibitor, enhanced the frequency and decay time of mIPSCs. CONCLUSION: The COX-2 inhibitor celecoxib decreased neuronal excitability and prevented epileptogenesis in pilocarpine-induced status epilepticus rats. Celecoxib regulates synaptic reorganization by inhibiting astrogliosis and ectopic neurogenesis by attenuating MAPK/ERK signal activity, mediated by a GABAergic mechanism.