Hua Tao

Epilepsy is a common neurological disorder that is increasingly recognized for its significant association with mitochondrial dysfunction. This review explores the intricate relationship between mitochondrial dysfunction and epilepsy, highlighting the molecular mechanisms, diagnostic strategies, and therapeutic approaches involved. Mitochondrial abnormalities, including defects in the electron transport chain, impaired mitochondrial dynamics, disrupted autophagy, and increased oxidative stress, are implicated in epilepsy pathogenesis. The molecular mechanisms involve respiratory chain impairments, fission–fusion imbalances, inadequate mitophagy, and oxidative stress-induced neuronal excitability. The diagnosis of mitochondrial epilepsy requires a multifaceted approach, combining clinical assessment, biochemical testing, imaging, and genetic analysis, with a particular focus on mtDNA mutations. Therapeutic strategies include antiepileptic drugs with variable mitochondrial effects, the ketogenic diet, and emerging potential approaches such as antioxidants and mitochondrial-targeted therapies. Despite advances in understanding and treatment, challenges persist due to the complexity of mtDNA mutations and treatment resistance. Future directions involve gene-editing technologies, mitochondrial transplantation, and induced pluripotent stem cells, which hold promise for addressing the underlying defects and improving epilepsy management.

Introduction: To confront the resistance to existing antiepileptic drugs, studies have gradually begun to investigate alternative pathologies distinct from the traditional treatments that overwhelmingly target ion channels. Microglia activation is the first inflammatory response in the brain, in which miR-155-5p plays a key proinflammatory role and thus represents a promising target for inflammatory modulation in epilepsy pathologies. Methods: In this study, a pentetrazol-induced acute seizure model was established, and the seizure degree was evaluated within 60 min after pentetrazol administration. Animals were then sacrificed for hippocampal tissue collection for biological experiments. Results: Intranasal delivery of miR-155-5p antagomir (30 min before pentetrazol administration) increased the percentage of animals with no induced seizures by 20%, extended the latency to generalized convulsions, and decreased seizure severity. In addition, miR-155-5p antagomir treatment alleviated hippocampal damage and decreased the expression of typical inflammatory modulators (TNF-α, IL-1β and IL-6). Further research revealed that intranasal delivery of miR-155-5p antagomir significantly decreased the relative level of miR-155-5p and increased the expression of its targets LXRα and SOCS1 in IBA1-labeled microglial cells in the hippocampus. Conclusion: These findings demonstrate that intranasal delivery of miR-155-5p antagomir alleviated acute seizures, likely by blocking hippocampal inflammation. However, other potential mechanisms of the effects of miR-155-5p antagomir and its long-term safety for epilepsy treatment remain to be investigated.

The prevalence of epileptic seizures in Alzheimer's disease (AD) has attracted an increasing amount of attention in recent years, and many cohort studies have found several risk factors associated with the genesis of seizures in AD. Among these factors, young age and severe dementia are seemingly contradictory and independent risk factors, indicating that the pathogenesis of epileptic seizures is, to a certain extent, stage‐dependent. A disintegrin and metalloproteinase domain‐containing protein 10 (ADAM10) is a crucial α‐secretase responsible for ectodomain shedding of its substrates; thus, the function of this protein depends on the biological effects of its substrates. Intriguingly, transgenic models have demonstrated ADAM10 to be associated with epilepsy. Based on the biological effects of its substrates, the potential pathogenic roles of ADAM10 in epileptic seizures can be classified into amyloidogenic processes in the ageing stage and cortical dysplasia in the developmental stage. Therefore, ADAM10 is reviewed here as a stage‐dependent modulator in the pathogenesis of epilepsy. Current data regarding ADAM10 in epileptic seizures were collected and reviewed for potential pathogenic roles (ie amyloidogenic processes and cortical dysplasia) and regulatory mechanisms (ie transcriptional and posttranscriptional regulation). These findings are then discussed in terms of the significance of the stage‐dependent functions of ADAM10 in epilepsy. Several potential targets for seizure control, such as candidate transcription factors and microRNAs that regulate ADAM10, as well as potential genetic screening tools for the early recognition of cortical dysplasia, have been suggested but must be studied in more detail.

D‐serine is a predominant N‐methyl‐D‐aspartate receptor co‐agonist with glutamate, and excessive activation of the receptor plays a substantial role in epileptic seizures. Serine racemase (SRR) is responsible for transforming L‐serine to D‐serine. In this study, we aimed to investigate the genetic roles ofSRRand a neighbouring gene, nonsense‐mediatedmRNAdecay factor (SMG6), in temporal lobe epilepsy (TLE). Here, a total of 496TLEpatients and 528 healthy individuals were successfully genotyped for threeSRRtag single nucleotide polymorphisms. The frequencies of theGGgenotype at rs4523957 T > G were reduced in theTLEcases in the initial cohort (cohort 1) and were confirmed in the independent cohort (cohort 2). An analysis of allTLEcases in cohort 1 + 2 revealed that the seizure frequency and drug‐resistant incidence were significantly decreased in carriers of theGGgenotype at rs4523957. Intriguingly, the activity of theSMG6 promoter with the mutant allele at rs4523957 decreased by 22% in the dual‐luciferase assay, and up‐regulated expression ofSMG6 was observed in an epilepsy rat model. This study provides the first demonstration that theGGgenotype is a protective marker againstTLE. In particular, variation at rs4523957 likely inhibitsSMG6 transcription and plays a key role against susceptibility to and severity ofTLE. The significance ofSMG6 hyperfunction in epileptic seizures deserves to be investigated in future studies.

Background: Clusterin (CLU) is implicated in the inflammatory and apoptotic mechanisms of epilepsy, and the CLU gene has been associated with a number of other neurological diseases. In this study, we investigated the genetic association of CLU polymorphisms with epilepsy in a Han Chinese population. Methods: A total of 249 epileptic patients and 289 healthy controls were included in this study. Three CLU single nucleotide polymorphisms (SNPs: rs11136000, rs9314349, and rs9331949) were selected and genotyped with the SNaPshot assay, and their associations with epilepsy were evaluated. Results: There was no statistically significant association between any of the CLU SNPs and epilepsy in our small cohort. In addition, no significant association was detected between any of the CLU SNPs and epilepsy after stratification based on gender, age of onset, temporal lobe epilepsy, and drug-resistant epilepsy. Conclusions: Our study failed to detect an association between CLU polymorphisms (rs11136000, rs9314349, and rs9331949) and epilepsy in a Han Chinese population. Further investigations with a larger sample size would be valuable to confirm our results.

Unveiling the key mechanism of temporal lobe epilepsy (TLE) for the development of novel treatments is of increasing interest, and anti-inflammatory miR-146a is now considered a promising molecular target for TLE. In the current study, a C57BL/6 TLE mouse model was established using the lithium-pilocarpine protocol. The seizure degree was evaluated according to the Racine scale, and level 5 was considered the threshold for generalized convulsions. Animals were sacrificed to analyze the hippocampus at three time points (2 h and 4 and 8 weeks after pilocarpine administration to evaluate the acute, latent, and chronic phases, resp.). After intranasal delivery of miR-146a mimics (30 min before pilocarpine injection), the percent of animals with no induced seizures increased by 6.7%, the latency to generalized convulsions was extended, and seizure severity was reduced. Additionally, hippocampal damage was alleviated. While the relative miR-146a levels significantly increased, the expression of its target mRNAs (IRAK-1 and TRAF-6) and typical inflammatory modulators (NF-κB, TNF-α, IL-1β, and IL-6) decreased, supporting an anti-inflammatory role of miR-146a via the TLR pathway. This study is the first to demonstrate that intranasal delivery of miR-146a mimics can improve seizure onset and hippocampal damage in the acute phase of lithium-pilocarpine-induced seizures, which provides inflammation-based clues for the development of novel TLE treatments.

Introduction: Although genetic variants of the A disintegrin and metalloproteinase 10 (ADAM10) gene have been shown to be associated with susceptibility to several inflammatory-related diseases, to date little is known about the clinical relationship in the development of sepsis.Methods: Two genetic variants in the promoter of ADAM10 were selected to analyze the potential association with the risk of sepsis. A total of 440 sepsis patients and 450 matched healthy individuals in two independent Chinese Han population were enrolled. Pyrosequencing and polymerase chain reaction-length polymorphism was used to determine the genotypes of the rs514049 and rs653765. A real-time qPCR method was used to detect the mRNA level of ADAM10. Enzyme-linked immunosorbent assay was used to measure the expression levels of substrates CX3CL1, interleukin (IL)-6R, tumor necrosis factor alpha (TNF-α), and the pro-inflammatory cytokines IL-1β and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10.Results: No statistically significant differences between sepsis cases and controls in the genotype or allele frequencies were observed, suggesting that ADAM10 single nucleotide polymorphisms (SNPs) may not be risk factors for the occurrence of sepsis. A significant difference in the genotype and allele frequencies of the rs653765 SNP between patients with sepsis subtype and severe sepsis (P = 0.0014) or severe sepsis/sepsis shock (P = 0.0037) were observed. Moreover, the rs653765 CC genotype in severe sepsis showed a higher ADAM10 level compared to healthy groups, and the rs653765 CC polymorphism had a strong impact on the production of the ADAM10 substrates CX3CL1, IL-6R and TNF-α. Furthermore, the functional assay showed that ADAM10 C-A haplotype carriers exhibited significantly higher reporter activity compared with the T-A carriers and T-C carriers in human acute monocytic leukemia cell line.Conclusions: Our data initially indicated the ADAM10 rs653765 polymorphism was associated with the development of severe sepsis; the risk CC genotype could functionally affect the expression level of ADAM10 mRNA and was accompanied by the up-regulation of its substrates. Thus, ADAM10 might be clinically important and play a critical role in the pathogenesis of the development of sepsis, with potentially important therapeutic implications.

Background: miR-146a polymorphisms have been involved in susceptibility to multiple diseases. The aim of the present study was to analyze the potential association between two functional miR-146a polymorphisms (rs2910164 and rs57095329) and multiple sclerosis (MS) in the Han Chinese population. Methods: A cohort of 525 patients and 568 healthy controls were genotyped to detect the two polymorphisms by SNaPshot. Results: No significant differences were detected in the distribution of the two miR-146a polymorphisms between the patients and controls (P > 0.05). However, stratification by gender showed a statistically significant difference in the frequency of the genotype rs2910164 between MS patients and control females (P=0.009). Further stratification analysis by subgroup revealed that the miR-146a rs2910164 C allele conferred a higher risk of developing relapsing-remitting MS (RRMS) (P=0.018). In addition, the rs2910164 C allele was significantly associated with increased expression of miR-146a in patients with RRMS (P=0.025). Moreover, patients with the rs2910164 C allele released more TNF-α and IFN-γ, but not IL-1β, compared with individuals carrying the homozygous GG genotype (P < 0.05). Conclusions: Our results provide evidence that rs2910164 may play a role in MS susceptibility in females. The rs2910164 G>C variation may affect the expression of miR-146a and the release of proinflammatory cytokines.