Figure - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Heat-map representation of the average expression of the 12 differentially expressed miRNAs in no GCP and GCP 2 from ten different tissues. The colors of the genes represented on the heat map correspond to the expression values normalized on miRNA mean expression across all samples: green indicates down-regulated; red indicates up-regulated in the tissue. Patients are identified by numbers (in parenthesis) that correspond to those reported in the Table 1.
Source publication
The microRNAs (miRNAs) are small size non-coding RNAs that regulate expression of target mRNAs at post-transcriptional level. miRNAs differentially expressed under pathological conditions may help identifying mechanisms underlying the disease and may represent biomarkers with prognostic value. However, this kind of studies are difficult in the brai...
Citations
... Hippocampal granule cells: 14 drug resistant TLE patients, who were candidates to epilepsy surgery, were recruited by Zucchini et al. (2014). All patients underwent tailored temporal lobe resection to remove the epileptogenic area according to the findings during pre-surgical investigation. ...
... It was noteworthy that several of the studies reviewed had included a substantial number of patients with hippocampal sclerosis in the TLE cohort. For instance, there were 9/30 (30%) in the study by Xiao et al. (2018), and patients with hippocampal sclerosis were included in the studies of Raoof et al. (2018) and Zucchini et al. (2014). Wu et al. (2021) reported that 11/65 (17%) TLE children had developed mesial sclerosis. ...
Temporal lobe epilepsy is the most common form of focal epilepsy in adults, accounting for one third of all diagnosed epileptic patients, with seizures originating from or involving mesial temporal structures such as the hippocampus, and many of these patients being refractory to treatment with anti-epileptic drugs. Temporal lobe epilepsy is the most common childhood neurological disorder and, compared with adults, the symptoms are greatly affected by age and brain development. Diagnosis of temporal lobe epilepsy relies on clinical examination, patient history, electroencephalographic recordings, and brain imaging. Misdiagnosis or delay in diagnosis is common. A molecular biomarker that could distinguish epilepsy from healthy subjects and other neurological conditions would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated. Among possible biomarkers of pathological changes as well as potential therapeutic targets in the epileptic brain are microRNAs. Most of the recent studies had performed microRNA profiling in body fluids such as blood plasma and blood serum and brain tissues such as temporal cortex tissue and hippocampal tissue. A large number of microRNAs were dysregulated when compared to healthy controls and with some overlap between individual studies that could serve as potential biomarkers. For example, in adults with temporal lobe epilepsy, possible biomarkers are miR-199a-3p in blood plasma and miR-142-5p in blood plasma and blood serum. In adults with mesial temporal lobe epilepsy, possible biomarkers are miR-153 in blood plasma and miR-145-3p in blood serum. However, in many of the studies involving patients who receive one or several anti-epileptic drugs, the influence of these on microRNA expression in body fluids and brain tissues is largely unknown. Further studies are warranted with children with temporal lobe epilepsy and consideration should be given to utilizing mouse or rat and non-human primate models of temporal lobe epilepsy. The animal models could be used to confirm microRNA findings in human patients and to test the effects of targeting specific microRNAs on disease progression and behavior.
... In a healthy brain, neuronal activity leads to an increase in myelination, supporting the transduction of signals within a neuronal network. In the case of epilepsy, aberrant neuronal activity during seizures may inhibit myelin formation despite the normal or increased presence of oligodendrocyte precursor cells (Gibson et al., 2018;Zucchini et al., 2014). In epileptic patients, myelin alterations are frequently reported. ...
Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in adults; it often starts in infancy or early childhood. Although TLE is primarily considered to be a grey matter pathology, a growing body of evidence links this disease with white matter abnormalities. In this study, we explore the impact of TLE onset and progression in the immature brain on white matter integrity and development utilising the rat model of Li-pilocarpine-induced TLE at the 12th postnatal day (P). Diffusion tensor imaging (DTI) and Black-Gold II histology uncovered disruptions in major white matter tracks (corpus callosum, internal and external capsules, and deep cerebral white matter) spreading through the whole brain at P28. These abnormalities were mostly not present any longer at three months after TLE induction, with only limited abnormalities detectable in the external capsule and deep cerebral white matter. Relaxation Along a Fictitious Field in the rotating frame of rank 4 indicated that white matter changes observed at both timepoints, P28 and P72, are consistent with decreased myelin content. The animals affected by TLE-induced white matter abnormalities exhibited increased functional connectivity between the thalamus and medial prefrontal and somatosensory cortex in adulthood. Furthermore, histological analyses of additional animal groups at P15 and P18 showed only mild changes in white matter integrity, suggesting a gradual age-dependent impact of TLE progression. Taken together, TLE progression in the immature brain distorts white matter development with a peak around postnatal day 28, followed by substantial recovery in adulthood. This developmental delay might give rise to cognitive and behavioural comorbidities typical for early-onset TLE.
... Out of the few tissue-profiling studies on patient tissue samples (summarized in Table 1), Zucchini et al. 85 provided the first profiling study on 14 paraffin-fixed formalin-embedded hippocampal or temporal lobe tissue specimens from DRE patients with hippocampal sclerosis. Although the research focused on granule cell pathology (GCP), it offered interesting initial insights into miRNAs' involvement in pharmacoresistance. ...
... Of the several targets of miR-487a, a transmembrane protein, anthrax toxin receptor 1, seems to be interesting, as its increased levels in case of miR-487a dysregulation could favor granule cell dispersion. 85 De Matteis et al. 86 provided a case report of significant upregulation of miR-301a-3p in a patient with drugresistant mTLE who died of sudden unexpected death in epilepsy. Based on literature search, miR-301a-3p, miR-194-5p, miR-30b-5p, miR-342-5p, and miR-4446-3p were measured in tissue and plasma. ...
... Comparisons of drug-resistant patients with their drug-responsive counterparts would be more appropriate. Despite the apparent advantages of blood samples in DRE patients, not all tissue-profiling studies contain validation of miRNA profiles in blood, 24,40,85 although providing an extensive analysis of the tissue transcriptome 40 is assuredly a valuable contribution to the field. On the other hand, there is a subgroup of studies that do not follow the correlation of miRNA profiles in brain tissue and serum and only focus on miRNA levels in blood, verifying the existing results from other teams. ...
Although many new antiseizure drugs have been developed in the past decade, approximately 30%–40% of patients remain pharmacoresistant. There are no clinical tools or guidelines for predicting therapeutic response in individual patients, leaving them no choice other than to try all antiseizure drugs available as they suffer debilitating seizures with no relief. The discovery of predictive biomarkers and early identification of pharmacoresistant patients is of the highest priority in this group. MicroRNAs (miRNAs), a class of short noncoding RNAs negatively regulating gene expression, have emerged in recent years in epilepsy, following a broader trend of their exploitation as biomarkers of various complex human diseases. We performed a systematic search of the PubMed database for original research articles focused on miRNA expression level profiling in patients with drug‐resistant epilepsy or drug‐resistant precilinical models and cell cultures. In this review, we summarize 17 publications concerning miRNAs as potential new biomarkers of resistance to antiseizure drugs and their potential role in the development of drug resistance or epilepsy. Although numerous knowledge gaps need to be filled and reviewed, and articles share some study design pitfalls, several miRNAs dysregulated in brain tissue and blood serum were identified independently by more than one paper. These results suggest a unique opportunity for disease monitoring and personalized therapeutic management in the future.
... Multiple studies have investigated the variation of miRNA expression patterns in various neurological diseases, including epilepsy, to assess their role in disease pathogenesis and their usefulness as diagnostic biomarkers, as well as to develop efficacious therapeutic strategies [33,34]. Different miRNAs have been implicated in a variety of processes involved in epileptogenesis, such as neuroinflammation, blood brain barrier (BBB) dysfunctions, apoptosis, ion channel dysregulation, axonal guidance, and synaptic plasticity [35][36][37][38][39][40][41][42][43][44], all of which point to them as promising therapeutic targets [45,46] (Figure 1, Table 1). (3), and Hsp70s (4) are increased in epilepsy (A). ...
... Several miRNAs have been found to be differentially expressed in the hippocampus of TLE or status epilepticus (SE) models. In patients with TLE, a subset of miRNAs was proposed to be a potential regulator of a variety of processes involved in epilepsy, such as neuroinflammation, BBB dysfunctions, apoptosis, ion channel abnormalities, tumors, and disorders of axonal guidance, cell proliferation, neuronal function, and synaptic plasticity [35][36][37][38][39][40][41][42][43][44]. For instance, the inflammation-related miR-21, miR-132 [39], and miR-146a [35,36] are upregulated in chronic stages following epileptic status in animal models and TLE patients. ...
Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.
... It was noted that this increase was especially in the regions where neuronal death and gliosis occurred (29). In a study of miRNA expression in hippocampal samples of patients who had refractory TLE and underwent surgical intervention, hsa-miR-487a was found to be related to prognosis during the post-surgical period (30). Wang et al. suggested that hsa-miR-106b-5p has high specificity and sensitivity for epilepsy diagnosis and hsa-miR-301a-3p could be a prognostic marker to predict the drug resistance (31,32). ...
Epilepsy affects millions of people worldwide and has a great burden on world health. Improvement of seizure outcomes mostly relies on establishment of individualized risk factors for epileptogenesis and drug resistance. Several circulating molecules could serve as diagnostic and prognostic biomarkers at different stages of the disease. Inflammatory markers, blood-brain barrier markers, oxidative stress markers, microRNAs, autoantibodies, hormones and growth factors are promising fields of research for biomarkers in epilepsy. Several experimental studies and only a few clinical studies have revealed associations between inflammatory biomarkers and clinical outcomes of epilepsy. Herein, we detail the clinical and immunological significance of several factors of inflammation that may in due time serve as biomarkers of epilepsy in an effort to potentially inspire the researchers towards the development of reliable prognostic biomarkers for epilepsy.
... All of the procedures were produced according to our previously published protocols. 30,31 Analysis Sections were analysed using a Leica microscope (DMRA2), by three expert pathologists under double blind conditions. Cell shape, consistency of parenchymal ...
Formalin-fixed, paraffinembedded (FFPE) human brain tissues are very often stored in formalin for long time. Formalin fixation reduces immunostaining, and the DNA/RNA extraction from FFPE brain tissue becomes suboptimal. At present, there are different protocols of fixation and several procedures and kits to extract DNA/RNA from paraffin embedding tissue, but a gold standard protocol remains distant. In this study, we analyzed four types of fixation systems and compared histo and immuno-staining. Based on our results, we propose a modified method of combined fixation in formalin and formic acid for the autoptic adult brain to obtain easy, fast, safe and efficient immunolabelling of long-stored FFPE tissue. In particular, we have achieved an improved preservation of cellular morphology and obtained success in postmortem immunostaining for NeuN. This nuclear antigen is an important marker for mapping neurons, for example, to evaluate the histopathology of temporal lobe epilepsy or to draw the topography of cardiorespiratory brainstem nuclei in sudden infant death syndrome (SIDS). However, NeuN staining is frequently faint or lost in postmortem human brain tissues. In addition, we attained Fluoro Jade C staining, a marker of neurodegeneration, and immunofluorescent staining for stem cell antigens in the postnatal human brain, utilizing custom fit fixation procedures.
... Cerebrospinal fluid is mainly generated in the choroid plexus tissues, and is created and absorbed into the veins constantly (22). The fluid serves a lymphatic role in the central nervous system; it provides a certain degree of nutrition to the brain cells, carries away metabolites of brain tissues, regulates the acid-base balance of the central nervous system, reduces the pressure in the brain and spinal cord, and protects and supports the brain and spinal cord (23). Meanwhile, cerebrospinal fluid envelops the brain parenchyma, can contact the external cell gap directly, and can reflect the pathological and physiological changes of brain tissues dynamically (22). ...
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of microRNA-155 in patients with temporal lobe epilepsy. Commercial kit and western blot analysis were used to measure gap-associated protein expression. The aim of the present study was to investigate the effect of microRNA‑155 (miRNA‑155) in the occurrence of epilepsy and the molecular mechanism involved. In patients with temporal lobe epilepsy, miRNA‑155 expression was evidently higher than that in patients of the normal volunteers group. Overexpression of miRNA‑155 resulted in decreased brain‑derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) protein expression, increased caspase‑3 activity, tumor protein p53 (p53) and apoptosis regulator BAX (Bax) protein expression, and inhibited phosphoinositide 3‑kinase (PI3K), phosphorylated (p‑)protein kinase B (Akt) and p‑mechanistic target of rapamycin (mTOR) protein expression in epilepsy cells. PI3K inhibitor accelerated the effect of miRNA‑155 on the inhibition of BDNF and TrkB protein expression, the promotion of caspase‑3 activity, p53 and Bax protein expression, and the inhibition of PI3K, p‑Akt and p‑mTOR protein expression in epilepsy cells. The present findings indicate that miRNA‑155 contributes to the occurrence of epilepsy through the PI3K/Akt/mTOR signaling pathway.
... Bioinformatics ANTXR1 may be an existing target of miR487a. With cell spread in granule cell dispersion, ANTXR1 may be implicated as an adhesion molecule and the first identified signature that may be helpful for evaluation leading to conclusive targets [46]. Serum hsa-miR-4521 is a promising novel biomarker in brain tissue and serum for refractory epilepsy and focal cortical dysplasia [5]. ...
Background:
Epilepsy is one of chronic severe neurological disorders possess to recurring seizures. And now anti-epileptic drugs are only effective in less than one third of epilepsy patients, and biomarkers predicting are not available when the specific antiepileptic drugs treated. Advanced studies have showed that miRNA may be a key in the pathogenesis of epilepsy beginning in the early 2000 years. Several target genes and pathways of miRNA which related to the therapeutic methods to epilepsy.
Method:
We searched PubMed from Jan 1,2000 to Jan 1, 2017, using the terms "epilepsy AND microRNA AND biomarker" and "seizure AND microRNA AND biomarker". We selected articles that featured novel miRNAs in vivo epilepsy models and patients. We then selected the most relevant articles based on a subjective appraisal of their quality and mechanistic insight that could be relevant to epilepsy.
Results:
Decrease the expression of has-miR134 could be a potential non-invasive biomarker to use in diagnosis for the epilepsy patients for using hsa-miR-134 also be identified to distinguish patients with and without epilepsy. miR-181a show significant downregulation in the acute stage, but up regulation in the chronic stage and in the latent stage there is no changing and how about this phenomenon appearance in different stage still should be discussed in the future. Besides that, miR- 146a can down-regulated in the patients using genome-wide for serum in circulating miRNAs.miR- 124, miR-199a, and miR-128 etc. could be a candidate for the biomarker in future. miR-15a-5p and -194-5p down-regulated in epilepsy patients, in the future, it may be used as a novel biomarker for improve diagnosis.
Conclusion:
These observations give a chance that new development for diagnosis and treatment of epilepsy patients. Advanced technique and miRNA combination may product more effective roles in epilepsy and other disease. These reports will be available to solve the application of miRNAs as biomarkers and novel therapy approaches for epilepsy. In summary, researcher who focus on miRNAs should be understanding of the causes, treatment, and diagnosis of epilepsy. exploration of any of these effects on the efficacy of these drugs is worthwhile.
... Some of these miRNA circulate through the body and thereby provide a bridge between genetic expression, either normal expression of mutated genes, or abnormal expression of otherwise normal genes, and clinical presentation. Two miRNAs, hsa-miR-487a and hsa-miR-9a-3p, have been found to correlate to neuro-inflammation and epileptogenesis, which perhaps one day could allow clinicians to determine if immunosuppression for the prevention of epileptogenesis is indicated in their patient (Zucchini et al., 2014;Roncon et al., 2015). The miRNA hsa-miR-106b-5p, part of an miRNA family implicated in cell proliferation, was found to diagnose idiopathic generalised epilepsy at a sensitivity and specificity of 80% and 81% respectively (Wang et al., 2015). ...
Biomarkers can be categorised from type 0 (genotype or phenotype), through 6 (clinical scales), each level representing a part of the processes involved in the biological system and drug treatment. This classification facilitates the identification and connection of information required to fully (mathematically) model a disease and its treatment using integrated information from biomarkers. Two recent reviews thoroughly discussed the current status and development of biomarkers for epilepsy, but a path towards the integration of such biomarkers for the personalisation of anti-epileptic drug treatment is lacking. Here we aim to 1) briefly categorise the available epilepsy biomarkers and identify gaps, and 2) provide a modelling perspective on approaches to fill such gaps. There is mainly a lack of biomarker types 2 (target occupancy) and 3 (target activation). Current literature typically focuses on qualitative biomarkers for diagnosis and prediction of treatment response or failure, leaving a need for biomarkers that help to quantitatively understand the overall system to explain and predict differences in disease and treatment outcome. Due to the complexity of epilepsy, filling the biomarker gaps will require collaboration and expertise from the fields of systems biology and systems pharmacology.
... These findings may be useful for prognostic evaluation of postsurgical epilepsy and may drive mechanistic studies leading to the identification of therapeutic targets. 45 Finally, two recent studies evaluated circulating miRNAs in patients with epilepsy. Wang et al. 46 measured serum miRNA levels in epilepsy patients and controls, and found six miRNAs that were de-regulated in epilepsy patients. ...
Objective:
Current medications for patients with epilepsy work in only two of three patients. For those medications that do work, they only suppress seizures. They treat the symptoms, but do not modify the underlying disease, forcing patients to take these drugs with significant side effects, often for the rest of their lives. A major limitation in our ability to advance new therapeutics that permanently prevent, reduce the frequency of, or cure epilepsy comes from a lack of understanding of the disease coupled with a lack of reliable biomarkers that can predict who has or who will get epilepsy.
Methods:
The main goal of this report is to present a number of approaches for identifying reliable biomarkers from observing patients with brain disorders that have a high probability of producing epilepsy.
Results:
A given biomarker, or more likely a profile of biomarkers, will have both a quantity and a time course during epileptogenesis that can be used to predict who will get the disease, to confirm epilepsy as a diagnosis, to identify coexisting pathologies, and to monitor the course of treatments.
Significance:
Additional studies in patients and animal models could identify common and clinically valuable biomarkers to successfully translate animal studies into new and effective clinical trials.
