ORCID Profile
0000-0002-6199-9415
Current Organisation
Vidyasirimedhi Institute of Science and Technology
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Publisher: Wiley
Date: 25-04-2023
DOI: 10.1002/EPI4.12738
Abstract: We used the lateral fluid percussion injury (LFPI) model of moderate‐to‐severe traumatic brain injury (TBI) to identify early plasma biomarkers predicting injury, early post‐traumatic seizures or neuromotor functional recovery (neuroscores), considering the effect of levetiracetam, which is commonly given after severe TBI. Adult male Sprague–Dawley rats underwent left parietal LFPI, received levetiracetam (200 mg/kg bolus, 200 mg/kg/day subcutaneously for 7 days [7d]) or vehicle post‐LFPI, and were continuously video‐EEG recorded (n = 14/group). Sham (craniotomy only, n = 6), and naïve controls (n = 10) were also used. Neuroscores and plasma collection were done at 2d or 7d post‐LFPI or equivalent timepoints in sham/naïve. Plasma protein biomarker levels were determined by reverse phase protein microarray and classified according to injury severity (LFPI vs. sham/control), levetiracetam treatment, early seizures, and 2d‐to‐7d neuroscore recovery, using machine learning. Low 2d plasma levels of Thr 231 ‐phosphorylated tau protein (pTAU‐Thr 231 ) and S100B combined (ROC AUC = 0.7790) predicted prior craniotomy surgery ( diagnostic biomarker ). Levetiracetam‐treated LFPI rats were differentiated from vehicle treated by the 2d‐HMGB1, 2d‐pTAU‐Thr 231 , and 2d‐UCHL1 plasma levels combined (ROC AUC = 0.9394) ( pharmacodynamic biomarker ). Levetiracetam prevented the seizure effects on two biomarkers that predicted early seizures only among vehicle‐treated LFPI rats: pTAU‐Thr 231 (ROC AUC = 1) and UCHL1 (ROC AUC = 0.8333) ( prognostic biomarker of early seizures among vehicle‐treated LFPI rats ). Levetiracetam‐resistant early seizures were predicted by high 2d‐IFNγ plasma levels (ROC AUC = 0.8750) ( response biomarker ). 2d‐to‐7d neuroscore recovery was best predicted by higher 2d‐S100B, lower 2d‐HMGB1, and 2d‐to‐7d increase in HMGB1 or decrease in TNF ( P 0.05) ( prognostic biomarkers ). Antiseizure medications and early seizures need to be considered in the interpretation of early post‐traumatic biomarkers.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Public Library of Science (PLoS)
Date: 14-07-2017
Publisher: Elsevier BV
Date: 10-2019
Publisher: Cold Spring Harbor Laboratory
Date: 24-12-2020
DOI: 10.1101/2020.12.24.423424
Abstract: Lung cancer is a chronic non-communicable disease and is the cancer with the world’s highest incidence in the 21 st century. One of the leading mechanisms underlying the development of lung cancer in nonsmokers is an lification of the epidermal growth factor receptor (EGFR) gene. However, laboratories employing conventional processes of drug discovery and development for such targets encounter several pain-points that are cost- and time-consuming. Moreover, high failure rates are caused by efficacy and safety problems during research and development. Therefore, it is imperative to develop improved methods for drug discovery. Herein, we developed a deep learning model with spatial graph embedding and molecular descriptors based on predicting pIC 50 potency estimates of small molecules and classifying hit compounds against the human epidermal growth factor receptor (LigEGFR). The model was generated with a large-scale cell line-based dataset containing broad lists of chemical features. LigEGFR outperformed baseline machine learning models for predicting pIC 50 . Our model was notable for higher performance in hit compound classification, compared to molecular docking and machine learning approaches. The proposed predictive model provides a powerful strategy that potentially helps researchers overcome major challenges in drug discovery and development processes, leading to a reduction of failure to discover novel hit compounds. We provide an online prediction platform and the source code that are freely available at ligegfr.vistec.ist , and cads-biochem/LigEGFR , respectively. LigEGFR is a regression model for predicting pIC 50 that was developed for the human EGFR target. It can also be applied to hit compound classification (pIC 50 ≥ 6) and has a higher performance than baseline machine learning algorithms and molecular docking approaches. Our spatial graph embedding and molecular descriptors based approach notably exhibited a high performance in predicting pIC 50 of small molecules against human EGFR. Non-hashed and hashed molecular descriptors were revealed to have the highest predictive performance by using in a convolutional layers and a fully connected layers, respectively. Our model used a large-scale and non-redundant dataset to enhance the ersity of the small molecules. The model showed robustness and reliability, which was evaluated by y-randomization and applicability domain analysis (ADAN), respectively. We developed a user-friendly online platform to predict pIC 50 of small molecules and classify the hit compounds for the drug discovery process of the EGFR target.
Publisher: Cold Spring Harbor Laboratory
Date: 19-05-2022
DOI: 10.1101/2022.05.17.492323
Abstract: There are no pharmacological disease-modifying treatments that can mitigate the seizures and comorbidities associated with established chronic temporal lobe epilepsy (TLE). This study evaluated the effect of sodium selenate in the post-status epilepticus (SE) rat model of chronic drug resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, rats were randomly assigned to receive either sodium selenate, levetiracetam, or vehicle treatments continuously for 4 weeks. To evaluate the effects of the treatments, 1 week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of disease severity. Sodium selenate treatment was able to mitigate disease severity, reducing the number of spontaneous seizures (p 0.05), cognitive dysfunction (p 0.05 in both novel object placement and recognition tasks), and sensorimotor deficits (p 0.01) 8 weeks post-treatment cessation. Moreover, increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening caused by SE (p 0.05). Network medicine integration of multi-omics/ pre-clinical outcomes identified protein-metabolite modules positively correlated with the TLE phenotype. Our results provide evidence that treatment with sodium selenate results in a sustained disease modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2023
Publisher: Elsevier BV
Date: 02-2019
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1002/EPI4.12386
Publisher: Wiley
Date: 11-08-2023
DOI: 10.1111/EPI.17735
Abstract: More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild‐to‐moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ‐aminobutyric acid transporter‐1, and to test its seizure suppression effects in a rat model of chronic MTLE. We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood s ling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid‐induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video‐electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. Plasma levels following continuous infusion of E2730 showed a clear dose‐related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose‐dependent manner, with 65% of rats becoming seizure‐free at the highest dose tested. Mean seizure class did not differ between the treatment groups. This study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose‐dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.
Publisher: Wiley
Date: 31-01-2023
DOI: 10.1002/EPI4.12692
Abstract: Epilepsy is associated with an increased risk of cardiovascular disease and mortality. Whether cardiac structure and function are altered in epilepsy remains unclear. To address this, we conducted a systematic review and meta‐analysis of studies evaluating cardiac structure and function in patients with epilepsy. We searched the electronic databases MEDLINE, PubMed, COCHRANE, and Web of Science from inception to 31 December 2021. Primary outcomes of interest included left ventricular ejection fraction (LVEF) for studies reporting echocardiogram findings and cardiac weight and fibrosis for postmortem investigations. Study quality was assessed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tools. Among the 10 case‐control studies with epilepsy patients (n = 515) and healthy controls (n = 445), LVEF was significantly decreased in epilepsy group compared with controls (MD: −1.80 95% confidence interval [CI]: −3.56 to −0.04 P = 0.045), whereas A‐wave velocity (MD: 4.73 95% CI: 1.87‐7.60 P = 0.001), E/e' ratio (MD: 0.39 95% CI: 0.06‐0.71 P = 0.019), and isovolumic relaxation time (MD: 10.18 95% CI: 2.05‐18.32 P = 0.014) were increased in epilepsy, compared with controls. A pooled analysis was performed in sudden unexpected death in epilepsy (SUDEP) cases with autopsy data (n = 714). Among SUDEP cases, the prevalence of cardiac hypertrophy was 16% (95% CI: 9%–23%) cardiac fibrosis was 20% (95% CI: 15%–26%). We found no marked differences in cardiac hypertrophy, heart weight, or cardiac fibrosis between SUDEP cases and epilepsy controls. Our findings suggest that epilepsy is associated with altered diastolic and systolic echocardiogram parameters compared with healthy controls. Notably, SUDEP does not appear to be associated with a higher incidence of structural cardiac abnormalities, compared with non‐SUDEP epilepsy controls. Longitudinal studies are needed to understand the prognostic significance of such changes. Echocardiography may be a useful noninvasive diagnostic test in epilepsy population.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.PNEUROBIO.2019.101677
Abstract: We evaluated whether pharmacologically targeting T-type Ca
Publisher: eLife Sciences Publications, Ltd
Date: 09-03-2023
DOI: 10.7554/ELIFE.78877
Abstract: There are no pharmacological disease-modifying treatments with an enduring effect to mitigate the seizures and comorbidities of established chronic temporal lobe epilepsy (TLE). This study aimed to evaluate for disease modifying effects of sodium selenate treatment in the chronically epileptic rat post-status epilepticus (SE) model of drug-resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, animals received sodium selenate, levetiracetam, or vehicle subcutaneousinfusion continuously for 4 weeks. To evaluate the effects of the treatments, one week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of epilepsy disease severity in our current study. The results showed that sodium selenate treatment was associated with mitigation of measures of disease severity at 8 weeks post-treatment cessation reducing the number of spontaneous seizures (p 0.05), cognitive dysfunction (p 0.05), and sensorimotor deficits (p 0.01). Moreover, selenate treatment was associated with increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening (p 0.05). Network medicine integration of multi-omics re-clinical outcomes identified protein-metabolite modules positively correlated with TLE. Our results provide evidence that treatment with sodium selenate results in a sustained disease-modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.
Publisher: eLife Sciences Publications, Ltd
Date: 08-11-2022
Location: Thailand
Location: Thailand
No related grants have been discovered for Pablo Casillas-Espinosa.