Dong-Cheol Woo

Refractory status epilepticus refers to persistent and recurrent seizures unresponsive to medication, often leading to neuronal injury and neurobehavioral deficits. Studies have demonstrated that intraperitoneal bolus administration of pyruvate attenuates neuronal damage in rodent models of chemically induced status epilepticus (SE), while the precise neuroprotective mechanism remains to be further explored. This study investigated the neuroprotective effects of long-term supplementation with exogenous pyruvate against SE. When male C57BL/6 mice received 3% sodium pyruvate (SP) in the drinking water ad libitum for 20 weeks, they exhibited elevated levels of essential neurochemicals and energy metabolites in the brain compared to the control mice that received the equimolar saline solution. Following the intraperitoneal administration of kainate (KA) to induce severe SE, the SP-fed mice showed enhanced resistance to seizure activity, reduced neuronal injury, and improved neurobehavioral performance compared to the saline-fed mice. Regarding the molecular mechanisms underlying their neuroprotective properties, the levels of pyruvate metabolism-mediating proteins, neuronal and synaptic proteins, and neuroprotective proteins remained upregulated in the brains of the SP-fed mice following KA-induced SE. Conversely, the levels of pro-apoptotic and oxidative stress markers were suppressed. Collectively, this study indicates that long-term pyruvate supplementation may sustainably augment neurochemical and energy metabolism in the normal brain, thereby eliciting intrinsic neuroprotective properties. These effects contribute to preventing or ameliorating seizure activity, neuronal damage, and neurobehavioral deficits in mice following KA-induced SE, suggesting its prophylactic or therapeutic potential against epileptic seizures and SE through metabolic preconditioning.

Purpose Despite the potential impact of sorafenib on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-mediated contrast enhancements, attempts to assess these effects are rare. This study aimed to investigate the interaction between Sorafenib and Gd-EOB-DTPA by quantifying the T1 and T2 relaxation times and the relative enhancement rates (RERs) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the liver. Procedures The effects on contrast enhancement were assessed using MRI with Chang liver cells and SD rats. MR phantom images were obtained after treating cells with varying dosages of Gd-EOB-DTPA (5, 10 mM) and sorafenib (10, 30 μM) to evaluate MR relaxivities. For the animal study, DCE-MRI was performed following intravenous administration of 25 µmol/kg Gd-EOB-DTPA and two different doses of sorafenib (10, 30 mg/kg). RER was analyzed to evaluate sorafenib's effects on Gd-EOB-DTPA uptake in the liver. Results Phantom experiments demonstrated alterations in T1 and T2 values, with a tendency towards shortening disrupted by the addition of sorafenib to Gd-EOB-DTPA-treated Chang liver cells. The RERs of DCE-MRI in the liver exhibited a dose-dependent decrease following sorafenib administration, with recovery observed after 4 h. Conclusions Our results provide quantitative information on sorafenib-mediated interference with Gd-EOB-DTPA-induced contrast enhancement and offer experimental evidence suggesting the possibility of drug-drug interactions between sorafenib and Gd-EOB-DTPA. Although further research is needed to fully elucidate the impact of these interactions, caution is warranted when using these two agents concurrently for liver MRI.

Brain metastasis (BrM) is a common occurrence in lung cancer and substantially worsens the prognosis due to the blood–brain barrier (BBB), which restricts drug entry into the brain. Here, we found that exosomes secreted by lung cancer cells that had acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance and undergone epithelial–mesenchymal transition (osimertinib- and WZ4002-resistant H1975) exhibited enhanced brain-specific distribution and a concomitant increase in BrM compared with exosomes from parental H1975 cells. To identify exosomal mediators of this phenotype, liquid chromatography-tandem mass spectrometry-based proteomic analysis was performed. Exosomes derived from resistant cell lines exhibited distinct protein profiles relative to parental cells, with 744 exosomal proteins significantly altered (fold change ≥ 2; P ≤ 0.05). Prioritization of membrane proteins and ligand–receptor interaction analysis identified ITGAV (integrin αV), ITGB3 (intergrin β3), and L1CAM (L1 cell adhesion molecule) as candidates interacting with brain-specific ligands, including neural cell adhesion molecule 1 (NCAM1) and contactin 2. Validation of exosomal association by Western blotting identified ITGB3 and L1CAM as final candidates. Subsequent functional modulation studies demonstrated that exosomal L1CAM plays a dominant role in brain distribution and metastatic progression. Exosomal L1CAM increased BBB permeability by disrupting endothelial tight-junction integrity both in vitro and in vivo. This effect was associated with the involvement of NCAM1 on BBB endothelial cells, as suggested by an exosomal L1CAM masking experiment. Clinically, exosomal L1CAM demonstrated diagnostic potential for BrM (area under the curve [AUC] = 0.80), and a combined exosomal L1CAM/ITGB3 panel significantly improved diagnostic accuracy (AUC = 0.98). Collectively, these findings identify exosomal L1CAM as a key regulator of brain-specific metastasis and support the clinical utility of the L1CAM/ITGB3 panel as a noninvasive biomarker for BrM in lung cancer.

Purpose Despite the potential impact of sorafenib on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-mediated contrast enhancements, attempts to assess these effects are rare. This study aimed to investigate the interaction between Sorafenib and Gd-EOB-DTPA by quantifying the T1 and T2 relaxation times and the relative enhancement rates (RERs) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the liver. Procedures: The effects on contrast enhancement were assessed using MRI with Chang liver cells and SD rats. MR phantom images were obtained after treating cells with varying dosages of Gd-EOB-DTPA (5, 10 mM) and sorafenib (10, 30 µM) to evaluate MR relaxivities. For the animal study, DCE-MRI was performed following intravenous administration of 25 µmol/kg Gd-EOB-DTPA and two different doses of sorafenib (10, 30 mg/kg). RER was analyzed to evaluate sorafenib's effects on Gd-EOB-DTPA uptake in the liver. Results Phantom experiments demonstrated alterations in T1 and T2 values, with a tendency towards shortening disrupted by the addition of Sorafenib to Gd-EOB-DTPA-treated Chang liver cells. The RERs of DCE-MRI in the liver exhibited a dose-dependent decrease following sorafenib administration, with recovery observed after 4 h. Conclusions Our results provide quantitative information on sorafenib-mediated interference with Gd-EOB-DTPA-induced contrast enhancement and offer experimental evidence suggesting the possibility of drug-drug interactions between sorafenib and Gd-EOB-DTPA. Although further research is needed to fully elucidate the impact of these interactions, caution is warranted when using these two agents concurrently for liver MRI.

Introduction: Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction secondary to systemic infection, occurring without direct central nervous system involvement. Despite its clinical relevance, reliable biomarkers for diagnosing SAE and assessing its severity remain limited. This study aimed to evaluate the feasibility of amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) MRI as a non-invasive molecular imaging technique for detecting metabolic alterations related to neuroinflammation in SAE. Using a lipopolysaccharide (LPS)-induced rat model, we focused on hippocampal changes associated with neuronal inflammation. Materials and Methods: Twenty-one Sprague–Dawley rats (8 weeks old, male) were divided into three groups: control (CTRL, n = 7), LPS-induced sepsis at 5 mg/kg (LPS05, n = 7), and 10 mg/kg (LPS10, n = 7). Sepsis was induced via a single intraperitoneal injection of LPS. APTw imaging was performed using a 7 T preclinical MRI system, and signal quantification in the hippocampus was conducted using the magnetization transfer ratio asymmetry analysis. Results and Discussion: APTw imaging at 7 T demonstrated significantly elevated hippocampal APTw signals in SAE model rats (LPS05 and LPS10) compared to the control (CTRL) group: CTRL (−1.940 ± 0.207%) vs. LPS05 (−0.472 ± 0.485%) (p < 0.001) and CTRL vs. LPS10 (−0.491 ± 0.279%) (p < 0.001). However, no statistically significant difference was observed between the LPS05 and LPS10 groups (p = 0.994). These results suggest that APTw imaging can effectively detect neuroinflammation-related metabolic alterations in the hippocampus. Conclusion: Our findings support the feasibility of APTw CEST imaging as a non-invasive molecular MRI technique for SAE, with potential applications in diagnosis, disease monitoring, and therapeutic evaluation.

Purpose Gadolinium (Gd)-based contrast agents are primarily used for contrast-enhanced magnetic resonance lymphangiography (MRL). However, overcoming venous contamination issues remains challenging. This study aims to assess the MRL efficacy of the newly developed iron-based contrast agent (INV-001) that is specially designed to mitigate venous contamination issues. The study further explores the optimal dosage, including both injection volume and concentration, required to achieve successful visualization of the popliteal lymph nodes and surrounding lymphatic vessels. Procedures. All animals utilized in this study were male Sprague–Dawley (SD) rats weighing between 250 and 300 g. The contrast agents prepared were injected intradermally in the fourth phalanx of both hind limbs using a 30-gauge syringe in SD rats. MRL was performed every 16 min on a coronal 3D time-of-flight sequence with saturation bands using a 9.4-T animal machine. Results Contrary to Gd-DOTA, which exhibited venous contamination in most animals irrespective of injection dosages and conditions, INV-001 showed no venous contamination. For Gd-DOTA, the popliteal lymph nodes and lymphatic vessels reached peak enhancement 16 min after injection from the injection site and then rapidly washed out. However, with INV-001, they reached peak enhancement between 16 and 32 min after injection, with prolonged visualization of the popliteal lymph node and lymphatic vessels. INV-001 at 0.45 μmol (15 mM, 30 μL) and 0.75 μmol (15 mM, 50 μL) achieved high scores for qualitative image analysis, providing good visualization of the popliteal lymph nodes and lymphatic vessels without issues of venous contamination, interstitial space enhancement, or lymph node enlargement. Conclusion In MRL, INV-001, a novel T₁ contrast agent based on iron, enables prolonged enhancement of popliteal lymph nodes and lymphatic vessels without venous contamination.

Background Injury to the cervical lymph nodes can lead to cervical lymphedema and subsequent fluid accumulation in the head and neck region, potentially causing pathophysiological alteration in the brain. This condition is thought to be linked with various neurological diseases, although the direct connection between cervical lymphatic obstruction and its effect on the brain has been difficult to establish. Methods We produced the disease animal models through lymph node dissection and radiation in fifteen male Sprague–Dawley rats aged 8 weeks and weighing 280–320 g. The models were specifically designed to induce lymphatic obstruction in the cervical region only, with no direct interventions applied to the brain. We evaluated swelling and lymphatic drainage in the head and neck for follow-up. The size of the lateral ventricles was verified through MRI, and changes in water content in brain tissue were directly measured. At 2 and 8 weeks, we observed immune cell infiltration, ventricular enlargement, and pathohistological changes in the harvested brain tissues. Results The experimental animals exhibited lymphatic obstruction in the cervical region, with swelling, abnormal lymphatic drainage, and immune cell infiltration into the brain’s white matter, reminiscent of extremities lymphedema. MRI revealed lateral ventricular enlargement in these animals, indicative of increased cerebrospinal fluid levels compared to the control group. This increase in cerebrospinal fluid was associated with an increase in brain tissue water content, leading to pathophysiological changes akin to those seen in hydrocephalus and cerebral edema. Conclusion The outcomes in this study underscore a significant link between lymphatic circulatory dysfunction and the onset of neurophysiological diseases. Cervical lymphedema showed pathophysiological changes similar to those seen in extremities lymphedema. However, these changes in the brain could be more critical than in the extremities. Our finding highlights the importance of understanding lymphatic system health in preventing and managing neurological conditions.

Chemical exchange saturation transfer with glutamate (GluCEST) imaging is a novel technique for the non-invasive detection and quantification of cerebral Glu levels in neuromolecular processes. Here we used GluCEST imaging and ¹H magnetic resonance spectroscopy (¹H MRS) to assess in vivo changes in Glu signals within the hippocampus in a rat model of depression induced by a forced swim test. The forced swimming test (FST) group exhibited markedly reduced GluCEST-weighted levels and Glu concentrations when examined using ¹H MRS in the hippocampal region compared to the control group (GluCEST-weighted levels: 3.67 ± 0.81% vs. 5.02 ± 0.44%, p < 0.001; and Glu concentrations: 6.560 ± 0.292 μmol/g vs. 7.133 ± 0.397 μmol/g, p = 0.001). Our results indicate that GluCEST imaging is a distinctive approach to detecting and monitoring Glu levels in a rat model of depression. Furthermore, the application of GluCEST imaging may provide a deeper insight into the neurochemical involvement of glutamate in various psychiatric disorders.