Search Results (191)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and chronic neuroinflammation. Emerging evidence suggests a crucial role of lipid signaling pathways in AD pathogenesis, particularly those mediated by autotaxin (ATX) and lysophosphatidic acid (LPA). ATX, an enzyme responsible for LPA production, has been implicated in neuroinflammatory processes, blood–brain barrier dysfunction, and neuronal degeneration. LPA signaling, through its interaction with specific G-protein-coupled receptors, influences neuroinflammation, synaptic plasticity, and tau pathology, all of which contribute to AD progression. This review synthesizes recent findings on the ATX/LPA axis in AD, exploring its potential as a biomarker and therapeutic target. Understanding the mechanistic links between ATX, LPA, and AD pathology may open new avenues for disease-modifying strategies. Full article

Glioblastoma is the most common and aggressive malignant primary brain tumour. Patients with glioblastoma have a median survival of only around 14.6 months after diagnosis, despite the availability of various conventional multimodal treatments including chemotherapy, radiation therapy, and surgery. Therefore, photodynamic therapy (PDT) has emerged as an advanced, selective and more controlled therapeutic approach, which has minimal systemic toxicity and fewer side effects. PDT is a less invasive therapy that targets all cells or tissues that possess the photosensitizer (PS) itself, without affecting the surrounding healthy tissues. Polymeric NPs (PNPs) as carriers can improve the targeting ability and stability of PSs and co-deliver various anticancer agents to achieve combined cancer therapy. Because of their versatile tuneable features, these PNPs have the capacity to open tight junctions of the blood–brain barrier (BBB), easily transport drugs across the BBB, protect against enzymatic degradation, prolong the systemic circulation, and sustainably release the drug. Conjugated polymer NPs, poly(lactic-co-glycolic acid)-based NPs, lipid–polymer hybrid NPs, and polyethylene-glycolated PNPs have demonstrated great potential in PDT owing to their unique biocompatibility and optical properties. Although the combination of PDT and PNPs has great potential and can provide several benefits over conventional cancer therapies, there are several limitations that are hindering its translation into clinical use. This review aims to summarize the recent advances in the combined use of PNPs and PDT in the case of glioblastoma treatment. By evaluating various types of PDT and PNPs, this review emphasizes how these innovative approaches can play an important role in overcoming glioblastoma-associated critical challenges, including BBB and tumour heterogeneity. Furthermore, this review also discusses the challenges and future directions for PNPs and PDT, which provides insight into the potential solutions to various problems that are hindering their clinical translation in glioblastoma treatment. Full article

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. Despite advances in understanding its genetic basis, particularly mutations in Chromosome 9 Open Reading Frame 72 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), and Fused in Sarcoma (FUS) gene, current diagnostic methods result in delayed intervention, and available treatments offer only modest benefits. This review examines innovative approaches transforming ALS research and clinical management. We explore emerging biomarkers, including the fluid-based markers such as neurofilament light chain, exosomes, and microRNAs in biological fluids, alongside the non-fluid-based biomarkers, including neuroimaging and electrophysiological markers, for early diagnosis and patient stratification. The integration of multi-omics data reveals complex molecular mechanisms underlying ALS heterogeneity, potentially identifying novel therapeutic targets. We highlight current gene therapy strategies, including antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR/Cas9 gene editing systems, alongside advanced delivery methods for crossing the blood–brain barrier. By bridging molecular neuroscience with bioengineering, these technologies promise to revolutionize ALS diagnosis and treatment, advancing toward truly disease-modifying interventions for this previously intractable condition. Full article

Background: Previous studies have suggested that electromagnetic pulse (EMP) can induce openings in the blood–brain barrier (BBB). However, the temporal variation and spatial distribution of BBB permeability after EMP radiation are difficult to assess using conventional histopathological approaches. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a valuable tool for the in vivo evaluation of BBB permeability. The main purpose of this study was to investigate the temporal variation and spatial distribution of BBB permeability after EMP radiation in rats using DCE-MRI. Methods: The dose of EMP was estimated through simulations utilizing a digital rat model comprising 16 distinct brain regions. Then, the changes in BBB permeability of the different rat brain regions at different time points (3 h and 24 h) after EMP radiation were evaluated using quantitative DCE-MRI. Furthermore, the spatial difference in BBB permeability was assessed 3 h after exposure. Finally, the dose–effect relationship between the electric field strength and the BBB permeability was also investigated. Results: The results demonstrated that the changes in the values of volume transfer constant (ΔK^trans) significantly increased in several rat brain regions at 3 h after 400 kV/m EMP radiation. These changes vanished 24 h after exposure. Meanwhile, no significant spatial differences in BBB permeability were observed after EMP radiation. Moreover, Pearson’s correlation analysis showed that there was a significant positive linear relationship between BBB permeability and the electric field strength within an external electric field strength range of 0 to 400 kV/m at 3 h after EMP radiation. Conclusions: EMP radiation can induce a reversible increase in BBB permeability in rats. Moreover, no significant differences in BBB permeability were found across different brain regions. Additionally, the degree of BBB permeability was positively correlated with the regional electric field strength of EMP radiation within an external electric field strength range of 0 to 400 kV/m at 3 h after EMP radiation. These results indicate the promising potential of employing EMP for transient openings in the BBB, which could facilitate clinical pharmacological interventions via drug delivery into the brain. Full article

Focused ultrasound (FUS) is an emerging noninvasive technology with significant therapeutic potential across various clinical domains. FUS enables precise targeting of tissues using mechanisms like thermoablation, mechanical disruption, and neuromodulation, minimizing damage to surrounding areas. In movement disorders such as essential tremor and Parkinson’s disease, MR-guided FUS thalamotomy has demonstrated substantial tremor reduction and improved quality of life. Psychiatric applications include anterior capsulotomy for treatment-resistant obsessive-compulsive disorder and major depressive disorder, with promising symptom relief and minimal cognitive side effects. FUS also facilitates blood-brain barrier opening for drug delivery in neurological conditions like Alzheimer’s disease. Musculoskeletal applications highlight its efficacy in managing chronic pain from knee osteoarthritis and lumbar facet joint syndrome through precise thermal ablation. Additionally, FUS has shown potential in neuropathic pain management and peripheral nerve stimulation, offering innovative approaches for amputees and cancer survivors. Cognitive and neuromodulatory research underscores its ability to enhance motor function and interhemispheric cortical balance, benefiting stroke and traumatic brain injury rehabilitation. Despite these conditions frequently leading to various kinds of disabilities, no direct exploration of the possible FUS application in rehabilitation is yet available in the literature. All this considered, this review aims to discuss how FUS could be applied in rehabilitation, exploring the current status of knowledge and highlighting future directions. Full article

Background/Objectives: The low permeability of the blood-brain barrier (BBB) represents a significant challenge to effective systemic chemotherapy for primary and metastatic brain cancers. Kinin receptors play a crucial role in modulating BBB permeability, and their agonist analogs have been explored in preclinical animal models to enhance drug delivery to the brain. In this study, we investigated whether des-Arg⁹-bradykinin (DBK), a physiological agonist of kinin B₁ receptor (B1R), acts as a brain drug delivery adjuvant by promoting the transient opening of the BBB. Methods: Human brain microvascular endothelial cells (HBMECs) were treated with DBK in the culture medium and in conditioned media from glioblastoma cell lines, namely T98G (CMT98G) and U87MG (CMU87). Immunofluorescence, RT-qPCR, in-cell Western assay, and proximity ligation assay (PLA) were performed to analyze BBB components, kinin receptors and TLR4, a receptor associated with the kinin pathway and inflammation. The effect of DBK on enhancing paracellular molecule transport was evaluated using Evans blue dye (EB) quantification in a cell culture insert assay and in an in vivo model, where mice with and without brain tumors were treated with DBK. To assess the functional impact of the transient BBB opening induced by DBK, the chemotherapeutic drug doxorubicin (DOX) was administered. Results: Treatment with DBK facilitates the presence of EB in the brain parenchyma by transiently disrupting the BBB, as further evidenced by the increased paracellular passage of the dye in an in vitro assay. B1R activation by DBK induces transient BBB opening lasting less than 48 h, enhancing the bioavailability of the DOX within the brain parenchyma and glioma tumor mass. The interaction between B1R and TLR4 is disrupted by the secreted factors released by glioblastoma cells, as conditioned media from T98G and U87 reduce TLR4 staining in endothelial cells without affecting B1R expression. Conclusions: These results further support the potential of B1R activation as a strategy to enhance targeted drug delivery to the brain. Full article

Background/Objectives: Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor diagnostic and theranostic probes. Methods: We assessed FOLH1 expression from the Open Pediatric Cancer Project (OpenPedCan, n = 2132 specimens), the Cancer Genome Atlas (TCGA, n = 10,411 specimens), and the Genotype Tissue Expression Project (GTEx, n = 17,382 specimens) in relation to published reports of PSMA radionuclide uptake in various tumors. Results: When comparing FOLH1 expression across tumor versus normal tissues, we found that non-CNS tumors exhibiting elevated expression of at least two-fold (FDR < 0.05) were reported to have significant PSMA radionuclide uptake in contrast to tumors with less than a two-fold elevation or with lower expression of FOLH1 relative to normal tissues. Notably, CNS tumors universally exhibited lower expression of FOLH1 relative to normal brain tissue, but we observed considerable variation in the expression of blood–tumor barrier (BTB) components associated with reports of BTB integrity and uptake of PSMA radiotracers. Conclusions: Large-scale transcriptomics data may help guide the application of PSMA-based radionuclide therapies in non-CNS tumors, but care should be taken to account for BTB effects in CNS tumors when assessing the potential for radionuclide success. This study demonstrates that FOLH1 showed a lack of tumor-specific expression for both adult and pediatric CNS tumors when compared to normal brain tissue, suggesting that PSMA is not a desirable target in brain tumors. Full article

Background: The blood–brain barrier (BBB) plays an important role in regulating homeostasis of the central nervous system (CNS), and it is an obstacle for molecules with a molecular weight higher than 500 Da seeking to reach it, making many drugs ineffective simply because they cannot be delivered to where they are needed. As a result, crossing the BBB remains the rate-limiting factor in brain drug delivery during the treatment of brain diseases, specifically tumors such as diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric tumor with onset in the pons Varolii, the middle portion of the three contiguous parts of the brainstem, located above the medulla and below the midbrain. Methods: Currently, radiotherapy (RT) relieves DIPG symptoms but chemotherapy drugs do not lead to significant results as they do not easily cross the BBB. Focused ultrasound (FUS) and microbubbles (MBs) can temporarily open the BBB, facilitating radiotherapy and the entry of drugs into the CNS. A patient-derived xenograft DIPG model exposed to high-intensity focalized ultrasound (HIFU) or low-intensity focalized ultrasound (LIFU) combined with MBs was treated with doxorubicin, panobinostat, olaparib, ONC201 (Dordaviprone^®) and anti-PD1. Panobinostat has also been used in children with diffuse midline glioma, a broad class of brain tumors to which DIPG belongs. Results: Preliminary studies were performed using FUS to temporarily open the BBB and allow a milder use of radiotherapy and facilitate the passage of drugs through the BBB. The data collected show that after opening the BBB with FUS and MBs, drug delivery to the CNS significantly improved. Conclusions: FUS associated with MBs appears safe and feasible and represents a new strategy to increase the uptake of drugs in the CNS and therefore enhance their effectiveness. This review reports pre-clinical and clinical studies performed to demonstrate the usefulness of FUS in patients with DIPG treated with some chemotherapy. The papers reviewed were published in PubMed until the end of 2024 and were found using a combination of the following keywords: diffuse intrinsic pontine glioma (DIPG), DIPG H3K27-altered, blood–brain barrier and BBB, focused ultrasound (FUS) and radiotherapy (RT). Full article

Objective: To evaluate the efficacy of the neurotropic action of cortexin in models of mental and physical developmental delays in rat offspring. Methods: The neurotropic properties of bovine brain cortex polypeptides were studied using two models of mental and physical developmental delays in rats: toxic CNS damage (oral administration of ethanol during the last week of pregnancy) and neonatal trauma (ischemia-hypoxia). The drug was administered intramuscularly or rectally as suppositories for 20 days. Treatment efficacy was evaluated using the mNSS scale, open field, rotarod, and adhesive removal tests. A histological examination of the brain was subsequently performed. In a separate series of experiments in mice, the concentration of the test drug cortexin and the reference drug cerebrolysin was determined in blood and brain tissue samples using radioactive iodine (Na125I) labeling of these preparations. Results: Modeling developmental delay in rat offspring (due to the toxic effect of ethanol in late pregnancy or neonatal trauma) led to pronounced neurological deficits, manifested by decreased motor activity, and sensorimotor, and coordination disorders. Administration of cortexin in all forms reduced the severity of neurological deficits as measured by mNSS scores, improved motor activity in the Open Field test, enhanced performance in the Adhesive Removal and Rotarod tests, and decreased structural changes in brain tissues. Histological examination revealed reduced neuronal damage in multiple cortical regions, with a significant increase in normal, unchanged neurons compared to placebo groups. Comparison of the blood concentrations of labeled Na125I cortexin depending on the type of administration showed similar distribution profiles in brain tissues, primarily dependent on its blood concentration, which was influenced by the route of administration. Conclusions: The results indicate that brain polypeptides (cortexin), administered either intramuscularly or rectally, can reach the systemic circulation and cross the blood-brain barrier, as demonstrated by our distribution studies using radiolabeled preparations. These polypeptides exert comparable neurotropic effects in models of mental and physical developmental delays in offspring caused by neonatal trauma or the toxic effect of ethanol in late pregnancy in rats. Full article

Neurodegenerative disorders present significant therapeutic challenges, particularly due to the complex nature of drug delivery to the central nervous system. This review investigates the applications of various biopolymers in neuroprotection and their potential role in treating neurodegeneration. We present a critical analysis of natural and synthetic biopolymers, focusing primarily on chitosan, fish collagen/gelatin, and alginate as key therapeutic agents. The review examines the fundamental mechanisms of brain development and neurodegeneration, establishing a framework for understanding how these biopolymers interact with neural tissues. By analyzing recent experimental studies, we evaluate the effectiveness of different biopolymer-based delivery systems in crossing the blood–brain barrier and their subsequent neuroprotective effects. Additionally, promising materials, including lignin, poly lactic-co-glycolic acid, and glucose-modified bovine serum albumin/procyanidin complexes, are briefly explored to provide a comprehensive overview of current developments in the field. Our analysis reveals that biopolymer-based approaches offer unique advantages in both neuroprotection and drug delivery, potentially opening new avenues for treating neurodegenerative conditions. This review synthesizes current knowledge and identifies promising directions for future research in biopolymer-based therapeutic strategies. Full article

Streptococcus suis (S. suis) is a major swine pathogen throughout the world as well as an emerging zoonotic agent. Among the symptoms caused by S. suis, including septicemia, pneumonia, endo-carditis, arthritis, and meningitis, the latter is the most overlooked. In the present study, we explored the mechanism of action of berberine against S. suis meningitis by obtaining berberine-related action targets, porcine S. suis meningitis targets, and human S. suis meningitis targets from open databases. We constructed a protein–protein interaction (PPI) network by using the STRING database and employed Cytoscape 3.8.0 to screen for core targets. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses through DAVID. We identified 31 potential targets of berberine, of which Toll-like receptor 4 (TLR4), fibronectin 1 (FN1), superoxide dismutase (SOD1), and catalase (CAT) were the four most critical targets. GO analysis revealed the enrichment of terms related to the response to oxidative stress and the inflammatory response. KEGG analysis revealed the enrichment of the interleukin 17 (IL-17), phosphoinositide 3-kinase (PI3K)-Akt, TLR, tumor necrosis factor (TNF), and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, the admetSAR results showed that berberine can cross the blood–brain barrier. The molecular docking results indicated key binding activity between TLR4–berberine and FN1–berberine. In summary, berberine protects against Streptococcus suis meningitis by regulating inflammatory response and oxidative stress in humans and pigs. Our study updates the current knowledge of the targets of S. suis meningitis to exploit new drugs in humans and pigs, to develop environmentally friendly and antibiotic-free animal-derived food products, and to improve the farming industry and economic development. Full article

This study investigates the biorefinery approach to extracting blood–brain barrier (BBB)-permeable compounds from Eucalyptus globulus Labill. and Salvia officinalis L. for neuroprotective purposes. A sequential extraction process was applied, starting with supercritical CO₂ extraction (SC-CO₂) to obtain non-polar terpenoids, followed by pressurized natural deep eutectic solvent extraction (PLE-NaDES) to recover phenolic compounds from the SC-CO₂ residue. PLE-NaDES extracts exhibited higher antioxidant and anticholinergic capacities than SC-CO₂ extracts for both plants, with S. officinalis extracts being more bioactive than E. globulus extracts. A total of 21 terpenoids were identified using gas chromatography–mass spectrometry from E. globulus while 24 were detected from S. officinalis SC-CO₂ extracts. In addition, 25 different phenolic compounds were identified in both plants using high-performance liquid chromatography coupled with mass spectrometry from PLE-NaDES extracts. The study of the permeability across the BBB showed limited permeability for non-polar compounds obtained by SC-CO₂ from both plants; however, the more polar compounds obtained by PLE-NaDES showed high permeability, particularly for flavonoids in E. globulus and rosmarinic acid in S. officinalis. This study revealed, for the first time, the antioxidant and neuroprotective potential of S. officinalis and E. globulus extracts obtained using SC-CO₂ followed by PLE-NaDES, as well as the high permeability of PLE-NaDES extracts when crossing the BBB to exert their protective effects. This research opens a new pathway for exploring alternatives to current drugs used in treating neurodegenerative diseases. Full article

Background/Objective: The blood–brain barrier (BBB) is selectively permeable, but it also poses significant challenges for treating CNS diseases. Low-intensity focused ultrasound (LiFUS), paired with microbubbles is a promising, non-invasive technique for transiently opening the BBB, allowing enhanced drug delivery to the central nervous system (CNS). However, the downstream physiological effects following BBB opening, particularly secondary responses, are not well understood. This study aimed to characterize the time-dependent changes in BBB permeability, transporter function, and inflammatory responses in both sonicated and non-sonicated brain tissues following LiFUS treatment. Methods: We employed in situ brain perfusion to assess alterations in BBB integrity and transporter function, as well as multiplex cytokine analysis to quantify the inflammatory response. Results: Our findings show that LiFUS significantly increased vascular volume and glucose uptake, with reduced P-gp function in brain tissues six hours post treatment, indicating biphasic BBB disruption. Additionally, elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6, were observed in both sonicated and non-sonicated regions. A comparative analysis between wild-type and immunodeficient mice revealed distinct patterns of cytokine release, with immunodeficient mice showing lower serum concentrations of IFN-γ and TNF-α, highlighting the potential impact of immune status on the inflammatory response to LiFUS. Conclusions: This study provides new insights into the biphasic nature of LiFUS-induced BBB disruption, emphasizing the importance of understanding the timing and extent of secondary physiological changes. Full article

The growing interest in minimal and non-invasive therapies, especially in the field of cancer treatment, highlights a significant shift toward safer and more effective options. Ablative therapies are well-established tools in cancer treatment, with known effects including locoregional control, while their role as modulators of the systemic immune response against cancer is emerging. The HIFU developed with magnetic resonance imaging (MRI) guidance enables treatment precision, improves real-time procedural control, and ensures accurate outcome assessment. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) induces deep coagulation necrosis within an elliptical focal area, effectively encompassing the entire tumor site and allowing for highly targeted radical ablation. The applications of MRgFUS in oncology are rapidly expanding, offering pain relief and curative treatment options for bone metastatic lesions. Additionally, the MRgFUS plays an effective role in targeted optional therapies for early prostate and breast cancers. Emerging research also focuses on the potential uses in treating abdominal cancers and harnessing capabilities to stimulate immune responses against tumors or to facilitate the delivery of anticancer drugs. This evolving landscape presents exciting opportunities for improving patient outcomes and advancing cancer treatment methodologies. In neuro-oncology, MRgFUS utilizes low-intensity focused ultrasound (LIFU) along with intravenous microbubbles to open the blood-brain barrier (BBB) and enhance the intra-tumoral delivery of chemotherapy drugs. Full article

Gliomas are a wide group of common brain tumors, with the most aggressive type being glioblastoma multiforme (GBM), with a 5-year survival rate of less than 5% and a median survival time of approximately 12–14 months. The standard treatment of GBM includes surgical excision, radiotherapy, and chemotherapy with temozolomide (TMZ). However, tumor recurrence and progression are common. Therefore, more effective treatment for GBM should be found. One of the main obstacles to the treatment of GBM and other gliomas is the blood–brain barrier (BBB), which impedes the penetration of antitumor chemotherapeutic agents into glioblastoma cells. Nowadays, one of the most promising novel methods for glioma treatment is Magnetic Resonance-guided Focused Ultrasound (MRgFUS). Low-intensity FUS causes the BBB to open transiently, which allows better drug delivery to the brain tissue. Under magnetic resonance guidance, ultrasound waves can be precisely directed to the tumor area to prevent side effects in healthy tissues. Through the open BBB, we can deliver targeted chemotherapeutics, anti-tumor agents, immunotherapy, and gene therapy directly to gliomas. Other strategies for MRgFUS include radiosensitization, sonodynamic therapy, histotripsy, and thermal ablation. FUS can also be used to monitor the treatment and progression of gliomas using blood-based liquid biopsy. All these methods are still under preclinical or clinical trials and are described in this review to summarize current knowledge and ongoing trials. Full article