Search Results (454)

Blood–brain barrier (BBB) deterioration with increasing age is an important factor contributing to vascular dementia. Previous studies show that endothelial nitric oxide synthase (eNOS) facilitates vascular endothelial growth factor-mediated angiogenesis and increased vascular permeability. In contrast, recent work has shown that aged hemi-deficient hemizygous eNOS^+/− mice manifest BBB disruption in association with increased incidence of thromboembolic events in the brain. To unravel whether eNOS contributes to or protects against hypoxia-induced cerebrovascular damage, we compared chronic mild hypoxia (CMH)-induced cerebrovascular angiogenic remodeling and BBB breakdown in aged (20 months old) eNOS^+/− and wild-type (WT) mice. This revealed that CMH strongly enhanced eNOS expression in cerebral blood vessels with much lower levels in eNOS^+/− mice. eNOS hemi-deficiency resulted in greater CMH-induced BBB disruption, but unexpectedly, had no effect on endothelial proliferation. eNOS^+/− mice also displayed enhanced endothelial expression of the endothelial activation markers MECA-32, VCAM-1, and β3 integrin in cerebral blood vessels, indicating greater vascular inflammation, and this correlated with increased levels of microglial activation and demyelination. Taken together, our results support the concept that eNOS plays an important protective function in the aged brain by suppressing endothelial activation and maintaining cerebrovascular health. Full article

Background/Objectives: Gut microbial dysbiosis, leaky gut, and increased transepithelial translocation of commensal bacteria have been documented in multiple sclerosis (MS). Intrathecal IgGs specific for Akkermansia muciniphila, a gut bacterium, are increased in patients with MS and associated with clinical disability. Our objective here was to explore the putative involvement of intrathecal anti-A. muciniphila IgG in MS pathogenesis by characterizing patients with different anti-A. muciniphila IgG indices. Methods: Serum and intrathecal IgG specific for A. muciniphila and other gut bacteria, as well as routine cerebrospinal fluid (CSF) parameters, were measured in 61 patients with MS. Examination of these patients included immunophenotyping of CSF-infiltrating and paired circulating lymphocytes, intrathecal markers of neurodegeneration and inflammation, and a detailed characterization of demographic, clinical, and magnetic resonance imaging (MRI) features. Results: Plasma blasts (p < 0.01), B cells (p < 0.01), and Th2 cells (p < 0.01), which might be involved in antibody production, were increased in the CSF of these patients, as well as blood pro-inflammatory Th17 cells (p < 0.05). Anti-A. muciniphila IgG indices were negatively associated with blood-brain barrier (BBB) permeability and circulating monocytes (p < 0.001), and positively with brain lesion load (p < 0.01). Conclusions: The differences between patients with low and high anti-A. muciniphila IgG indexes regarding BBB permeability, CSF cell infiltrates, and pro-inflammatory peripheral immune cells, as well as imaging features, support a role of anti-A. muciniphila immune response in MS pathogenesis. Full article

Tumor necrosis factor (TNF) receptor-associated factor 7 (TRAF7) is a signal transducer in the TNF receptor superfamily. TRAF7 is unique among its superfamily in that it does not contain a TRAF-C domain but does contain WD-40 domains. TRAF7 interacts with mitogen-activated protein kinases (MAPK), which are known regulators of inflammation and shear stress response. Notably, these molecular interactions have profound implications for the function of brain endothelial cells (ECs), which are pivotal for sustaining the integrity of the blood–brain barrier (BBB), orchestrating neurovascular coupling (NVC), and modulating the vascular architecture. By directly influencing MAPK signaling pathways, particularly the shear stress-responsive MAPK kinase kinase 3 (MEKK3)–MAPK kinase 5 (MEK5)–extracellular-regulated protein kinase 5 (ERK5) cascade, TRAF7 contributes to vascular homeostasis, as exemplified by its role in phosphorylating ERK5. Such molecular events underpin the capacity of brain ECs to regulate substance exchange, adjust blood flow in response to neural activity, and maintain efficient cerebral perfusion, all of which are essential for preserving brain health and cognitive performance. By synthesizing the current evidence regarding TRAF7’s molecular functions and its impact on brain endothelial integrity, cerebrovascular aging, and exploring implications for therapeutic strategies targeting vascular dysfunction in the aging brain, this review fills a crucial gap in the literature. Given the limited number of original studies directly addressing these contexts, the review will integrate broader insights from related literature to provide a foundational overview for future research in this developing field. The culmination of this literature will provide a rationale for the development of novel TRAF7-targeted therapies to restore vascular integrity in the context of aging, which could maintain cognitive health. Although TRAF7 has been implicated in regulating endothelial permeability during inflammation, its precise functions in brain ECs and the subsequent effects on cerebrovascular structure and cognitive function remain to be fully elucidated. Full article

Microtubules play a key role in cell division and cell migration. Thus, microtubule-targeting agents (MTAs) are pivotal in cancer therapy due to their ability to disrupt cell division microtubule dynamics. Traditionally divided into stabilizers and destabilizers, MTAs are increasingly being repurposed for central nervous system (CNS) applications, including brain malignancies such as gliomas and neurodegenerative diseases like Alzheimer’s and Parkinson’s. Microtubule-stabilizing agents, such as taxanes and epothilones, promote microtubule assembly and have shown efficacy in both tumour suppression and neuronal repair, though their CNS use is hindered by blood–brain barrier (BBB) permeability and neurotoxicity. Destabilizing agents, including colchicine-site and vinca domain binders, offer potent anticancer effects but pose greater risks for neuronal toxicity. This review highlights the mapping of nine distinct tubulin binding pockets—including classical (taxane, vinca, colchicine) and emerging (tumabulin, pironetin) sites—that offer new pharmacological entry points. We summarize the recent advances in structural biology and drug design, enabling MTAs to move beyond anti-mitotic roles, unlocking applications in both cancer and neurodegeneration for next-generation MTAs with enhanced specificity and BBB penetration. We further discuss the therapeutic potential of combination strategies, including MTAs with radiation, histone deacetylase (HDAC) inhibitors, or antibody–drug conjugates, that show synergistic effects in glioblastoma models. Furthermore, innovative delivery systems like nanoparticles and liposomes are enhancing CNS drug delivery. Overall, MTAs continue to evolve as multifunctional tools with expanding applications across oncology and neurology, with future therapies focusing on optimizing efficacy, reducing toxicity, and overcoming therapeutic resistance in brain-related diseases. Full article

Iridoids are compounds recognized for their neuroprotective properties and their potential application in the treatment of neurodegenerative diseases. Geniposide (GP) and asperuloside (ASP) are iridoids that have demonstrated some biological activities. In this study, the potential neuroprotective effects of these iridoids were evaluated through in silico and in vivo assays, using Caenorhabditis elegans (C. elegans) strains CF1553 (sod-3::GFP), GA800 (cat::GFP), and CL2166 (gst-4::GFP). The results suggested that neither compound appears to have good passive permeability through the blood–brain barrier (BBB). However, an active transport mechanism involving the glucose transporter GLUT-1 may be present, as both compounds contain glucose in their molecular structure. In addition, they can inhibit the activity of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). GP at 1 and 2 mM reversed the H₂O₂-induced increase in sod-3 expression, while ASP at 1 and 2 mM reversed the increase in gst-4 expression. Worm survival was more adversely affected by higher concentrations of GP than ASP, although both similarly reduced acetylcholinesterase activity. These findings suggest that GP and ASP exhibit very low toxicity both in silico and in vivo in C. elegans, and positively modulate key enzymes involved in antioxidant pathways, highlighting their potential for neuroprotective applications. Full article

Donepezil (DPZ) is an Alzheimer’s disease (AD) drug that promotes cholinergic neurotransmission and exhibits excellent acetylcholinesterase (AChE) selectivity. The current oral formulations of DPZ demonstrate decreased bioavailability, attributed to limited drug permeability across the blood–brain barrier (BBB). In order to overcome these limitations, various dosage forms aimed at delivering DPZ have been explored. This discussion will focus on the nose-to-brain (N2B) delivery system, which represents the most promising approach for brain drug delivery. Intranasal (IN) drug delivery is a suitable system for directly delivering drugs to the brain, as it bypasses the BBB and avoids the first-pass effect, thereby targeting the central nervous system (CNS). Currently developed formulations include lipid-based, solid particle-based, solution-based, gel-based, and film-based types, and a systematic review of the N2B research related to these formulations has been conducted. According to the in vivo results, the brain drug concentration 15 min after IN administration was more than twice as high those from other routes of administration, and the direct delivery ratio of the N2B system improved to 80.32%. The research findings collectively suggest low toxicity and high therapeutic efficacy for AD. This review examines drug formulations and delivery methods optimized for the N2B delivery of DPZ, focusing on technologies that enhance mucosal residence time and bioavailability while discussing recent advancements in the field. Full article

The blood–brain barrier (BBB) is a highly selective interface between the bloodstream and the brain that prevents systemically administered therapeutics from effectively reaching tumor cells. As tumors progress, this barrier undergoes structural and functional alterations, giving rise to the blood–tumor barrier (BTB)—a pathologically modified structure that, despite increased permeability, often exhibits heterogeneous and clinically insufficient drug transport. Although a new generation of therapies is promising, their therapeutic potential cannot be realized unless the challenges posed by these barriers are effectively addressed. Various pharmacological strategies were explored to enhance brain tumor drug delivery. These include receptor-mediated disruption, inhibition of efflux transporters, and the engineering of delivery platforms that leverage endogenous transport pathways—such as carrier-mediated, adsorptive-mediated, and receptor-mediated mechanisms—as well as cell-mediated drug delivery. This review synthesizes (1) the BBB and BTB’s structural characteristics; (2) the influence of the tumor microenvironment (TME) on drug delivery; (3) pharmacological strategies to enhance drug accumulation within brain tumors; (4) the integration of pharmacological methods with neurosurgical techniques to enhance drug delivery. As efforts to improve drug delivery across the BBB and BTB accelerate, this review aims to map the current landscape of pharmacological approaches for enhancing drug penetration into brain tumors. Full article

Brain cancer is a heterogeneous collection of malignant neoplasms, such as glioblastoma multiforme (GBM), astrocytomas and medulloblastomas, with high morbidity and mortality. Its treatment is complicated by the tumor’s site, infiltrative growth mode and selective permeability of the blood–brain barrier (BBB). During tumor formation, the BBB dynamically remodels into the blood–brain tumor barrier (BBTB), disrupting homeostasis and preventing drug delivery. Furthermore, the TME (Tumor Micro Environment) supports drug resistance, immune evasion and treatment failure. This review points out the ways in which nanomedicine overcomes these obstacles with custom-designed delivery systems, sophisticated diagnostics and personalized therapies. Traditional treatments fail through a lack of BBB penetration, non-specific cytotoxicity and swift tumor adaptation. Nanomedicine provides greater drug solubility, protection against enzymatic degradation, target drug delivery and control over the release. Nanotheranostics’ confluence of therapeutic and diagnostic modalities allows for dynamic adjustment and real-time monitoring. Nanotechnology has paved the way for the initiation of a new era in precision neuro-oncology. Transcending the limitations of conventional therapy protocols, nanomedicine promises to deliver better outcomes by way of enhanced targeting, BBB penetration and real-time monitoring. Multidisciplinary collaboration, regulatory advancements and patient-centered therapy protocols customized to the individual patient’s tumor biology will be necessary to facilitate translation success in the future. Full article

Brain metastases (BM), which most commonly originate from lung, breast, or skin cancers, remain a major clinical challenge, with standard treatments such as stereotactic radiosurgery (SRS), surgical resection, and whole-brain radiation therapy (WBRT). The prognosis for patients with BM remains poor, with a median overall survival (OS) of just 10–16 months. Although recent advances in systemic therapies, including small molecule inhibitors, monoclonal antibodies, chemotherapeutics, and gene therapies, have demonstrated success in other malignancies, their effectiveness in central nervous system (CNS) cancers is significantly limited by poor blood–brain barrier (BBB) permeability and subtherapeutic drug concentrations in the brain. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome these limitations by enhancing CNS drug penetration and selectively targeting metastatic brain tumor cells while minimizing off-target effects. This review summarizes recent preclinical and clinical developments in nanoparticle-based therapies for BM. It is evident from these studies that NPs can carry with them a range of therapeutics, including chemotherapy, immunotherapy, small molecule inhibitors, gene therapies, radiosensitizers, and modulators of tumor microenvironment to the BM. Moreover, preclinical studies have shown encouraging efficacy in murine models, highlighting the potential of these platforms to improve therapeutic outcomes. However, clinical translation remains limited, with few ongoing trials. To close this translational gap, future work must address clinical challenges such as trial design, regulatory hurdles, and variability in BBB permeability while developing personalized nanoparticle-based therapies tailored to individual tumor characteristics. Full article

The area postrema (AP) is a circumventricular organ (CVO) at the base of the fourth ventricle. It has a crucial role in regulating nausea and vomiting due to its unique blood–brain barrier (BBB)-permeability and extensive neural connectivity. Here, we present two cases of area postrema syndrome (APS), a rare condition of intractable nausea and vomiting resulting from direct AP injury. Our cases each occurred in the context of infratentorial neoplasms or their treatment. Using these cases as a framework, we review the literature on central emetic pathways and propose a treatment algorithm for managing refractory nausea and vomiting of central origin. We also highlight other targets beyond conventional serotonergic, dopaminergic, or histaminergic blockade and their roles in central hyperemesis. Our literature review suggests that APS is due to the disruption of the baseline inhibitory tone of outgoing AP signals. When other options fail, our algorithm culminates in the off-label use of combined serotonergic and neurokinin-1 blockade, which is otherwise used to manage chemotherapy-induced nausea and vomiting (CINV). We believe multimodal CNS receptor blockade is efficacious in APS because it addresses the underlying central neural dysregulation, rather than solely targeting peripheral emetic triggers. Full article

Brain endothelial cells (BECs) constitute the core component of the blood–brain barrier (BBB), regulating substance exchange between blood and the brain parenchyma to maintain central nervous system homeostasis. In pathological states, the BBB exhibits the disruption of tight junctions, endothelial cell (EC) damage, and increased permeability, accompanied by neuroinflammation, oxidative stress, and abnormal molecular signaling pathways, leading to neurotoxic effects in the brain parenchyma and exacerbating neurodegeneration and disease progression. This review systematically summarizes the developmental origin, structural characteristics, and pathological mechanisms of BECs in diseases such as Alzheimer’s disease, multiple sclerosis, stroke, and glioblastoma with a particular focus on the regulatory mechanisms of the Wnt/β-catenin and VEGF signaling pathways. By integrating the latest research advances, this review aims to provide a comprehensive perspective for understanding the role of BECs in physiological and pathological states and to provide a theoretical basis for the development of BBB-based therapeutic approaches for neurological diseases. Full article

Background: Glioblastoma (GBM) is a highly aggressive primary brain tumor with limited therapeutic options, particularly due to the limited blood–brain barrier (BBB) permeability. Nanoparticle-based drug delivery systems, such as liposomes, can prolong drugs’ circulation time and enhance their accumulation within brain tumors, thereby improving therapeutic outcomes. Controlled drug release further contributes to high local drug concentrations while minimizing systemic toxicity. Oleic acid (OA), a monounsaturated fatty acid, is commonly used to enhance drug loading and increase lipid membrane fluidity. In this study, we developed liposomal formulations with optimized temozolomide (TMZ)’s loading and analyze its response to focused ultrasound (FUS). Methods: We synthetized OA-based liposomes with different lipid composition, performed physicochemical characterization (DLS, TEM) and analyzed the TMZ loading efficiency. Different FUS parameters were tested for effective OA-based liposomes destruction. Safety of selected parameters was evaluated in vivo by MRI, histological staining and RT-PCR of pro-inflammatory cytokines. Results: All the formulations exhibited comparable hydrodynamic diameters; however, OA-containing liposomes demonstrated a significantly higher TMZ encapsulation efficiency and enhanced cytotoxicity in U87 glioma cells. Moreover, it was shown that OA-liposomes were disrupted at lower acoustic pressures (5 MPa), while conventional liposomes required higher thresholds (>8 MPa). A safety analysis of FUS parameters indicated that pressures exceeding 11 MPa induced brain edema, necrotic lesions and elevated cytokine levels within 72 h post-treatment. Conclusions: These results suggest that OA-based liposomes possess favorable characteristics, with an increased sonosensitivity for the site-specific delivery of TMZ, offering a promising strategy for glioma treatment. Full article

Seliciclib, a cyclin-dependent kinase 5 (CDK5) inhibitor, has demonstrated neuroprotective potential. However, its therapeutic application is limited by poor permeability across the blood–brain barrier (BBB). In this study, polymeric nanoparticles (NPs) modified with a BBB-targeting peptide ligand (His-Ala-Ile-Tyr-Pro-Arg-His) were employed to encapsulate seliciclib. In vitro transport studies showed that the peptide-modified NPs exhibited significantly greater translocation across a bEnd.3 cell monolayer compared to unmodified NPs. Furthermore, in vivo biodistribution analysis revealed that the brain accumulation of peptide-modified NPs was 3.38-fold higher than that of unmodified NPs. Notably, the peptide-conjugated, seliciclib-loaded NPs demonstrated a significant neuroprotective effect against the neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺) in differentiated SH-SY5Y cells. Full article

Posidonia oceanica (L.) Delile, a Mediterranean seagrass, is rich in bioactive compounds with anti-inflammatory potential. While marine-derived molecules are increasingly studied, their direct effects on blood–brain barrier (BBB) integrity under inflammatory conditions remain largely unexplored. This study evaluated the ability of aqueous extracts from its green leaves (GLEs) and rhizomes (REs) to protect the BBB using a human in vitro model consisting of brain-like endothelial cells co-cultured with brain pericytes. The model was exposed to TNFα, with or without GLEs or REs. We assessed NO production, endothelial permeability, expression of IL-6, NLRP3, ICAM-1, VCAM-1, CLAUDIN-5, and VE-CADHERIN, and the localization of junctional proteins. TNFα increased NO and IL-6 release, upregulated ICAM-1, VCAM-1, and NLRP3, and impaired BBB integrity by altering junctional protein levels and distribution. Co-treatment with GLEs or REs reduced the production of NO, the expression of NLRP3 and adhesion molecules and restored tight and adherens junction integrity. IL-6 levels remained unaffected. These findings suggest that P. oceanica’s extracts may help preserve BBB function and mitigate inflammation-induced damage. While further studies are needed to assess their bioavailability and in vivo efficacy, these natural compounds represent promising candidates for developing preventive strategies against neuroinflammatory disorders. Full article

Background: The blood–brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) but also limits drug delivery. Insufficient knowledge of how the CNS promotes the onset and maintenance of peripheral neuropathic pain limits therapeutic methods for the treatment of persistent neuropathic pain. Thus, this study aimed to evaluate the ability of a novel combination of Palmitoylethanolamide (PEA) and Equisetum arvense L. (Equisetum A.L.) to cross the BBB and modulate nociceptive pathways. Methods: Using a humanised in vitro BBB tri-culture model, the permeability, cytotoxicity, and integrity of the barrier were assessed after exposure to two different PEA forms, PEA ultramicronized (PEA-um) and PEA80mesh, Equisetum A.L., and a combination of the last two samples. The samples exhibited no cytotoxicity, maintained tight junction integrity, and efficiently crossed the blood–brain barrier (BBB), with the combination displaying the highest permeability. The eluate from the BBB model was then used to stimulate the co-culture of CCF-STTG1 astrocytes and SH-SY5Y neurons pre-treated with H₂O₂ 200 µM. Results: Treatment with the combination significantly increased cell viability (1.8-fold, p < 0.05), reduced oxidative stress (2.5-fold, p < 0.05), and decreased pro-inflammatory cytokines (TNFα, IL-1β) compared to single agents. Mechanistic analysis revealed modulation of key targets involved in pain pathways, including decreased FAAH and NAAA activity, increased levels of endocannabinoids (AEA and 2-AG), upregulation of CB2 receptor expression, enhanced PPARα activity, and reduced phosphorylation of PKA and TRPV1. Conclusions: These findings suggest that the combination of PEA and Equisetum A.L. effectively crosses the BBB and exerts combined anti-inflammatory and analgesic effects at the CNS level, suggesting a possible role in modulating neuroinflammatory and nociception responses. Full article