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Inflammation within the brain is a hallmark of a wide range of brain diseases. The complex role of inflammatory processes in these conditions suggests that neuroinflammation could be a valuable therapeutic target. While several promising anti-inflammatory agents have been identified, their clinical application in brain diseases is often hampered by the inability to cross the blood-brain barrier (BBB) and reach therapeutically effective concentrations at the pathological sites. This limitation highlights the urgent need for effective BBB-penetrating drug delivery systems designed to target brain inflammation. This review critically examines the recent advances over the past five years in drug delivery strategies aimed at mitigating brain inflammation in Alzheimer's disease and ischemic stroke─two of the leading causes of death and disability worldwide. Additionally, we address the key challenges in this field, offering insights into future directions for targeting neuroinflammation in the treatment of brain diseases.

The study evaluates the impact of environmental toxicants, such as polycyclic aromatic hydrocarbons (PAHs), on circadian regulations and functions of brain endothelial cells, which form the main structural element of the blood-brain barrier (BBB). PAH are lipophilic and highly toxic environmental pollutants that accumulate in human and animal tissues. Environmental factors related to climate change, such as an increase in frequency and intensity of wildfires or enhanced strength of hurricanes or tropical cyclones, may lead to redistribution of these toxicants and enhanced human exposure. These natural disasters are also associated with disruption of circadian rhythms in affected populations, linking increased exposure to environmental toxicants to alterations of circadian rhythm pathways. Several vital physiological processes are coordinated by circadian rhythms, and disruption of the circadian clock can contribute to the development of several diseases. The blood-brain barrier (BBB) is crucial for protecting the brain from blood-borne harmful substances, and its integrity is influenced by circadian rhythms. Exposure of brain endothelial cells to a human and environmentally-relevant PAH mixture resulted in dose-dependent alterations of expression of critical circadian modulators, such as Clock, Bmal1, Cry1/2, and Per1/2. Moreover, silencing of the circadian Clock gene potentiated the impact of PAHs on the expression of the main tight junction genes and proteins (namely, claudin-5, occludin, JAM-2, and ZO-2), as well as mitochondrial bioenergetics. Findings from this study contribute to a better understanding of pathological influence of PAH-induced health effects, especially those related to circadian rhythm disruption., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationship that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Protection against blood-brain barrier (BBB) dysfunction is key to reduce the cerebral ischemia injury as its breakdown causes edema formation and extravasation of blood components and immune cells. The maintenance of BBB integrity requires the GSK-3β/β-catenin pathway activity. Naringenin (NAR), an effective monomer from Chinese herbal medicine, had potent protective effect on brain inflammatory and oxidative injury. However, whether NAR could protect the integrity of BBB during cerebral ischemia injury and the involvement of GSK-3β/β-catenin pathway in the beneficial effect of NAR was unknown. Therefore, mouse middle cerebral artery occlusion/reperfusion (IR) model was employed to answer these questions. NAR was intraperitoneally administrated once daily for 6 days immediately after IR with the dose of 10 mg/kg. BBB damage was evaluated with Evans blue. Protein levels of GSK-3β and β-catenin in vascular endothelial cells at penumbra were assessed with western blotting and immunofluorescence. The experimental data suggested that NAR improved neurological deficits, decreased the percentage of infarct volumes and neuronal apoptosis at 7d after IR. NAR improved BBB damage as evidenced by a lower permeability of Evans blue dye and upregulation of tight junction proteins such as zonula occludens-1(ZO-1), Occludin and Claudin-5. Importantly, GSK-3β/β-catenin pathway activity was related to the improvement of BBB integrity rendered by NAR. Our findings demonstrated that NAR might become a potential therapeutic drug for IR., Competing Interests: Declarations Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Astrocyte swelling, blood brain barrier (BBB) dissipation and the subsequent brain edema are serious consequences of persistent hyperammonemia in hepatic encephalopathy (HE) in which if inadequately controlled it will lead to brain death. The current study highlights the potential neuroprotective effect of diacerein against thioacetamide (TAA)-induced HE in acute liver failure rat model. HE was induced in male Sprague-Dawley rats via I.P. injection of TAA (200 mg/kg) for three alternative times/week at 3 rd week of the experiment. Diacerein (50 mg/kg) was gavaged for 14 days prior to induction of HE and for further 7 days together with TAA injection for an overall period of 21 days. Diacerein attenuated TAA-induced HE in acute liver failure rat model; as proofed by significant lowering of serum and brain ammonia concentrations, serum AST and ALT activities and significant attenuation of both brain and hepatic MDA contents and IL-1β with marked increases in GSH contents (P < 0.0001). The neuroprotective effect of diacerein was demonstrated by marked improvement of motor and cognitive deficits, brain histopathological changes; hallmarks of HE. As shown by immunohistochemical results, diacerein markedly downregulated brain TLR4 expression which in turn significantly increased the GFAP expression, and significantly decreased AQP4 expression; the astrocytes swelling biomarkers (P < 0.0001). Moreover, diacerein preserved BBB integrity via downregulation of MMP-9 mediated digestion of tight junction proteins such as occludin (P < 0.0001). Collectively, diacerein ameliorated cerebral edema and maintained BBB integrity via modulation of TLR4/AQP4/MMP-9 axis thus may decrease the progression of HE induced in acute liver failure., Competing Interests: Declarations Ethics approval Study protocols and animal care were approved by the Animal Care and Use Committee (MU-ACUC) (Approval Number: PHARM.R.23.04.16), Mansoura University, Egypt, in accordance with “Guide for the Care and Use of Laboratory Animals” (National Research Council publication 8th edition, USA, 2011). Consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The global demographic shift towards an aging population is generating a rise in neurodegenerative conditions, with Alzheimer's disease (AD) as the most prominent problem. In this landscape, the use of natural supplements has garnered attention for their potential in dementia prevention. Curcumin (Cur), derived from Curcuma longa, has demonstrated promising pharmacological effects against AD by reducing the levels of inflammatory mediators. However, its clinical efficacy is hindered by poor solubility and bioavailability. Our study introduces the use of H-Ferritin nanocages (HFn) as a nanoformulation vehicle for Cur, aiming to enhance its therapeutic potential for AD. In this work, we characterized a nanoformulation of Cur in HFn (HFn-CUR) by evaluating its safety, stability, and its transport across the blood-brain barrier (BBB) in vitro. Moreover, we evaluated the efficacy of HFn-CUR by transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from both AD patients and healthy controls (HC), and by using the well-established 5xFAD mouse model of AD., Results: Our data show that HFn-CUR exhibits improved water dispersibility, is non-toxic, and can traverse the BBB. Regarding its activity on PBMCs from AD patients, HFn-CUR enhances cellular responses to inflammation and reduces RAGE-mediated stress. Studies on an AD mouse model demonstrate that HFn-CUR exhibits mild beneficial effects on cognitive performance. Moreover, it effectively reduces microgliosis and astrogliosis and in vivo in mouse, suggesting potential neuroprotective benefits., Conclusions: Our data suggest that HFn-CUR is safe and effective in reducing inflammation in both in vitro and in vivo models of AD, supporting the need for further experiments to define its optimal use., Competing Interests: Declarations Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki declaration and its later amendments or comparable ethical standards. The study design was examined by the IRBs of the enrolling institutions. The study protocol to obtain blood from patients was approved by the Ethical Committee of the IRCCS Mondino Foundation (Pavia, Italy) (Code: 20170001758). Informed consent was obtained from all subjects involved in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Proprotein convertase substilin/kexin type 9 (PCSK9), a pivotal protein regulating lipid metabolism, has been implicated in promoting microthrombotic formation and inflammatory cascades, thereby contributing to cardiovascular ischemia/reperfusion (I/R) injury. However, its involvement in cerebral I/R injury and its potential role in microcirculation protection remain unexplored. In this investigation, we utilized a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate ischemic stroke. Different concentrations of evolocumab (1, 5, 10 mg/kg, i.v.), a PCSK9 inhibitor, were administered to assess its impact. Immunofluorescence staining was employed to analyze changes in the expression of occludin, claudin-5, thrombocyte, ICAM-1, VCAM-1, and CD45, providing insights into blood-brain barrier integrity, platelet adhesion, and immune cell infiltration. Moreover, the Morris water maze and elevated plus maze were utilized to evaluate neurological and behavioral functions in MCAO/R mice, shedding light on the effects of PCSK9 inhibition. Our findings revealed a surge in plasma PCSK9 levels post-MCAO/R, peaking at 24 h post-reperfusion. Evolocumab (10 mg/kg) treatment significantly mitigated brain infarction and neurological deficits, evidenced by enhanced locomotor function and reduced post-stroke anxiety. However, it did not ameliorate cognitive impairment following MCAO/R. Additionally, evolocumab administration led to diminished leakage of evans blue solution and upregulated expression of occludin and claudin-5. Thrombocyte, ICAM-1, VCAM-1, and CD45 levels were notably reduced in the penumbral area post-evolocumab treatment. These protective effects are speculated to be mediated through the inhibition of the ERK/NF-κB pathway. The PCSK9 inhibitor evolocumab holds promise as a therapeutic agent during the acute phase of stroke, exerting its beneficial effects by modulating the ERK/NF-κB signaling pathway., Competing Interests: Declarations Competing Interests The authors declare no competing interests. Ethics Approval This study was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University (Date 2022-03-07/No. 2022DZGKJDWLS-0043). Consent to Participate Not applicable. Consent to Publish Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neurological disorders pose a huge worldwide challenge to the healthcare system, necessitating innovative strategies for targeted drug delivery to the central nervous system. Alzheimer's disease (AD) is an untreatable neurodegenerative condition characterized by dementia and alterations in a patient's physiological and mental states. Since ancient times, medicinal plants have been an important source of bioactive phytochemicals with immense therapeutic potential. This review investigates new and safer alternatives for prevention and treatment of disease related to inevitable side effects associated with synthetic compounds. This review examines how nanotechnology can help in enhancing the delivery of neuroprotective phytochemicals in AD. Nevertheless, despite their remarkable neuroprotective properties, these natural products often have poor therapeutic efficacy due to low bioavailability, limited solubility and imperfect blood brain barrier (BBB) penetration. Nanotechnology produces personalized drug delivery systems which are necessary for solving such problems. In overcoming these challenges, nanotechnology might be employed as a way forward whereby customized medication delivery systems would be established as a result. The use of nanocarriers in the design and application of important phytochemicals is highlighted by this review, which indicate potential for revolutionizing neuroprotective drug delivery. We also explore the complications and possibilities of using nanocarriers to supply nutraceuticals and improve patients' standard of living, and preclinical as well as clinical investigations displaying that these techniques are effective in mitigating neurodegenerative diseases. In order to fight brain diseases and improve patient's health, scientists and doctors can employ nanotechnology with its possible therapeutic interventions., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The main pathological mechanisms of Alzheimer's Disease (AD) are extracellular senile plaques caused by β-amyloid (Aβ) deposition and intracellular neurofibrillary tangles derived from hyperphosphorylated Tau protein (p-Tau). However, it is difficult to obtain a good curative effect because of the poor brain bioavailability of drugs, which is attributed to the blood-brain barrier (BBB) restriction and complicated brain conditions. Herein, HM-DK was proposed for synergistic therapy of AD by using hollow mesoporous manganese dioxide (HM) as a carrier to deliver an Aβ-inhibiting peptide and a Dp-peptide inhibitor of Tau-related fibril formation synergistically. Inspired by 4T1 cancer cells promoting BBB penetration during brain metastasis, a prospective biomimetic nanocarrier (HM-DK@CM) encapsulated by 4T1 cell membranes was designed. After crossing the BBB, HM-DK@CM inhibited Aβ aggregation and prevented Tau phosphorylation simultaneously. Moreover, by taking advantage of the catalase-like activity of HM, HM-DK@CM relieved oxidative stress and altered the microenvironment associated with the development of AD. Compared with the single therapeutic drug, HM-DK@CM restored nerve damage and improved AD mice's learning and memory abilities by decreasing Aβ oligomer, p-Tau protein, and inflammation through various pathways for synergistic therapy, which has broad prospects for the effective treatment of AD.

Glioblastoma multiforme (GBM) represents one of the most prevailing and aggressive primary brain tumors among adults. Despite advances in therapeutic approaches, the complex microenvironment of GBM poses significant challenges in its optimal therapy, which are attributed to immune evasion, tumor repopulation by stem cells, and limited drug penetration across the blood-brain barrier (BBB). Nanotechnology has emerged as a promising avenue for GBM treatment, offering biosafety, sustained drug release, enhanced solubility, and improved BBB penetrability. In this review, a comprehensive overview of recent advancements in nanocarrier-based drug delivery systems for GBM therapy is emphasized. The conventional and novel treatment modalities for GBM and the potential of nanocarriers to overcome existing limitations are comprehensively covered. Furthermore, the updates in the clinical landscape of GBM therapeutics are presented in addition to the current status of drugs and patents in the same context. Through a critical evaluation of existing literature, the therapeutic prospect and limitations of nanocarrier-based drug delivery strategies are highlighted offering insights into future research directions and clinical translation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Nanoparticle-based drug delivery presents a promising solution in enhancing therapies for neurological diseases, particularly cognitive impairment. These nanoparticles address challenges related to the physicochemical profiles of drugs that hinder their delivery to the central nervous system (CNS). Benefits include improved solubility due to particle size reduction, enhanced drug penetration across the blood-brain barrier (BBB), and sustained release mechanisms suitable for long-term therapy. Successful application of nanoparticle delivery systems requires careful consideration of their characteristics tailored for CNS delivery, encompassing particle size and distribution, surface charge and morphology, loading capacity, and drug release kinetics. Literature review reveals three main types of nanoparticles developed for cognitive function enhancement: polymeric nanoparticles, lipid-based nanoparticles, and metallic or inorganic nanoparticles. Each type and its production methods possess distinct advantages and limitations. Further modifications such as coating agents or ligand conjugation have been explored to enhance their brain cell uptake. Evidence supporting their development shows improved efficacy outcomes, evidenced by enhanced cognitive function assessments, modulation of pro-oxidant markers, and anti-inflammatory activities. Despite these advancements, clinical trials validating the efficacy of nanoparticle systems in treating cognitive defects are lacking. Therefore, these findings underscore the need for researchers to expedite clinical testing to provide robust evidence of the potential of nanoparticle-based drug delivery systems., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Wilar et al.)

The blood-brain barrier (BBB) is a highly restrictive barrier at the interface between the brain and the vascular system. Even under BBB dysfunction, it is extremely difficult to deliver therapies across the barrier, limiting the options for treatment of neurological injuries and disorders. To circumvent these challenges, there is interest in developing therapies that directly engage with the damaged BBB to restore its function. Previous studies revealed that poloxamer 188 (P188), a water-soluble triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), partially mitigated BBB dysfunction in vivo. In the context of stabilization of the damaged BBB, the mechanism of action of PEO-PPO block copolymers is unknown, and there has been minimal exploration of polymers beyond P188. In this study, a human-based in vitro BBB model under oxidative stress was used to investigate polymer-BBB interactions since oxidative stress is closely linked with BBB dysfunction in many neurological injuries and disorders. PEO-PPO block copolymers of varied numbers of chemically distinct blocks, PEO block length, and functionality of the end group of the PPO block were assessed for their efficacy in improving key physiological readouts associated with BBB dysfunction. While treatment with P188 did not mitigate damage in the in vitro BBB model, treatment with three diblock copolymers improved barrier integrity under oxidative stress to a similar extent. Of the considered variations in the block copolymer design, the reduction in the number of chemically distinct blocks had the strongest influence on therapeutic function. The demonstrated efficacy of three alternative PEO-PPO diblock copolymers in this work reveals the potential of these polymers as a class of therapeutics that directly treat the damaged BBB, expanding the options for treatment of neurological injuries and disorders.

Aβ accumulation in the blood-brain barrier (BBB) endothelium, which lines the cerebrovascular lumen, is a significant contributor to cerebrovascular dysfunction in Alzheimer's disease (AD). Reduced high-density lipoprotein (HDL) levels are associated with increased AD risk, and the HDL mimetic peptide 4F has been developed as a promising therapeutic agent to improve cerebrovascular health in AD. In this study, we evaluated the impact of 4F on 125 I-Aβ 42 blood-to-brain distribution using dynamic SPECT/CT imaging in both wild-type and APP/PS1 transgenic mice. Graphical analysis of the imaging data demonstrated that 4F significantly reduced the blood-to-brain influx rate in wild-type mice and the distribution of 125 I-Aβ 42 in the BBB endothelium in APP/PS1 mice. To elucidate the molecular mechanisms underlying the effect of 4F, we evaluated its impact on the p38 pathway and its role in mediating Aβ 42 trafficking in human BBB endothelial cell monolayers. Treatment with 4F significantly decreased Aβ 42 induced p38 activation in BBB endothelial cells. Furthermore, inhibition of p38 kinase significantly reduced endothelial accumulation of fluorescence-labeled Aβ 42 and luminal-to-abluminal permeability across the cell monolayer. While our previous publication has hinted at the potential of 4F to reduce Aβ accumulation in the brain parenchyma, the current findings demonstrated the protective effect of 4F in reducing Aβ 42 accumulation in the BBB endothelium of AD transgenic mice. These findings revealed the impact of a clinically tested agent, the HDL mimetic peptide 4F, on Aβ exposure to the BBB endothelium and offer novel mechanistic insights into potential therapeutic strategies to treat cerebrovascular dysfunction in AD.

Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers., Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs)., Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge., Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cocaine abuse has been strongly linked to blood-brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine-induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR-320a, which in turn suppresses GLUT1 expression via the beta 2-adrenergic receptor (ADRB2). Notably, the administration of adeno-associated viruses encoding full-length GLUT1 or miR-320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine-induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well-known neuroprotective hormone, alleviates cocaine-induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR-320a-dependent GLUT1 expression in brain endothelial cells via MT 1 receptor-mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine-related complications., (© 2024 John Wiley & Sons Ltd.)

Background: The oxidative stress and neuroinflammation are important factors in acute ischemic stroke (AIS). Our former study showed the 1,2,4- triazole derivative (SYS18) had obviously neuroprotection by anti- oxidative stress on rat middle cerebral artery occlusion (MCAO) model., Aim: In this study, we continue to investigate its neuroprotection by anti-inflammatory effects and protecting BBB integrity in AIS., Methods and Results: First, its effect on acute inflammation was evaluated by the mice model of increased peritoneal capillary permeability. Then, the MCAO cerebral edema models were built to evaluate its neuroprotection by reducing the neurological score, cerebral edema, improving the biochemical indicators, and pathological damage of brain tissue. At the same time, its protection on blood-brain barrier (BBB) integrity was proved by decreasing the BBB permeability and inhibiting glycocalyx degradation and regulating the BBB tight junction proteins expression of matrix metalloproteinase- 9 (MMP- 9) and claudin- 5 in brain tissue. Meanwhile, pharmacokinetic experiments showed that the compound had good BBB penetration. It has some advantages in the intensity of efficacy compared with the marketed drug edaravone., Conclusion: Based on these findings, SYS18 has a strong potential to become a neuroprotectant in the future., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Glioblastoma multiforme (GBM) is an aggressive tumor, difficult to treat pharmacologically because of the blood-brain barrier (BBB), which is rich in ATP-binding cassette (ABC) transporters and tight junction (TJ) proteins. The BBB is disrupted within GBM bulk, but it is competent in brain-adjacent-to-tumor areas, where eventual GBM foci can trigger tumor relapse. How GBM cells influence the permeability of BBB is poorly investigated., Methods: To clarify this point, we co-cultured human BBB models with 3 patient-derived GBM cells, after separating from each tumor the stem cell/neurosphere (SC/NS) and the differentiated/adherent cell (AC) components. Also, we set up cultures of BBB cells with the conditioned medium of NS or AC, enriched or depleted of IL-6. Extracellular cytokines were measured by protein arrays and ELISA. The intracellular signaling in BBB cells was measured by immunoblotting, in the presence of STAT3 pharmacological inhibitor or specific PROTAC. The competence of BBB was evaluated by permeability assays and TEER measurement., Results: The presence of GBM cells or their conditioned medium increased the permeability to doxorubicin, mitoxantrone and dextran-70, decreased TEER, down-regulated ABC transporters and TJ proteins at the transcriptional level. These effects were higher with AC or their medium than with NS. The secretome analysis identified IL-6 as significantly more produced by AC than by NS. Notably, AC-conditioned medium treated with an IL-6 neutralizing antibody reduced the BBB permeability to NS levels, while NS-conditioned medium enriched with IL-6 increased BBB permeability to AC levels. Mechanistically, IL-6 released by AC GBM cells activated STAT3 in BBB cells. In turn, STAT3 down-regulated ABC transporter and TJ expression, increased permeability and decreased TEER. The same effects were obtained in BBB cells treated with STA-21, a pharmacological inhibitor of STAT3, or with a PROTAC targeting STAT3., Conclusions: Our work demonstrates for the first time that the degree of GBM differentiation influences BBB permeability. The crosstalk between GBM cells that release IL-6 and BBB cells that respond by activating STAT3, controls the expression of ABC transporters and TJ proteins on BBB. These results may pave the way for novel therapeutic tools to tune BBB permeability and improve drug delivery to GBM., (© 2024. The Author(s).)

The purpose of this research was to assess the impact of different doses of Daphnetin (DAP, a natural compound derived from coumarin) on hippocampus neuronal injury, neurobehavioral function, blood-brain barrier (BBB) integrity, expression of claudin-5, brain-derived neurotrophic factor (BDNF), superoxide dismutase (SOD), and inflammatory markers in a mouse model of cerebral ischemia. Cerebral ischemia was induced in mice through 30 minutes of bilateral common carotid occlusion (BCCAO), followed by 48 hours of reperfusion. The viability of hippocampal neurons was assessed using Cresyl violet staining and BBB function was determined by measuring Evans blue (E.B) dye leakage. Spatial memory was tested using the Radial Arm Water Maze (RAWM) task. Claudin-5 and BDNF were measured by immunofluorescence, while SOD, interleukin-1 beta (IL-1β), and nuclear factor-κB (NF-κB) expression were determined through western blotting. Administering DAP significantly increased neuron survival in the hippocampus CA1, CA3, and dentate gyrus (DG) regions and improved spatial memory dose-dependently (P<0.0001). Treatment with DAP (40 mg/kg IP) significantly reduced E.B leakage and brain water content (P<0.001). Furthermore, it increased the claudin-5, BDNF, and SOD levels and diminished NF-κB and IL-1β expression (P<0.0001). The research found that DAP protected neurons in the CA1, CA3, and DG areas of the hippocampus, enhanced behavioral functions, and preserved BBB integrity in a cerebral ischemia model. This positive impact is achieved by increasing the expression of claudin-5, BDNF, and SOD and diminishing neuroinflammation. Further research is required to clarify the mechanisms and possible clinical uses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cellular senescence, characterized by expressing the cell cycle inhibitory proteins, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D + Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), longitudinally assessed brain physiology and high-resolution structural MRI evaluated the brain regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D + Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D + Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p16/Ink4a. D + Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D + Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders., Competing Interests: Declaration of competing interest The authors declare no other competing financial interests., (Copyright © 2024. Published by Elsevier Inc.)

Ischemic stroke, characterized by vascular occlusion, has recently emerged as one of the primary causes of mortality and disability worldwide. Conventional treatment modalities, such as thrombolytic and neuroprotective therapies, face numerous challenges, including limited bioavailability, significant neurotoxicity, suboptimal targeting, short half-life, and poor blood-brain barrier (BBB) penetration. Nanoparticle-based drug delivery systems present distinct advantages, such as small size, enhanced lipophilicity, and modifiability, which can potentially address these limitations. Utilizing nanoparticles for drug delivery in ischemic stroke therapy offers improved drug bioavailability, reduced neurotoxicity, enhanced targeted delivery, prolonged drug half-life, and better dissolution kinetics. This review aims to provide a comprehensive overview of current strategies in preclinical studies for managing or preventing ischemic stroke from a nanomaterial perspective, highlighting the advantages and limitations of each approach., Competing Interests: Declaration of Competing Interest The authors declared that they have no conflicts of interest in this study, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The dynamic protective capacity of (poly)phenols, attributed to their potent antioxidant and anti-inflammatory properties, has been consistently reported. Due to their capacity to alter gut microbiome composition, further actions of (poly)phenols may be exerted through the modulation of the microbiota-gut-brain axis. However, the underlying mechanisms remain poorly defined. Here, we investigated the protective effect of a (poly)phenol-rich grape and blueberry extract (Memophenol™), on the microbiota-gut-brain axis in a model of chronic low-grade inflammation (0.5 mg/kg/wk lipopolysaccharide (LPS) for 8 weeks). Dietary supplementation of male C57BL/6 J mice with Memophenol™ prevented LPS-induced increases in the microbe-derived uremia-associated molecules, indoxyl sulfate (IS) and trimethylamine N-oxide (TMAO). These changes coincided with shifts in gut microbiome composition, notably Romboutsia and Desulfovibrio abundance, respectively. In the brain, LPS exposure disrupted the marginal localisation of the endothelial tight junction ZO-1 and downregulated ZO-1 mRNA expression to an extent closely correlated with TMAO and IS levels; a process prevented by Memophenol™ intake. Hippocampal mRNA sequencing analysis revealed significant downregulation in regulatory pathways of neurodegeneration with Memophenol™ intake. These findings may indicate a novel protective role of the (poly)phenol-rich grape and blueberry extract on the endothelial tight junction component ZO-1, acting through modulation of gut microbial metabolism., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Vauzour reports financial support was provided by Activ’Inside. David Vauzour reports a relationship with Activ’Inside that includes: funding grants and travel reimbursement. David Gaudout has patent #WO/2017/072,219 licensed to Activ’Inside. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Blood-brain barrier (BBB) breakdown, an early hallmark of multiple sclerosis (MS), remains crucial for MS progression. Our previous works have confirmed that Astragalus polysaccharides (APS) can significantly ameliorate demyelination and disease progression in experimental autoimmune encephalomyelitis (EAE) mice. However, it remains unclear whether APS protects BBB and the potential mechanism. In this study, we found that APS effectively reduced BBB leakage in EAE mice, which was accompanied by a decreased level of endothelial-to-mesenchymal transition (EndoMT) in the central nervous system (CNS). We further induced EndoMT in the mouse brain endothelial cells (bEnd.3) by interleukin-1β (IL-1β) in vitro. The results showed that APS treatment could inhibit IL-1β-induced EndoMT and endothelial cell dysfunction. In addition, the transcription factor ETS1 is a central regulator of EndoMT related to the compromise of BBB. We tested the regulation of APS on ETS1 and identified the expression of ETS1 was upregulated in both EAE mice and bEnd.3 cells by APS. ETS1 knockdown facilitated EndoMT and endothelial cell dysfunction, which completely abolished the regulatory effect of APS. Collectively, APS treatment could protect BBB integrity by inhibiting EndoMT, which might be associated with upregulating ETS1 expression. Our findings indicated that APS has potential value in the prevention of MS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background and Purpose: Oxidative stress plays a critical role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). The small molecule ULK1 agonist, BL-918, demonstrated neuroprotective effects in other central nervous system diseases; however, its role in SAH has not yet been explored. This study aimed to evaluate whether BL-918 could provide neuroprotective effects in rats following SAH., Methods: An SAH model was established in Sprague-Dawley rats using endovascular perforation. BL-918 was administered intraperitoneally after SAH, while the ULK1 inhibitor SBI was given intraperitoneally prior to SAH modeling. PINK1 siRNA was administered into the lateral ventricle before SAH induction. The neuroprotective effects and mechanisms of BL-918 were assessed through SAH grading, brain water content measurement, blood-brain barrier permeability, neurobehavioral tests, Western blot, immunofluorescence, TUNEL staining, DHE staining, and transmission electron microscopy (TEM)., Results: After SAH, the expression levels of p-ULK1, PINK1, Parkin, and LC3Ⅱ increased, peaking at 24 h post-SAH. BL-918 treatment improved neurological function in rats, reduced brain water content and blood-brain barrier permeability, and exhibited anti-oxidative stress and anti-apoptotic effects. Western blot analysis revealed that BL-918 increased the expression of p-ULK1, PINK1, Parkin, LC3Ⅱ, Bcl-xl, and Bcl-2 while inhibiting the expression of Bax and Cleaved Caspase-3. Oxidative stress-related indicators showed that BL-918 alleviated oxidative stress. Immunofluorescence and TEM results demonstrated that BL-918 promoted mitophagy and preserved mitochondrial morphology. Furthermore, the positive effects of BL-918 were reversed by SBI and PINK1 siRNA, respectively., Conclusion: BL-918 improved both short-term and long-term neurological impairments in rats after SAH and reduced oxidative stress by promoting mitophagy, at least partially through the ULK1/PINK1/Parkin signaling pathway., Competing Interests: Declaration of competing interest The authors declare that the research was conducted without any commercial or financial relationships that could be considered potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive., Methods: Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan-Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses., Findings: From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM users, and 1,184,809 AHM non-users. The unadjusted KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non-users (P < 0.0001). In Cox PH analysis, ARB users showed a 20% lower adjusted hazard of developing ADRD compared to angiotensin-converting enzyme inhibitor (ACEI) users and a 29% and 18% reduced hazard when compared to non-ARB/ACEI AHM users and AHM non-users (all P < 0.0001). Consumption of BBB-crossing ARBs was linked to a lower hazard of ADRD development than non-BBB-crossing ARBs, undetermined ARBs, and non-consumption of AHMs by 11%, 25%, and 31% (all P < 0.0001)., Interpretation: This study suggests that ARBs are superior to ACEIs, non-ARB/ACEI AHMs, or non-use of AHMs in reducing the hazard of ADRD among patients with hypertension. Also, BBB-permeability in ARBs was associated with lower ADRD incidence. There is no cure for AD, ADRD, or vascular dementia; hence, these findings are significant in preventing those disorders in an inexpensive, convenient, and safe way. Limitations in claims data should be considered when interpreting our findings., Funding: This research was supported by the National Institute on Aging grants (R01AG084236, R01AG083039, RF1AG072799, R56AG074604)., Competing Interests: Declaration of interests Paul E. Schulz declares payment or honoraria for lectures on disease modifying therapies at Biogen Inc., lectures on psychosis in Parkinsons at Acadia Healthcare Company, Inc., and lectures on disease in modifying therapies at Eisai Co., Ltd. He declares payment for legal expert testimony unrelated to the International Committee of Medical Journal Editors (ICJME). He declares participation on a data safety monitoring board or advisory board at Eli Lilly and Company and Eisai Co., Ltd. unrelated to this study. Other authors declare no conflict of interests regarding any financial and personal relationships with other people or organisations that could inappropriately influence our work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease, a neurodegenerative condition, is characterized by the slow and progressive deterioration of the cognitive functions of geriatric patients. It occurs due to exacerbation of neurons in the brain, indicated by loss of memory, mood instability, and even death. The aggregation of amyloid β protein and neurofibrillary tangles-atypical forms of tau protein is the major cause of this disease. Phytoconstituents have been frequently employed in treating Alzheimer's disease. These natural compounds act through different molecular mechanisms to treat the disease. However, their potential in Alzheimer's disease therapy may be limited due to poor blood-brain barrier permeability, off-target effects, low bioavailability, etc. In recent times, nanotechnology has gained attraction to overcome these challenges. This article focuses on the potential phytoconstituents for Alzheimer's disease treatment and the associated limitations. Moreover, it highlights various nanoformulation strategies employed to penetrate the blood-brain barrier effectively, avoid side effects, improve bioavailability, and target specificity in treating Alzheimer's disease. The integration of nanotechnology with plant-derived compounds has the potential to revolutionize the therapeutic landscape for Alzheimer's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neutrophil elastase (NE) is a protease released by activated neutrophils in the brain parenchyma after cerebral ischemia, which plays a pivotal role in the regulation of neutrophil extracellular traps (NETs) formation. The excess NETs could lead to blood-brain barrier (BBB) breakdown, overwhelming neuroinflammation, and neuronal injury. While the potential of targeting neutrophils and inhibiting NE activity to mitigate ischemic stroke (IS) pathology has been recognized, effective strategies that inhibit NETs formation remain under-explored. Herein, a biomimic multifunctional nanoplatform (HM@ST/TeTeLipos) was developed for active NE targeting and IS treatment. The core of the HM@ST/TeTeLipos consisted of sivelestat-loaded ditelluride-containing liposomes with ROS-responsive and NE-inhibiting properties. The outer shell was composed of platelet-neutrophil hybrid membrane vesicles (HMVs), which acted to hijack neutrophils and neutralize proinflammatory cytokines. Our studies revealed that HM@ST/TeTeLipos could effectively inhibit NE activity, thereby suppressing the release of NETs, impeding the activation of the AIM2 inflammasome, and consequently redirecting the immune response away from a pro-inflammatory M1 microglia phenotype. This resulted in enhanced neurovascular remodeling, reduced BBB disruption, and diminished neuroinflammation, ultimately promoting neuron survival. We believe that this innovative approach holds significant potential for improving the treatment of IS and various NE-mediated inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ., Methods: Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors., Results: TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma., Conclusion: Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

One of the current challenges in targeting neurological disorders is that many therapeutic molecules cannot cross the blood-brain barrier (BBB), which limits the use of natural molecules in nervous tissue regeneration. Thus, the development of new drugs to effectively treat neurological disorders would be a challenge. Natural resources are well known as a source of several therapeutic agents for the treatment of neurologic disorders. Recently, chitosan (CTS) and its derivatives from arthropod exoskeletons, have attracted much attention as a drug delivery system to transport therapeutic substances across the BBB and thanks to other neuroprotective effects including the participation to the CNS regenerations scaffolds to replicate the extracellular matrix and microenvironment of the body. This review will discuss the place of natural resource therapy in targeting neurological disorders. In particular, it will highlight recent understanding and progress in the applications of CTS as drug delivery systems and their therapeutic effects on these disorders through tissue regeneration, as well as the molecular mechanisms by which they exert these effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) is the most aggressive brain tumor for which current therapies have limited efficacy. Immunosuppression and difficulties in accessing tumors with therapeutic agents are major obstacles for GBM treatments. Classical monocytes (CMs) possess the strongest infiltration among myeloid cells recruited into tumors during tumorigenesis. In this study, CMs are utilized to deliver the small-molecule CUDC-907 encapsulated in nanoparticles (907-NPs@CMs) for GBM therapy. Hitchhiking on CMs enables more 907-NPs to successfully penetrate the blood-brain barrier (BBB) and reach the interior of tumors. Results demonstrate that 907-NPs@CMs significantly improve the survival rates by suppressing tumor growth and reversing the immunosuppression of tumor microenvironment (TME). Furthermore, the high delivery efficiency of CMs reduces the amount of CUDC-907 required for treatments, reducing the physiological toxicity and off-target effects caused by high doses. 907-NPs@CMs is a safe and versatile therapeutic system that provides a platform for targeted drug delivery to tumors and the ability to treat GBM through a combination of chemotherapy and immunotherapy., (© 2024 Wiley‐VCH GmbH.)

Vascular dementia (VaD) is a complex neurodegenerative condition, with cerebral small vessel dysfunctions as the central role in its pathogenesis. Given the lack of suitable animal models to study the disease pathogenesis, we developed a mouse model to closely emulate the clinical scenarios of recurrent transient ischemic attacks (TIAs) leading to VaD using vasoconstricting peptide Endothelin-1(ET-1). We observed that administration of ET-1 led to blood-brain barrier (BBB) disruption and detrimental changes in its components, such as endothelial cells and pericytes, along with neuronal loss and synaptic dysfunction, resulting in irreversible memory loss. Further, in our pursuit of understanding potential interventions, we co-administered pleiotrophin (PTN) alongside ET-1 injections. PTN exhibited remarkable efficacy in preserving vital components of the BBB, including endothelial cells and pericytes, thereby restoring BBB integrity, preventing neuronal loss, and enhancing memory function. Our findings give a valuable framework for understanding the detrimental effects of multiple TIAs on brain health and provide a useful animal model to explore VaD's underlying mechanisms further and pave the way for promising therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cocaine use disorder is a condition that leads to tremendous morbidity and mortality for which there are currently no FDA-approved pharmacotherapies. Previous research has demonstrated an important role for the resident population of bacteria of the large intestine, collectively dubbed the gut microbiome, in modulating brain and behavior in models of cocaine and other substance use disorders. Importantly, previous work has repeatedly shown that depletion of the gut microbiome leads to increased cocaine taking and seeking behaviors in multiple models. While the precise mechanism of these gut-brain signaling pathways in models of cocaine use is not fully clear, and intriguing possibility is through gut microbiome influences on innate immune system function. In this manuscript we identify the cytokine colony stimulating factor 2 (CSF2) as an immune factor that is increased by cocaine in a gut microbiome dependent manner. Peripherally injected CSF2 crosses the blood-brain barrier into the nucleus accumbens, a brain region central to behavioral responses to cocaine. Treatment with peripheral CSF2 reduces acute and sensitized locomotor responses to cocaine as well as reducing cocaine place preference at high doses. On a molecular level, we find that peripheral injections of CSF2 alter the transcriptional response to both acute and repeated cocaine in the nucleus accumbens. Finally, treatment of microbiome depleted mice with CSF2 reverses the behavioral effects of microbiome depletion on the conditioned place preference assay. Taken together, this work identifies an innate immune factor that represents a novel gut-brain signaling cascade in models of cocaine use and lays the foundations for further translational work targeting this pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Nanoparticles (NPs) that target multiple transport mechanisms facilitate targeted delivery of active therapeutic agents to the central nervous system (CNS) and improve therapeutic transport and efficacy across the blood-brain barrier (BBB). CNS nanotherapeutics mostly target neurons and endothelial cells, however, microglial immune cells are the first line of defense against neuronal damage and brain infections. Through triggering release of inflammatory cytokines, chemokines and proteases, microglia can however precipitate neurological damage-a significant factor in neurodegenerative diseases. Thus, microglial inhibitory agents are attracting much attention among those researching and developing novel treatments for neurodegenerative disorders. The most established inhibitors of microglia investigated to date are resveratrol, curcumin, quercetin, and minocycline. Thus, there is great interest in developing novel agents that can bypass or easily cross the BBB. One such approach is the use of modified-nanocarriers as, or for, delivery of, therapeutic agents to the brain and wider CNS. For microglial inhibition, polymeric NPs are the preferred vehicles for choice. Here, we summarize the immunologic and neuroinflammatory role of microglia, established microglia inhibitor agents, challenges of CNS drug delivery, and the nanotherapeutics explored for microglia inhibition to date. We also discuss applications of the currently considered "most useful" polymeric NPs for microglial-inhibitor drug delivery in CNS-related diseases., (© 2024 Wiley Periodicals LLC.)

Alzheimer's disease (AD) is a chronic, insidious, and progressive neurodegenerative disease that remains a clinical challenge for society. The fully approved drug lecanemab exhibits the prospect of therapy against the pathological processes, while debatable adverse events conflict with the drug concentration required for the anticipated therapeutic effects. Reactive oxygen species (ROS) are involved in the pathological progression of AD, as has been demonstrated in much research regarding oxidative stress (OS). The contradiction between anticipated dosage and adverse event may be resolved through targeted transport by biomaterials and get therapeutic effects through pathological progression via regulation of ROS. Besides, biomaterials fix delivery issues by promoting the penetration of drugs across the blood-brain barrier (BBB), protecting the drug from peripheral degradation, and elevating bioavailability. The goal is to comprehensively understand the mechanisms of ROS in the progression of AD disease and the potential of ROS-related biomaterials in the treatment of AD. This review focuses on OS and its connection with AD and novel biomaterials in recent years against AD via OS to inspire novel biomaterial development. Revisiting these biomaterials and mechanisms associated with OS in AD via thorough investigations presents a considerable potential and bright future for improving effective interventions for AD., (© 2024 Wiley‐VCH GmbH.)

Glioblastoma multiforme is a very combative and threatening type of cancer. The standard course of treatment involves excising the tumor surgically, then administering chemotherapy and radiation therapy. Because of the presence of the blood-brain barrier and the unique characteristics of the tumor microenvironment, chemotherapy is extremely difficult and has a high incidence of relapse. With their capacity to precisely target and transport therapeutic medications to the tumor while overcoming the challenges provided by invasive and infiltrative gliomas, nanocarriers offer a potentially beneficial treatment option for gliomas. Drug repositioning or, in other words, finding novel therapeutic uses for medications that have received approval for previous uses has also recently emerged to provide alternative treatments for many diseases, with glioblastoma being among them. In this article, our goal is to shed light on the pathogenesis of glioma and summarize the proposed treatment approaches in the last decade, highlighting how combining repositioned drugs and nanocarriers technology can reduce drug resistance and improve therapeutic efficacy in primary glioma., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Blood-brain barrier (BBB) is a distinguishing checkpoint that segregates peripheral organs from neural compartment. It protects the central nervous system from harmful ambush of antigens and pathogens. Owing to such explicit selectivity, the BBB hinders passage of various neuroprotective drug molecules that escalates into poor attainability of neuroprotective agents towards the brain. However, few molecules can surpass the BBB and gain access in the brain parenchyma by exploiting surface transporters and receptors. For successful development of brain-targeted therapy, understanding of BBB transporters and receptors is crucial. This review focuses on the transporter and receptor-based mechanistic pathway that can be manoeuvred for better comprehension of reciprocity of receptors and nanotechnological vehicle delivery. Nanotechnology has emerged as one of the expedient noninvasive approaches for brain targeting via manipulating the hurdle of the BBB. Various nanovehicles are being reported for brain-targeted delivery such as nanoparticles, nanocrystals, nanoemulsion, nanolipid carriers, liposomes and other nanovesicles. Nanotechnology-aided brain targeting can be a strategic approach to circumvent the BBB without altering the inherent nature of the BBB., (© 2024. The Author(s).)

Current phototherapeutic approaches for Alzheimer's disease (AD) exhibit restricted clinical outcomes due to the limited physical penetration and comprised brain microenvironment of noninvasive nanomedicine. Herein, a hydrogen-bonded organic framework (HOF) based sonosensitizer is designed and synthesized. Mn-TCPP, a planar molecule where Mn 2+ ion is chelated in the core with a large p-conjugated system and 4 carboxylate acid groups, has been successfully used as building blocks to construct an ultrasound-sensitive HOF (USI-MHOF), which can go deep in the brain of AD animal models. The both in vitro and in vivo studies indicate that USI-MHOF can generate singlet oxygen ( 1 O 2 ) and oxidize β-amyloid (Aβ) to inhibit aggregation, consequently attenuating Aβ neurotoxicity. More intriguingly, USI-MHOF exhibits catalase (CAT)- and superoxide dismutase (SOD)-like activities, mitigating neuron oxidative stress and reprograming the brain microenvironment. For better crossing the blood-brain barrier (BBB), the peptide KLVFFAED (KD8) has been covalently grafted to USI-MHOF for improving BBB permeability and Aβ selectivity. Further, in vivo experiments demonstrate a significant reduction of the craniocerebral Aβ plaques and improvement of the cognition deficits in triple-transgenic AD (3×Tg-AD) mice models following deep-penetration ultrasound treatment. The work provides the first example of an ultrasound-responsive biocompatible HOF as non-invasive nanomedicine for in-depth treatment of AD., (© 2024 Wiley‐VCH GmbH.)

As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain., (© 2024. The Author(s).)

Despite the availability of a number of efficacious treatments for Parkinson's disease, their limitations and drawbacks, particularly related to low brain bioavailability and associated side effects, emphasize the need for alternative and more effective therapeutic approaches. Nanomedicine, the application of nanotechnology in medicine, has received considerable interest in recent years as a method of effectively delivering potentially therapeutic molecules to the brain. In particular, polymeric nanoparticles, constructed from biodegradable polymer, have shown great promise in enhancing therapeutic efficacy, reducing toxicity, and ensuring targeted delivery. However, their clinical translation remains a considerable challenge. This article reviews recent in vitro and in vivo studies using polymeric nanoparticles as drug and gene delivery systems for Parkinson's disease with their challenges and future directions. We are also particularly interested in the technical properties, mechanism, drugs release patterns, and delivery strategies to overcome the blood-brain barrier. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1β that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Ischemic stroke (IS) remains one of the most serious threats to human life. Early blood-brain barrier damage (BBB) is the cause of parenchymal cell damage. Repair of the structure and function of the BBB is beneficial for the treatment of IS. The traditional prescription ginseng aconitum decoction (GAD) has a long history in the treatment of cardiovascular and cerebrovascular diseases, however, the effect of GAD on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, in vitro models of BBB were established with brain endothelial cells (bEnd.3). We found that GAD reduced the leakage of the fluorescent probe FITC-dextran (P < 0.01) and increased the expression of tight junction proteins (Claudin-5, ZO-1) (P < 0.05) in the BBB model in vitro. Furthermore, to investigate the BBB protective effects of GAD in vivo. A total of 25 male C57/BL6 mice (20 - 22 g) were randomly divided into 5 groups (n = 5 per group): (1) Sham group (saline), (2) MCAO group (saline), (3) MCAO + CG group (Chinese ginseng 8 mg/kg/day), (4) MCAO + AC group (aconite 8 mg/kg/day), (5) MCAO + GAD group (GAD 8 mg/kg/day).We constructed IS model in mice and found that GAD treatment reduced IgG leakage (P < 0.05), up-regulated the expression of tight junction proteins Claudin-5, Occludin, and ZO-1 (P < 0.05). Further mechanism study showed that fatty acid oxidation (FAO) of vascular endothelial cells is involved in the protection of the BBB after IS, and GAD regulates FAO (P < 0.05) to protect BBB. In addition, we found the effect of GAD was stronger than that of Chinese ginseng (CG) (P < 0.05) and aconite (AC) (P < 0.01) alone. We concluded that GAD ameliorated the BBB dysfunction by regulating FAO involving vascular endothelial cells after IS. At the same time, the prescription is more effective than single traditional Chinese medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Endothelial blood-brain barrier (BBB) dysfunction is critical in the pathophysiology of brain injury. Rho-associated protein kinase (ROCK) activation disrupts BBB integrity in the injured brain. We aimed to test the efficacy of a novel ROCK2 inhibitor in preserving the BBB after acute brain injury. We characterized the molecular structure and pharmacodynamic and pharmacokinetic properties of a novel selective ROCK2 inhibitor, NRL-1049, and its first metabolite, 1-hydroxy-NRL-1049 (referred to as NRL-2017 hereon) and tested the efficacy of NRL-1049 on the BBB integrity in rodent models of acute brain injury. Our data show that NRL-1049 and NRL-2017 both inhibit ROCK activity and are 44-fold and 17-fold more selective towards ROCK2 than ROCK1, respectively. When tested in a mouse model of cortical cryoinjury, NRL-1049 significantly attenuated the increase in water content. Interestingly, 60% of the mice in the vehicle arm developed seizures within 2 hours after cryoinjury versus none in the NRL-1049 arm. In spontaneously hypertensive rats, NRL-1049 attenuated the dramatic surge in Evans Blue extravasation compared with the vehicle arm after transient middle cerebral artery occlusion. Hemorrhagic transformation was also reduced. We show that NRL-1049, a selective ROCK2 inhibitor, is a promising drug candidate to preserve the BBB after brain injury., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. McKerracher is CEO of BioAxone BioSciences, Inc. and hold an ownership interest in the company and has a significant competing interest. The data for this article were collected while Drs. Abbinanti, Woller, Ruschel and Rosen were employed at BioAxone BioSciences, and they have a modest conflict of interest. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Neurelis, Inc. acquired the rights to BA-1049 (now referred to as NRL-1049) from BioAxone in June 2021. Ayata is on the scientific advisory board of Neurelis, Inc. and declares sponsored research agreements with Praxis and Takeda Pharmaceutical Company. Mulder declares a past sponsored research agreement with BioAxone BioSciences, Inc. (concerning work not included in this manuscript). The other authors declare no conflict of interest. No writing assistance was utilized in the production of this manuscript.

Preeclampsia (preE) is a hypertensive disorder in pregnancies. It is the third leading cause of mortality among pregnant women and fetuses worldwide, and there is much we have yet to learn about its pathophysiology. One complication includes cerebral edema, which causes a breach of the blood-brain barrier (BBB). Urinary marinobufagenin (MBG) is elevated in a preE rat model prior to developing hypertension and proteinuria. We investigated what effect MBG has on the endothelial cell permeability of the BBB. Human brain microvascular endothelial cells (HBMECs) were utilized to examine the permeability caused by MBG. The phosphorylation of ERK1/2, Jnk, p38, and Src was evaluated after the treatment with MBG. Apoptosis was evaluated by examining caspase 3/7. MBG ≥ 1 nM inhibited the proliferation of HBMECs by 46-50%. MBG induced monolayer permeability, causing a decrease in the phosphorylation of ERK1/2 and the activated phosphorylation of Jnk, p38, and Src. MBG increased the caspase 3/7 expression, indicating the activation of apoptosis. Apoptotic signaling or the disruption of endothelia tight junction proteins was not observed when using the p38 inhibitor as a pretreatment in MBG-treated cells. The MBG-induced enhancement of the HBMEC monolayer permeability occurs by the downregulation of ERK1/2, the activation of Jnk, p38, Src, and apoptosis, resulting in the cleavage of tight junction proteins, and are attenuated by p38 inhibition.

Background: Triptans are potent 5-HT 1B/1D/1F receptor agonists used in migraine therapy, thought to act through peripheral mechanisms. It remains unclear whether triptans cross the blood-brain barrier (BBB) sufficiently to stimulate central 5-HT 1B/1D/1F receptors. This study investigates the disposition of eletriptan and sumatriptan in central nervous system (CNS) and peripheral nervous system (PNS) regions and predicts regional 5-HT 1B/1D/1F receptor occupancies at clinically relevant concentrations., Methods: Using the Combinatory Mapping Approach (CMA) for regions of interest (ROI), we assessed the unbound tissue-to-plasma concentration ratio (K p, uu, ROI ) in rats at steady state across CNS (hypothalamus, brain stem, cerebellum, frontal cortex, parietal cortex, striatum, hippocampus, whole brain, and spinal cord) and PNS (trigeminal ganglion and sciatic nerve) regions. We used K p, uu, ROI values to estimate unbound target-site concentrations and 5-HT 1B/1D/1F receptor occupancies in humans., Results: We observed heterogenous triptan transport across CNS and PNS regions with the highest extent of unbound drug transport across the blood-nerve barrier in the trigeminal ganglion (K p, uu, TG : eletriptan: 0.519, and sumatriptan: 0.923). Both drugs displayed restricted entry across the BBB (K p, uu, whole brain : eletriptan: 0.058, and sumatriptan: 0.045) combined with high inter-regional variability. We estimated near-complete receptor occupancy in the trigeminal ganglion, while lower occupancies were observed in the whole brain, irrespective of the drug or receptor subtype. For instance, eletriptan was predicted to achieve 84% 5-HT 1B receptor occupancy in the trigeminal ganglion and 37% in the whole brain at clinically relevant concentrations., Conclusions: This study suggests that despite low BBB transport, both eletriptan and sumatriptan achieve unbound concentrations sufficient to stimulate 5-HT 1B, 5-HT 1D , and 5-HT 1F receptors not only in the trigeminal ganglion, but also in the CNS. Further research is needed to determine whether central mechanisms contribute to triptan's antimigraine effect and/or side effects., (© 2024. The Author(s).)

Glioblastoma (GBM) is a highly prevalent and aggressive brain tumor in adults with limited treatment response, leading to a 5-year survival rate of less than 5%. Standard therapies, including surgery, radiation, and chemotherapy, often fall short due to the tumor's location, hypoxic conditions, and the challenge of complete removal. Moreover, brain metastases from cancers such as breast and melanoma carry similarly poor prognoses. Recent advancements in nanomedicine offer promising solutions for targeted GBM therapies, with nanoparticles (NPs) capable of delivering chemotherapy drugs or radiation sensitizers across the blood-brain barrier (BBB) to specific tumor sites. Leveraging the enhanced permeability and retention effect, NPs can preferentially accumulate in tumor tissues, where compromised BBB regions enhance delivery efficiency. By modifying NP characteristics such as size, shape, and surface charge, researchers have improved circulation times and cellular uptake, enhancing therapeutic efficacy. Recent studies show that combining photothermal therapy with magnetic hyperthermia using AuNPs and magnetic NPs induces ROS-dependent apoptosis and immunogenic cell death providing dual-targeted, immune-activating approaches. This review discusses the latest NP-based drug delivery strategies, including gene therapy, receptor-mediated transport, and multi-modal approaches like photothermal-magnetic hyperthermia combinations, all aimed at optimizing therapeutic outcomes for GBM., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The gut microbiome influences neurological disorders through bidirectional communication between the gut and the brain, i.e., the gut-brain axis. Artemisia asiatica ex, an extract of Artemisia asiatica Nakai (Stillen®, DA-9601) has been reported to improve depression by increasing brain-derived neurotropic factor. Therefore, we hypothesized that DA-9601 can be a potential therapeutic candidate for Alzheimer's disease (AD) acting through the gut-brain axis. Four groups of Tg2576 mice were used as the animal model for AD: wild type mice (n = 6), AD mice (n = 6), and DA-9601-administered AD mice given dosages of 30mg/kg/day (DA&#95;30mg; n = 6) or 100mg/kg/day (DA&#95;100mg; n = 6). Microglial activation, blood‒brain barrier integrity, amyloid beta accumulation, cognitive behavior, and changes in the gut microbiome were analyzed. DA-9601 improved the cognitive behavior of mice (DA&#95;30mg **p<0.01; DA&#95;100mg **p<0.01) and reduced amyloid beta accumulation (DA&#95;30mg ***p<0.001; DA&#95;100mg **p<0.01). Increased Iba-1 and upregulation of claudin-5 (DA&#95;30mg *p<0.05) and occludin (DA&#95;30mg **p<0.01; DA&#95;100mg ***p<0.001) indicated altered microglial activation and improved blood‒brain barrier integrity. Akkermansia muciniphila was dramatically increased by DA-9601 administration (DA&#95;30mg 47%; DA&#95;100mg 61%). DA-9601 improved AD pathology with Akkermansia muciniphila dominance in the gut microbiome in a mouse model of AD, inferring that DA-9601 can affect AD through the gut-brain axis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Treating mitochondrial dysfunction is a promising approach for the treatment of post-stroke cognitive impairment (PSCI). HuMSC-derived exosomes (H-Ex) have shown powerful therapeutic effects in improving mitochondrial function, but the specific effects are unclear and its brain tissue targeting needs to be further optimized., Results: In this study, we found that H-Ex can improve mitochondrial dysfunction of neurons and significantly enhance the cognitive behavior performance of MCAO mice in OGD/R-induced SHSY5Y cells and MCAO mouse models. Based on this, we have developed an exosome delivery system loaded with superparamagnetic iron oxide nanoparticles (Spion-Ex) that can effectively penetrate the blood-brain barrier (BBB). The research results showed that under magnetic attraction, Spion-Ex can more effectively target the brain tissue and significantly improve mitochondrial function of neurons after stroke. Meanwhile, we further confirmed that miR-1228-5p is a key factor for H-Ex to improve mitochondrial function and cognitive behavior both in vivo and in vitro. The specific mechanism is that the increase of miR-1228-5p mediated by H-Ex can inhibit the expression of TRAF6 and activate the TRAF6-NADPH oxidase 1 (NOX1) pathway, thereby exerting protective effects against oxidative damage. More importantly, we found that under magnetic attraction, Spion-Ex exhibited excellent cognitive improvement effects by delivering miR-1228-5p., Conclusions: Our research found that H-Ex has a good therapeutic effect on PSCI by increasing the expression of miR-1228-5p in PSCI, while H-Ex loaded with Spion-Ex exhibited more excellent effects on improving mitochondrial function and cognitive impairment under magnetic attraction, which can be used as a novel strategy for the treatment of PSCI., (© 2024. The Author(s).)

Pericytes (PCs) contribute to brain capillary/BBB integrity and PC migration is a hallmark for brain capillary leakage following pro-inflammatory insults. Estradiol promotes endothelial barrier integrity by inhibiting tumor necrosis factor-alpha (TNF-α)-induced PC migration. However, the underlying mechanisms remain unclear. Since micro-RNAs (miRs) regulate BBB integrity and increases in miR638 and TNF-α occur in pathological events associated with capillary leakage, we hypothesize that TNF-α mediates its capillary disruptive actions via miR638 and that estradiol blocks these actions. Using quantitative reverse transcription PCR, we first assessed the modulatory effects of TNF-α on miR638. The treatment of PCs with TNF-α significantly induced miR638. Moreover, transfection with miR638 mimic induced PC migration, whereas inhibitory miR638 (anti-miR) abrogated the pro-migratory actions of TNF-α, suggesting that TNF-α stimulates PC migration via miR638. At a molecular level, the pro-migratory effects of miR638 involved the phosphorylation of ERK1/2 but not Akt. Interestingly, estradiol downregulated the constitutive and TNF-α-stimulated expression of miR638 and inhibited the TNF-α-induced migration of PCs. In PCs treated with estrogen receptor (ER) ER-α, ER-β, and GPR30 agonists, a significant downregulation in miR638 expression was solely observed in response to DPN, an ER-β agonist. DPN inhibited the pro-migratory effects of TNF-α but not miR638. Additionally, the ectopic expression of miR638 prevented the inhibitory effects of DPN on TNF-α-induced PC migration, suggesting that interference in miR638 formation plays a key role in mediating the inhibitory actions of estradiol/DPN. In conclusion, these findings provide the first evidence that estradiol inhibits TNF-α-induced PC migration by specifically downregulating miR638 via ER-β and may protect the neurovascular unit during injury/stroke via this mechanism.

Cobalt toxicity is difficult to detect and therefore often underdiagnosed. The aim of this study was to explore the pathophysiology of cobalt-induced oxidative stress in the brain and its impact on structure and function. Thirty-five wild-type C57B16 mice received intraperitoneal cobalt chloride injections: a single high dose with evaluations at 24, 48, and 72 h ( n = 5, each) or daily low doses for 28 ( n = 5) or 56 days ( n = 15). A part of the 56-day group also received minocycline ( n = 5), while 10 mice served as controls. Behavioral changes were evaluated, and cobalt levels in tissues were measured with particle-induced X-ray emission. Brain sections underwent magnetic resonance imaging (MRI), electron microscopy, and histological, immunohistochemical, and molecular analyses. High-dose cobalt caused transient illness, whereas chronic daily low-dose administration led to long-term elevations in cobalt levels accompanied by brain inflammation. Significant neurodegeneration was evidenced by demyelination, increased blood-brain barrier permeability, and mitochondrial dysfunction. Treated mice exhibited extended latency periods in the Morris water maze test and heightened anxiety in the open field test. Minocycline partially mitigated brain injury. The observed signs of neurodegeneration were dose- and time-dependent. The neurotoxicity after acute exposure was reversible, but the neurological and functional changes following chronic cobalt administration were not.

Treatment strategies that are efficient against established Alzheimer's disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid β (Aβ) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized the expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood-brain barrier (BBB) in age-matched wild-type mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes that affect cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology., (© 2024. The Author(s).)

Background: Brain microglia and infiltrating monocyte-derived macrophages are vital in preserving blood vessel integrity after stroke. Understanding mechanisms that induce immune cells to adopt vascular-protective phenotypes may hasten the development of stroke treatments. IL-33 is a potent chemokine released from damaged cells, such as CNS glia after stroke. The activation of IL-33/ST2 signaling has been shown to promote neuronal viability and white matter integrity after ischemic stroke. The impact of IL-33/ST2 on blood-brain barrier (BBB) integrity, however, remains unknown. The current study fills this gap and reveals a critical role of IL-33/ST2 signaling in macrophage-mediated BBB protection after stroke., Methods: Transient middle cerebral artery occlusion (tMCAO) was performed to induce ischemic stroke in wildtype (WT) versus ST2 knockout (KO) male mice. IL-33 was applied intranasally to tMCAO mice with or without dietary PLX5622 to deplete microglia/macrophages. ST2 KO versus WT bone marrow or macrophage cell transplantations were used to test the involvement of ST2 + macrophages in BBB integrity. Macrophages were cocultured in transwells with brain endothelial cells (ECs) after oxygen-glucose deprivation (OGD) to test potential direct effects of IL33-treated macrophages on the BBB in vitro., Results: The ST2 receptor was expressed in brain ECs, microglia, and infiltrating macrophages. Global KO of ST2 led to more IgG extravasation and loss of ZO-1 in cerebral microvessels 3 days post-tMCAO. Intranasal IL-33 administration reduced BBB leakage and infarct severity in microglia/macrophage competent mice, but not in microglia/macrophage depleted mice. Worse BBB injury was observed after tMCAO in chimeric WT mice reconstituted with ST2 KO bone marrow, and in WT mice whose monocytes were replaced by ST2 KO monocytes. Macrophages treated with IL-33 reduced in vitro barrier leakage and maintained tight junction integrity after OGD. In contrast, IL-33 exerted minimal direct effects on the endothelial barrier in the absence of macrophages. IL-33-treated macrophages demonstrated transcriptional upregulation of an array of protective factors, suggesting a shift towards favorable phenotypes., Conclusion: Our results demonstrate that early-stage IL-33/ST2 signaling in infiltrating macrophages reduces the extent of acute BBB disruption after stroke. Intranasal IL-33 administration may represent a new strategy to reduce BBB leakage and infarct severity., (© 2024. The Author(s).)