RESUMO
The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.
Assuntos
Doença de Alzheimer , Apoptose , Barreira Hematoencefálica , Azul de Metileno , Nanomedicina , Doenças Neuroinflamatórias , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Apoptose/efeitos dos fármacos , Células PC12 , Doenças Neuroinflamatórias/tratamento farmacológico , Ratos , Camundongos , Nanomedicina/métodos , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Masculino , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Introduction: Alzheimer's disease (AD), a neurodegenerative condition, stands as the most prevalent form of dementia. Its complex pathological mechanisms and the formidable blood-brain barrier (BBB) pose significant challenges to current treatment approaches. Oxidative stress is recognized as a central factor in AD, underscoring the importance of antioxidative strategies in its treatment. In this study, we developed a novel brain-targeted nanoparticle, Ce/Zr-MOF@Cur-Lf, for AD therapy. Methods: Layer-by-layer self-assembly technology was used to prepare Ce/Zr-MOF@Cur-Lf. In addition, the effect on the intracellular reactive oxygen species level, the uptake effect by PC12 and bEnd.3 cells and the in vitro BBB permeation effect were investigated. Finally, the mouse AD model was established by intrahippocampal injection of Aß1-42, and the in vivo biodistribution, AD therapeutic effect and biosafety of the nanoparticles were researched at the animal level. Results: As anticipated, Ce/Zr-MOF@Cur-Lf demonstrated efficient BBB penetration and uptake by PC12 cells, leading to attenuation of H2O2-induced oxidative damage. Moreover, intravenous administration of Ce/Zr-MOF@Cur-Lf resulted in rapid brain access and improvement of various pathological features of AD, including neuronal damage, amyloid-ß deposition, dysregulated central cholinergic system, oxidative stress, and neuroinflammation. Conclusion: Overall, Ce/Zr-MOF@Cur-Lf represents a promising approach for precise brain targeting and multi-target mechanisms in AD therapy, potentially serving as a viable option for future clinical treatment.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Cério , Curcumina , Estresse Oxidativo , Zircônio , Animais , Doença de Alzheimer/tratamento farmacológico , Células PC12 , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Zircônio/química , Zircônio/farmacocinética , Camundongos , Ratos , Curcumina/química , Curcumina/farmacocinética , Curcumina/farmacologia , Curcumina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Cério/química , Cério/farmacocinética , Cério/farmacologia , Cério/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/química , Distribuição Tecidual , Espécies Reativas de Oxigênio/metabolismo , Nanopartículas/química , Modelos Animais de Doenças , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacocinética , Estruturas Metalorgânicas/farmacologia , Masculino , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismoRESUMO
Neurodegenerative diseases such as Alzheimer's disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hurdles due to limited delivery across the blood-brain barrier (BBB). This limitation necessitates high doses, resulting in increased costs and a higher risk of side effects. This study explores transferrin receptor (TfR)-binding camelid single-domain antibodies (VHHs) for facilitated brain delivery. We developed and evaluated fusion proteins (FPs) combining VHHs with human IgG Fc domains or single-chain variable fragments (scFvs) of the anti-amyloid-beta (Aß) antibody 3D6. In vitro assessments showed varying affinities of the FPs for TfR. In vivo evaluations indicated that specific VHH-Fc and VHH-scFv fusions reached significant brain concentrations, emphasizing the importance of optimal TfR binding affinities. The VHH-scFv fusions were further investigated in mouse models with Aß pathology, showing higher retention compared to wild-type mice without Aß pathology. Our findings suggest that these novel VHH-based FPs hold potential for therapeutic and diagnostic applications in AD, providing a strategy to overcome BBB limitations and enhance brain targeting of antibody-based treatments. Furthermore, our results suggest that a given bispecific TfR-binding fusion format has a window of "optimal" affinity where parenchymal delivery is adequate, while blood pharmacokinetics aligns with the desired application of the fusion protein.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Barreira Hematoencefálica , Receptores da Transferrina , Anticorpos de Cadeia Única , Anticorpos de Domínio Único , Barreira Hematoencefálica/metabolismo , Animais , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Receptores da Transferrina/imunologia , Receptores da Transferrina/metabolismo , Anticorpos de Cadeia Única/imunologia , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Anticorpos de Domínio Único/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Encéfalo/metabolismo , Encéfalo/imunologia , Imunoconjugados/imunologia , Imunoconjugados/farmacologia , Imunoconjugados/farmacocinéticaRESUMO
Major depressive disorder (MDD), affecting over 264 million individuals globally, is associated with immune system dysregulation and chronic neuroinflammation, potentially linked to neurodegenerative processes. This review examines blood-brain barrier (BBB) dysfunction in MDD, focusing on key regulators like matrix metalloproteinase 9 (MMP9), aquaporin-4 (AQP4), and ATP-binding cassette subfamily B member 1 (ABCB1). We explore potential mechanisms by which compromised BBB integrity in MDD may contribute to neuroinflammation and discuss the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs). n-3 PUFAs have demonstrated anti-inflammatory and neuroprotective effects, and potential ability to modulate MMP9, AQP4, and ABCB1, thereby restoring BBB integrity in MDD. This review aims to elucidate these potential mechanisms and evaluate the evidence for n-3 PUFAs as a strategy to mitigate BBB dysfunction and neuroinflammation in MDD.
Assuntos
Barreira Hematoencefálica , Transtorno Depressivo Maior , Ácidos Graxos Ômega-3 , Doenças Neuroinflamatórias , Humanos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Neuroproteção , Animais , Inflamação/metabolismo , Inflamação/tratamento farmacológicoRESUMO
Convection-enhanced delivery (CED) can effectively overcome the blood-brain barrier by infusing drugs directly into diseased sites in the brain using a catheter, but its clinical performance still needs to be improved. This is strongly related to the highly anisotropic characteristics of brain white matter, which results in difficulties in controlling drug transport and distribution in space. In this study, the potential to improve the delivery of six drugs by adjusting the placement of the infusion catheter is examined using a mathematical model and accurate numerical simulations that account simultaneously for the interstitial fluid (ISF) flow and drug transport processes in CED. The results demonstrate the ability of this direct infusion to enhance ISF flow and therefore facilitate drug transport. However, this enhancement is highly anisotropic, subject to the orientation of local axon bundles and is limited within a small region close to the infusion site. Drugs respond in different ways to infusion direction: the results of our simulations show that while some drugs are almost insensitive to infusion direction, this strongly affects other compounds in terms of isotropy of drug distribution from the catheter. These findings can serve as a reference for planning treatments using CED.
Assuntos
Sistemas de Liberação de Medicamentos , Humanos , Anisotropia , Convecção , Modelos Biológicos , Barreira Hematoencefálica/metabolismo , Simulação por Computador , Líquido Extracelular/metabolismo , Encéfalo/metabolismoRESUMO
Mast cells serve as crucial effector cells within the innate immune system and are predominantly localized in the skin, airways, gastrointestinal tract, urinary and reproductive tracts, as well as in the brain. Under physiological conditions, brain-resident mast cells secrete a diverse array of neuro-regulatory mediators to actively participate in neuroprotection. Meanwhile, as the primary source of molecules causing brain inflammation, mast cells also function as the "first responders" in brain injury. They interact with neuroglial cells and neurons to facilitate the release of numerous inflammatory mediators, proteases, and reactive oxygen species. This process initiates and amplifies immune-inflammatory responses in the brain, thereby contributing to the regulation of neuroinflammation and blood-brain barrier permeability. This article provides a comprehensive overview of the potential mechanisms through which mast cells in the brain may modulate neuroprotection and their pathological implications in various neurological disorders. It is our contention that the inhibition of mast cell activation in brain disorders could represent a novel avenue for therapeutic breakthroughs.
Assuntos
Mastócitos , Humanos , Mastócitos/imunologia , Mastócitos/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/metabolismo , Encefalopatias/imunologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/patologiaRESUMO
Periodontitis is a common chronic inflammatory disease, affecting approximately 19% of the global adult population. A relationship between periodontal disease and Alzheimer disease has long been recognized, and recent evidence has been uncovered to link these 2 diseases mechanistically. Periodontitis is caused by dysbiosis in the subgingival plaque microbiome, with a pronounced shift in the oral microbiota from one consisting primarily of Gram-positive aerobic bacteria to one predominated by Gram-negative anaerobes, such as Porphyromonas gingivalis. A common phenomenon shared by all bacteria is the release of membrane vesicles to facilitate biomolecule delivery across long distances. In particular, the vesicles released by P gingivalis and other oral pathogens have been found to transport bacterial components across the blood-brain barrier, initiating the physiologic changes involved in Alzheimer disease. In this review, we summarize recent data that support the relationship between vesicles secreted by periodontal pathogens to Alzheimer disease pathology.
Assuntos
Doença de Alzheimer , Periodontite , Porphyromonas gingivalis , Doença de Alzheimer/microbiologia , Doença de Alzheimer/metabolismo , Humanos , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Disbiose/microbiologia , Infecções Bacterianas/microbiologia , Barreira Hematoencefálica/microbiologia , Animais , MicrobiotaRESUMO
Glioblastoma (GBM) stands for the most common and aggressive type of brain tumour in adults. It is highly invasive, which explains its short rate of survival. Little is known about its risk factors, and current therapy is still ineffective. Hence, efforts are underway to develop novel and effective treatment approaches against this type of cancer. Exosomes are being explored as a promising strategy for conveying and delivering therapeutic cargo to GBM cells. They can fuse with the GBM cell membrane and, consequently, serve as delivery systems in this context. Due to their nanoscale size, exosomes can cross the blood-brain barrier (BBB), which constitutes a significant hurdle to most chemotherapeutic drugs used against GBM. They can subsequently inhibit oncogenes, activate tumour suppressor genes, induce immune responses, and control cell growth. However, despite representing a promising tool for the treatment of GBM, further research and clinical studies regarding exosome biology, engineering, and clinical applications still need to be completed. Here, we sought to review the application of exosomes in the treatment of GBM through an in-depth analysis of the scientific and clinical studies on the entire process, from the isolation and purification of exosomes to their design and transformation into anti-oncogenic drug delivery systems. Surface modification of exosomes to enhance BBB penetration and GBM-cell targeting is also a topic of discussion.
Assuntos
Antineoplásicos , Barreira Hematoencefálica , Neoplasias Encefálicas , Sistemas de Liberação de Medicamentos , Exossomos , Glioblastoma , Exossomos/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Humanos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Sistemas de Liberação de Medicamentos/métodos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagemRESUMO
Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory loss, cognitive decline, personality changes, and various neurological symptoms. The role of blood-brain barrier (BBB) injury, extracellular matrix (ECM) abnormalities, and oligodendrocytes (ODCs) dysfunction in AD has gained increasing attention, yet the detailed pathogenesis remains elusive. This study integrates single-cell sequencing of AD patients' cerebrovascular system with a genome-wide association analysis. It aims to elucidate the associations and potential mechanisms behind pericytes injury, ECM disorder, and ODCs dysfunction in AD pathogenesis. Finally, we identified that abnormalities in the pericyte PI3K-AKT-FOXO signaling pathway may be involved in the pathogenic process of AD. This comprehensive approach sheds new light on the complex etiology of AD and opens avenues for advanced research into its pathogenesis and therapeutic strategies.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Estudo de Associação Genômica Ampla , Pericitos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/etiologia , Humanos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Pericitos/patologia , Pericitos/metabolismo , Transdução de Sinais , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Matriz Extracelular/metabolismo , Microvasos/patologia , Microvasos/metabolismo , Análise de Célula Única , Feminino , Masculino , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
OBJECTIVE: The exacerbation of extreme high-temperature events due to global climate change poses a significant challenge to public health, particularly impacting the central nervous system through heat stroke. This study aims to develop Poly(amidoamine) (PAMAM) nanoparticles loaded with curcumin (PAMAM@Cur) to enhance its therapeutic efficacy in hypothalamic neural damage in a heat stroke model and explore its potential mechanisms. METHODS: Curcumin (Cur) was encapsulated into PAMAM nanoparticles through a hydrophobic interaction method, and various techniques were employed to characterize their physicochemical properties. A heat stroke mouse model was established to monitor body temperature and serum biochemical parameters, conduct behavioral assessments, histological examinations, and biochemical analyses. Transcriptomic and proteomic analyses were performed to investigate the therapeutic mechanisms of PAMAM@Cur, validated in an N2a cell model. RESULTS: PAMAM@Cur demonstrated good stability, photostability, cell compatibility, significant blood-brain barrier (BBB) penetration capability, and effective accumulation in the brain. PAMAM@Cur markedly improved behavioral performance and neural cell structural integrity in heat stroke mice, alleviated inflammatory responses, with superior therapeutic effects compared to Cur or PAMAM alone. Multi-omics analysis revealed that PAMAM@Cur regulated antioxidant defense genes and iron death-related genes, particularly upregulating the PCBP2 protein, stabilizing SLC7A11 and GPX4 mRNA, and reducing iron-dependent cell death. CONCLUSION: By enhancing the drug delivery properties of Cur and modulating molecular pathways relevant to disease treatment, PAMAM@Cur significantly enhances the therapeutic effects against hypothalamic neural damage induced by heat stroke, showcasing the potential of nanotechnology in improving traditional drug efficacy and providing new strategies for future clinical applications. SIGNIFICANCE: This study highlights the outlook of nanotechnology in treating neurological disorders caused by heat stroke, offering a novel therapeutic approach with potential clinical applications.
Assuntos
Curcumina , Golpe de Calor , Nanopartículas , Curcumina/farmacologia , Curcumina/química , Animais , Golpe de Calor/tratamento farmacológico , Camundongos , Nanopartículas/química , Masculino , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/química , Dendrímeros/química , Dendrímeros/farmacologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Linhagem Celular , PoliaminasRESUMO
Glioblastoma (GBM), the most common primary brain malignancy in adults, is notoriously difficult to treat due to several factors: tendency to be radiation resistant, the presence of the blood brain barrier (BBB) which limits drug delivery and immune-privileged status which hampers effective immune responses. Traditionally, high-dose irradiation (8 Gy) is known to effectively enhance anti-tumor immune responses, but its application is limited by the risk of severe brain damage. Currently, conventional dose segmentation (2 Gy) is the standard radiotherapy method, which does not fully exploit the potential of high-dose irradiation for immune activation. The hypothesis of our study posits that instead of directly applying high doses of radiation, which is risky, a strategy could be developed to harness the immune-stimulating benefits of high-dose irradiation indirectly. This involves using nanoparticles to enhance antigen presentation and immune responses in a safer manner. Angiopep-2 (A2) was proved a satisfactory BBB and brain targeting and Dbait is a small molecule that hijack DNA double strand break damage (DSB) repair proteins to make cancer cells more sensitive to radiation. In view of that, the following two nanoparticles were designed to combine immunity of GBM, radiation resistance and BBB innovatively. One is cationic liposome nanoparticle interacting with Dbait (A2-CL/Dbait NPs) for radiosensitization effect; the other is PLGA-PEG-Mal nanoparticle conjugated with OX40 antibody (A2-PLGA-PEG-Mal/anti-OX40 NPs) for tumor-derived protein antigens capture and optimistic immunoregulatory effect of anti-OX40 (which is known to enhance the activation and proliferation T cells). Both types of nanoparticles showed favorable targeting and low toxicity in experimental models. Specifically, the combination of A2-CL/Dbait NPs and A2-PLGA-PEG-Mal/anti-OX40 NPs led to a significant extension in the survival time and a significant tumor shrinkage of mice with GBM. The study demonstrates that combining these innovative nanoparticles with conventional radiotherapy can effectively address key challenges in GBM treatment. It represents a significant step toward more effective and safer therapeutic options for GBM patients.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Radiossensibilizantes , Glioblastoma/radioterapia , Glioblastoma/imunologia , Animais , Camundongos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/imunologia , Humanos , Radiossensibilizantes/administração & dosagem , Nanopartículas/química , Barreira Hematoencefálica/efeitos da radiação , Sistemas de Liberação de Fármacos por Nanopartículas/química , Sistemas de Liberação de Medicamentos , Linhagem Celular TumoralRESUMO
Japanese encephalitis is an acute infectious disease of the central nervous system caused by neurotropic Japanese encephalitis virus (JEV). As a member of TAM (Tyro3, Axl and Mertk) family, Mertk has involved in multiple biological processes by engaging with its bridging ligands Gas6 and Protein S, including invasion of pathogens, phagocytosis of apoptotic cells, inflammatory response regulation, and the maintenance of blood brain barrier (BBB) integrity. However, its role in encephalitis caused by JEV infection has not been studied in detail. Here, we found that Mertk-/- mice exhibited higher mortality and more rapid disease progression than wild-type mice after JEV challenge. There were no significant differences in viral load and cytokines expression level in peripheral tissues between Wild type and Mertk-/- mice. Furthermore, the absence of Mertk had little effect on the inflammatory response and immunopathological damage while it can cause an increased viral load in the brain. For the in vitro model of BBB, Mertk was shown to maintain the integrity of the BBB. In vivo, Mertk-/- mice exhibited higher BBB permeability and lower BBB integrity. Taken together, our findings demonstrate that Mertk acts as a protective factor in the development of encephalitis induced by JEV infection, which is mainly associated with its beneficial effect on BBB integrity, rather than its regulation of inflammatory response.
Assuntos
Barreira Hematoencefálica , Vírus da Encefalite Japonesa (Espécie) , Encefalite Japonesa , c-Mer Tirosina Quinase , Animais , Camundongos , Barreira Hematoencefálica/metabolismo , Encéfalo/virologia , Encéfalo/patologia , c-Mer Tirosina Quinase/metabolismo , c-Mer Tirosina Quinase/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Vírus da Encefalite Japonesa (Espécie)/fisiologia , Encefalite Japonesa/virologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Carga ViralRESUMO
Cerebral ischemia has the highest global rate of morbidity and mortality. It occurs when a sudden occlusion develops in the arterial system, and consequently some parts of the brain are deprived from glucose and oxygen due to the cessation of blood flow. The ensuing reperfusion of the ischemic area results in a cascade of pathological alternations like neuronal apoptosis by producing excessive reactive oxygen species (ROS), oxidative stress and neuroinflammation. Edaravone Dexborneol is a novel agent, comprised of Edaravone and Dexborneol in a 4:1 ratio. It has documented neuroprotective effects against cerebral ischemia injury. Edaravone Dexborneol improves neurobehavioral and sensorimotor function, cognitive function, brain edema, and blood-brain barrier (BBB) integrity in experimental models. It at dosages ranging between 0.375 and 15 mg/kg (from immediately after ischemia until the 28th post-ischemic days) has shown neuroprotective effects in experimental models of cerebral ischemia by inhibiting cell death-signaling pathways. For example, it inhibits apoptosis by increasing Bcl2, and reducing Bax and caspase-3 expression. Edaravone Dexborneol also inhibits pyroptosis by attenuating NF-κB/NLRP3/GSDMD signaling, as well as ferroptosis by activating the Nrf-2/HO-1/GPX4 signaling pathway. It also inhibits autophagy by targeting PI3K/Akt/mTOR signaling pathway. Here, we provide a review on the impacts of Edaravone Dexborneol on cerebral ischemia.
Assuntos
Isquemia Encefálica , Edaravone , Fármacos Neuroprotetores , Transdução de Sinais , Edaravone/farmacologia , Edaravone/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismoRESUMO
The treatment of brain tumors is significantly hindered by the Blood-Brain Barrier (BBB), a selective barrier that restricts the passage of therapeutic agents to the brain. Recent advancements in BBB-targeting therapies offer promising strategies to overcome this challenge, providing new avenues for the effective treatment of brain cancer. This article reviews innovative approaches, including Convection-Enhanced Delivery (CED) and RNA-based therapeutics, which enhance drug delivery directly to tumor sites, bypassing the BBB and reducing systemic toxicity. Additionally, the use of theranostic nanoparticles and CRISPR-Cas9 gene editing presents novel opportunities for real-time monitoring and precision-targeted therapy, respectively. Techniques such as magnetic nanoparticles, intranasal drug administration, and focused ultrasound with microbubbles are also being refined to improve drug penetration across the BBB. Furthermore, peptide-based delivery systems and small molecules designed to mimic endogenous transport pathways are accelerating the discovery of more effective therapies. The exploration of combination therapies that synergize BBB-penetrant drugs with conventional chemotherapeutic agents or immunotherapies holds the potential to enhance treatment efficacy and patient outcomes. Continued research and interdisciplinary collaboration are essential to develop predictive models, personalized treatment strategies, and alternative delivery methods that ensure the long-term safety and effectiveness of these novel therapies. Advancements in BBB-targeting therapeutics are poised to transform the landscape of brain cancer treatment, offering renewed hope for improved survival rates and quality of life for patients.
Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Sistemas de Liberação de Medicamentos , Medicina de Precisão , Humanos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Medicina de Precisão/métodos , Sistemas de Liberação de Medicamentos/métodos , Resultado do Tratamento , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagemRESUMO
Neurological disorders have for a long time been a global challenge dismissed by drug companies, especially due to the low efficiency of most therapeutic compounds to cross the brain capillary wall, that forms the blood-brain barrier (BBB) and reach the brain. This has boosted an incessant search for novel carriers and methodologies to drive these compounds throughout the BBB. However, it remains a challenge to artificially mimic the physiology and function of the human BBB, allowing a reliable, reproducible and throughput screening of these rapidly growing technologies and nanoformulations (NFs). To surpass these challenges, brain-on-a-chip (BoC) - advanced microphysiological platforms that emulate key features of the brain composition and functionality, with the potential to emulate pathophysiological signatures of neurological disorders, are emerging as a microfluidic tool to screen new brain-targeting drugs, investigate neuropathogenesis and reach personalized medicine. In this review, the advance of BoC as a bioengineered screening tool of new brain-targeting drugs and NFs, enabling to decipher the intricate nanotechnology-biology interface is discussed. Firstly, the main challenges to model the brain are outlined, then, examples of BoC platforms to recapitulate the neurodegenerative diseases and screen NFs are summarized, emphasizing the current most promising nanotechnological-based drug delivery strategies and lastly, the integration of high-throughput screening biosensing systems as possible cutting-edge technologies for an end-use perspective is discussed as future perspective.
Assuntos
Barreira Hematoencefálica , Encéfalo , Dispositivos Lab-On-A-Chip , Nanotecnologia , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Barreira Hematoencefálica/metabolismo , Nanotecnologia/métodos , Encéfalo/metabolismo , Animais , Sistemas de Liberação de Medicamentos/métodosRESUMO
No single treatment significantly reduces the mortality rate and improves neurological outcomes after intracerebral haemorrhage (ICH). New evidence suggests that pyroptosis-specific proteins are highly expressed in the perihaematomal tissues of patients with ICH and that the disulfiram (DSF) inhibits pyroptosis. An ICH model was established in C57BL/6 mice by intracranial injection of collagenase, after which DSF was used to treat the mice. Cell model of ICH was constructed, and DSF was used to treat the cells. HE, TUNEL, Nissl, FJC and IF staining were performed to evaluate the morphology of brain tissues; Western blotting and ELISA were performed to measure the protein expression of NOD-like receptor protein 3 (NLRP3)/Caspase-1/gasdermin D (GSDMD) classical pyroptosis pathway and Toll-likereceptor4 (TLR4)/nuclear factor-kappaB (NF-κB) inflammatory signaling pathway and bloodâbrain barrier-associated factoes, and the wet/dry weight method was used to determine the brain water content. The expression of proteins related to the NLRP3/Caspase-1/GSDMD pathway and the TLR4/NF-κB pathway was upregulated in tissues surrounding the haematoma compared with that in control tissues; Moreover, the expression of the blood-brain barrier structural proteins occludin and zonula occludens-1 (ZO-1) was downregulated, and the expression of Aquaporin Protein-4 (AQP4) and matrix metalloprotein 9 (MMP-9) was upregulated. DSF significantly inhibited these changes, reduced the haematoma volume, decreased the brain water content, reduced neuronal death and degeneration and improved neurological function after ICH. ICH activated the classical pyroptosis pathway and TLR4/NF-κB inflammatory pathway, disruped the expression of blood-brain barrier structural proteins, and exacerbated brain injury and neurological dysfunction. DSF inhibited these changes and exerted the therapeutic effects on pathological changes and dysfunction caused by ICH.
Assuntos
Barreira Hematoencefálica , Dissulfiram , Camundongos Endogâmicos C57BL , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Transdução de Sinais , Receptor 4 Toll-Like , Animais , Piroptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Dissulfiram/farmacologia , Transdução de Sinais/efeitos dos fármacos , Masculino , Receptor 4 Toll-Like/metabolismo , NF-kappa B/metabolismo , Modelos Animais de Doenças , Caspase 1/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Hemorragias Intracranianas/tratamento farmacológico , Hemorragias Intracranianas/metabolismo , Ocludina/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Humanos , GasderminasRESUMO
OBJECTIVE: To explore whether miR-199a-5p regulated BBB integrity through PI3K/Akt pathway after ischemia stroke. METHODS: Adult male Sprague-Dawley rats with permanent middle cerebral artery occlusion(MCAO) were used in experiment. The Ludmila Belayev 12-point scoring was used to measure the neurological function of MCAO rats. The Evans Blue Stain, immunofluorescence staining, western-blotting and RT-PCR were performed to evaluate the effects of miR-199a-5p mimic on BBB integrity in rats following MCAO. RESULTS: The result suggested that miR-199a-5p mimic treatment possessed the potential to boost proprioception and motor activity of MCAO rats. MiR-199a-5p decreased the expression of PIK3R2 after MCAO, activated Akt signaling pathway, and increased the expression of Claudin-5 and VEGF in the ischemic penumbra. Furthermore, miR-199a-5p alleviated inflammation after cerebral ischemia. BBB leakage and neurocyte apoptosis were cut down in MCAO rats treated with miR-199a-5p mimic. CONCLUSIONS: MiR-199a-5p mimic decreased the expression of PIK3R2 and activated Akt signaling pathway after ischemia stroke, reduced the expression of inflammatory cytokines, and attenuated BBB disruption after ischemic stroke.
Assuntos
Barreira Hematoencefálica , AVC Isquêmico , MicroRNAs , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Transdução de Sinais , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Barreira Hematoencefálica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Masculino , Ratos , AVC Isquêmico/metabolismo , AVC Isquêmico/genética , AVC Isquêmico/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Apoptose , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/patologiaRESUMO
Neurotropic viruses have been implicated in altering the central nervous system microenvironment and promoting brain metastasis of breast cancer through complex interactions involving viral entry mechanisms, modulation of the blood-brain barrier, immune evasion, and alteration of the tumour microenvironment. This narrative review explores the molecular mechanisms by which neurotropic viruses such as Herpes Simplex Virus, Human Immunodeficiency Virus, Japanese Encephalitis Virus, and Rabies Virus facilitate brain metastasis, focusing on their ability to disrupt blood-brain barrier integrity, modulate immune responses, and create a permissive environment for metastatic cell survival and growth within the central nervous system. Current therapeutic implications and challenges in targeting neurotropic viruses to prevent or treat brain metastasis are discussed, highlighting the need for innovative strategies and multidisciplinary approaches in virology, oncology, and immunology.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/virologia , Neoplasias da Mama/terapia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/virologia , Neoplasias Encefálicas/terapia , Feminino , Barreira Hematoencefálica/virologia , Animais , Microambiente Tumoral , Vírus da Raiva/fisiologia , Vírus da Raiva/patogenicidade , Vírus da Raiva/imunologia , Simplexvirus/fisiologiaRESUMO
BACKGROUND: The choroid plexus (ChP) helps maintain the homeostasis of the brain by forming the blood-CSF barrier via tight junctions (TJ) at the choroid plexus epithelial cells, and subsequently preventing neuroinflammation by restricting immune cells infiltration into the central nervous system. However, whether chronic cerebral hypoperfusion causes ChP structural damage and blood-CSF barrier impairment remains understudied. METHODS: The bilateral carotid stenosis (BCAS) model in adult male C57BL/6 J mice was used to induce cerebral hypoperfusion, a model for vascular contributions to cognitive impairment and dementia (VCID). BCAS-mediated changes of the blood-CSF barrier TJ proteins, apical secretory Na+-K+-Cl- cotransporter isoform 1 (NKCC1) protein and regulatory serine-threonine kinases SPAK, and brain infiltration of myeloid-derived immune cells were assessed. RESULTS: BCAS triggered dynamic changes of TJ proteins (claudin 1, claudin 5) accompanied with stimulation of SPAK-NKCC1 complex and NF-κB in the ChP epithelial cells. These changes impacted the integrity of the blood-CSF barrier, as evidenced by ChP infiltration of macrophages/microglia, neutrophils and T cells. Importantly, pharmacological blockade of SPAK with its potent inhibitor ZT1a in BCAS mice attenuated brain immune cell infiltration and improved cognitive neurological function. CONCLUSIONS: BCAS causes chronic ChP blood-CSF damage and immune cell infiltration. Our study sheds light on the SPAK-NKCC1 complex as a therapeutic target in neuroinflammation.
Assuntos
Estenose das Carótidas , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Animais , Camundongos , Masculino , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/etiologia , Estenose das Carótidas/patologia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/metabolismo , Plexo Corióideo/patologia , Plexo Corióideo/metabolismoRESUMO
BACKGROUND: The blood-cerebrospinal fluid barrier (BCSFB) comprises the choroid plexus epithelia. It is important for brain development, maintenance, function, and especially for maintaining immune homeostasis in the cerebrospinal fluid (CSF). Although previous studies have shown that the peripheral immune function of the body is impaired upon exposure to microgravity, no studies have reported changes in immune cells and cytokines in the CSF that reflect neuroimmune status. The purpose of this study is to investigate the alterations in cerebrospinal fluid (CSF) immune homeostasis induced by microgravity and its mechanisms. This research is expected to provide basic data for brain protection of astronauts during spaceflight. METHODS: The proportions of immune cells in the CSF and peripheral blood (PB) of SMG rats were analyzed using flow cytometry. Immune function was evaluated by measuring cytokine concentrations using the Luminex method. The histomorphology and ultrastructure of the choroid plexus epithelia were determined. The concentrations of intercellular junction proteins in choroid plexus epithelial cells, including vascular endothelial-cadherin (VE-cadherin), zonula occludens 1 (ZO-1), Claudin-1 and occludin, were detected using western blotting and immunofluorescence staining to characterize BCSFB injury. RESULTS: We found that SMG caused significant changes in the proportion of CD4 and CD8 T cells in the CSF and a significant increase in the levels of cytokines (GRO/KC, IL-18, MCP-1, and RANTES). In the PB, there was a significant decrease in the proportion of T cells and NKT cells and a significant increase in cytokine levels (GRO/KC, IL-18, MCP-1, and TNF-α). Additionally, we observed that the trends in immune markers in the PB and CSF were synchronized within specific SMG durations, suggesting that longer SMG periods (≥21 days) have a more pronounced impact on immune markers. Furthermore, 21d-SMG resulted in ultrastructural disruption and downregulated expression of intercellular junction proteins in rat choroid plexus epithelial cells. CONCLUSIONS: We found that SMG disrupts the BCSFB and affects the CSF immune homeostasis. This study provides new insights into the health protection of astronauts during spaceflight.