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Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours.

ABSTRACT: Drug delivery is one of the major challenges in the treatment of central nervous system disorders. The brain needs to be protected from harmful agents, which are done by the capillary network, the so-called blood-brain barrier (BBB). This protective guard also prevents the delivery of therapeutic agents to the brain and limits the effectiveness of treatment. For this reason, various strategies have been explored by scientists for overcoming the BBB from disruption of the BBB to targeted delivery of nanoparticles (NPs) and cells and immunotherapy. In this review, different promising brain drug delivery strategies including disruption of tight junctions in the BBB, enhanced transcellular transport by peptide-based delivery, local delivery strategies, NP delivery, and cell-based delivery have been fully discussed.

SUBMITTER: Ebrahimi Z

PROVIDER: S-EPMC8676526 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours.

Ebrahimi Zahra Z Talaei Sam S Aghamiri Shahin S Goradel Nasser Hashemi NH Jafarpour Ali A Negahdari Babak B

IET nanobiotechnology 20200801 6

Drug delivery is one of the major challenges in the treatment of central nervous system disorders. The brain needs to be protected from harmful agents, which are done by the capillary network, the so-called blood-brain barrier (BBB). This protective guard also prevents the delivery of therapeutic agents to the brain and limits the effectiveness of treatment. For this reason, various strategies have been explored by scientists for overcoming the BBB from disruption of the BBB to targeted delivery ...[more]

PMID: 32755952

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Project description:BackgroundBlood-brain barrier dysfunction is associated with many late-stage neurodegenerative diseases. An emerging question is whether the mutations associated with neurodegenerative diseases can independently lead to blood-brain barrier (BBB) dysfunction. Studies from patient-derived induced pluripotent stem cells suggest that mutations associated with neurodegenerative disease are non-cell autonomous, resulting in gain of toxic function in derived neurons and astrocytes. Here we assess whether selected mutations associated with neurodegenerative diseases can contribute to impairment of the blood-brain barrier.MethodsWe assessed barrier function of confluent monolayers of human brain microvascular endothelial cells (hBMECs) derived from induced pluripotent stem cells (iPSC) from three healthy individuals and eight individuals with neurodegenerative disease. We systematically assessed protein and gene expression of BBB biomarkers, transendothelial resistance (TEER), permeability of Lucifer yellow, permeability of D-glucose, permeability of rhodamine 123, the efflux ratio of rhodamine 123, and P-gp inhibition using Tariquidar for confluent monolayers of human brain microvascular endothelial cell (hBMECs).ResultsWe provide evidence supporting the hypothesis that mutations associated with neurodegenerative disease can independently cause BBB dysfunction. These functional changes are not catastrophic since barrier breakdown would result in BBB impairment during development. Synergistic interactions between non-cell autonomous cerebrovascular dysfunction and the effects of gain-of-toxic function in neurons (e.g. toxic oligomers) are likely to increase disease burden through a positive feedback mechanism.ConclusionsThese results suggest that the accumulation of defects in brain microvascular endothelial cells may ultimately lead to impairment of the BBB. Small changes in barrier function over time could lead to accumulated defects that result in positive feedback to unrelated central nervous system diseases.

Project description:BackgroundAutism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene-environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood-brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD.MethodsPostmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated.ResultsClaudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls.ConclusionsIn the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

Dataset Information

Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours.

Publications

Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours.

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