scholarly journals Systemically Administered Brain-Targeted Nanoparticles Transport Peptides across the Blood—Brain Barrier and Provide Neuroprotection

2015 ◽  
Vol 35 (3) ◽  
pp. 469-475 ◽  
Author(s):  
Muge Yemisci ◽  
Secil Caban ◽  
Yasemin Gursoy-Ozdemir ◽  
Sevda Lule ◽  
Ramon Novoa-Carballal ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Drug Carriers ◽  
Artery Occlusion ◽  
Systemic Administration ◽  
Brain Barrier ◽  
Therapeutic Window ◽  
Targeted Nanoparticles ◽  
Blood Brain ◽  
The Brain

Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood—brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against stroke.

Comparative changes in the blood-brain barrier and cerebral infarction of SHR and WKY rats

2007 ◽  
Vol 292 (5) ◽  
pp. R1881-R1892 ◽  
Author(s):  
Sharon Hom ◽  
Melissa A. Fleegal ◽  
Richard D. Egleton ◽  
Christopher R. Campos ◽  
Brian T. Hawkins ◽  
...  
Keyword(s):  
Cerebral Infarction ◽  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Brain Barrier ◽  
Ion Transporter ◽  
Transporter Proteins ◽  
Wky Rats ◽  
Blood Brain ◽  
Hypertension Development ◽  
The Brain

Hypertension is involved in the exacerbation of stroke. It is unclear how blood-brain barrier (BBB) tight-junction (TJ) and ion transporter proteins critical for maintaining brain homeostasis contribute to cerebral infarction during hypertension development. In the present study, we investigated cerebral infarct volume following permanent 4-h middle cerebral artery occlusion (MCAO) and characterized the expression of BBB TJ and ion transporter proteins in brain microvessels of spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto (WKY) rats at 5 wk (prehypertension), 10 wk (early-stage hypertension), and 15 wk (later-stage hypertension) of age. Hypertensive SHR show increased infarct volume following MCAO compared with WKY control rats. BBB TJ and ion transporter proteins, known to contribute to edema and fluid volume changes in the brain, show differential protein expression patterns during hypertension development. Western blot analysis of TJ protein zonula occludens-2 (ZO-2) showed decreased expression, while ion transporter, Na+/H+ exchanger 1 (NHE-1), was markedly increased in hypertensive SHR. Expression of TJ proteins ZO-1, occludin, actin, claudin-5, and Na+-K+-2Cl− cotransporter remain unaffected in SHR compared with control. Selective inhibition of NHE-1 using dimethylamiloride significantly attenuated ischemia-induced infarct volume in hypertensive SHR following MCAO, suggesting a novel role for NHE-1 in the brain in the regulation of ischemia-induced infarct volume in SHR.

scholarly journals Modulating the Blood-Brain Barrier by Light Stimulation of Molecular-Targeted Nanoparticles

2020 ◽  
Author(s):  
Xiaoqing Li ◽  
Vamsidhara Vemireddy ◽  
Qi Cai ◽  
Hejian Xiong ◽  
Peiyuan Kang ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Light Stimulation ◽  
Targeted Nanoparticles ◽  
Blood Brain ◽  
The Brain ◽  
Stimulation Of

AbstractThe blood-brain barrier (BBB) tightly regulates the entry of molecules into the brain by tight junctions that seals the paracellular space and receptor-mediated transcytosis. It remains elusive to selectively modulate these mechanisms and to overcome BBB without significant neurotoxicity. Here we report that light stimulation of tight junction-targeted plasmonic nanoparticles selectively opens up the paracellular route to allow diffusion through the compromised tight junction and into the brain parenchyma. The BBB modulation does not impair vascular dynamics and associated neurovascular coupling, or cause significant neural injury. It further allows antibody and adeno-associated virus delivery into local brain regions. This novel method offers the first evidence of selectively modulating BBB tight junctions and opens new avenues for therapeutic interventions in the central nervous system.One Sentence SummaryGentle stimulation of molecular-targeted nanoparticles selectively opens up the paracellular pathway and allows macromolecules and gene therapy vectors into the brain.

scholarly journals Nose-to-Brain Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 138 ◽  
Author(s):  
Paolo Giunchedi ◽  
Elisabetta Gavini ◽  
Maria Cristina Bonferoni
Keyword(s):  
Side Effects ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Systemic Administration ◽  
Brain Barrier ◽  
Brain Delivery ◽  
Special Issue ◽  
Drug Bioavailability ◽  
Blood Brain ◽  
The Brain

Nose-to-brain delivery represents a big challenge. In fact there is a large number of neurological diseases that require therapies in which the drug must reach the brain, avoiding the difficulties due to the blood–brain barrier (BBB) and the problems connected with systemic administration, such as drug bioavailability and side-effects. For these reasons the development of nasal formulations able to deliver the drug directly into the brain is of increasing importance. This Editorial regards the contributions present in the Special Issue “Nose-to-Brain Delivery”.

scholarly journals Detrimental role of pericyte Nox4 in the acute phase of brain ischemia

2015 ◽  
Vol 36 (6) ◽  
pp. 1143-1154 ◽  
Author(s):  
Ataru Nishimura ◽  
Tetsuro Ago ◽  
Junya Kuroda ◽  
Koichi Arimura ◽  
Masaki Tachibana ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Blood Brain Barrier ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Blood Brain ◽  
Barrier Breakdown ◽  
Cerebral Artery Occlusion

Pericytes are mural cells abundantly present in cerebral microvessels and play important roles, including the formation and maintenance of the blood–brain barrier. Nox4 is a major source of reactive oxygen species in cardiovascular cells and modulate cellular functions, particularly under pathological conditions. In the present study, we found that the expression of Nox4 was markedly induced in microvascular cells, including pericytes, in peri-infarct areas after middle cerebral artery occlusion stroke models in mice. The upregulation of Nox4 was greater in a permanent middle cerebral artery occlusion model compared with an ischemia/reperfusion transient middle cerebral artery occlusion model. We performed permanent middle cerebral artery occlusion on mice with Nox4 overexpression in pericytes (Tg-Nox4). Infarct volume was significantly greater with enhanced reactive oxygen species production and blood–brain barrier breakdown in peri-infarct areas in Tg-Nox4, compared with littermate controls. In cultured brain pericytes, Nox4 was significantly upregulated by hypoxia and was promptly downregulated by reoxygenation. Phosphorylation of NFκB and production of matrix metalloproteinase 9 were significantly increased in both cultured pericytes overexpressing Nox4 and in peri-infarct areas in Tg-Nox4. Collectively, Nox4 is upregulated in pericytes in peri-infarct areas after acute brain ischemia and may enhance blood–brain barrier breakdown through activation of NFκB and matrix metalloproteinase 9, thereby causing enlargement of infarct volume.

scholarly journals Junctional Protein Regulation by Sphingosine Kinase 2 Contributes to Blood–Brain Barrier Protection in Hypoxic Preconditioning-Induced Cerebral Ischemic Tolerance

2012 ◽  
Vol 32 (6) ◽  
pp. 1014-1023 ◽  
Author(s):  
Bradley K Wacker ◽  
Angela B Freie ◽  
Jennifer L Perfater ◽  
Jeffrey M Gidday
Keyword(s):  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Sphingosine Kinase ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Hypoxic Preconditioning ◽  
Brain Barrier ◽  
Protein Regulation ◽  
Blood Brain ◽  
Junctional Protein

Protection of the blood–brain barrier (BBB) is correlated with improved outcome in stroke. Sphingosine kinase (SphK)-directed production of sphingosine-1-phosphate, which we previously documented as being vital to preconditioning-induced stroke protection, mediates peripheral vascular integrity via junctional protein regulation. We used a hypoxic preconditioning (HPC) model in adult wild-type and SphK2-null mice to examine the isoform-specific role of SphK2 signaling for ischemic tolerance to transient middle cerebral artery occlusion and attendant BBB protection. Reductions in infarct volume and BBB permeability in HPC-treated mice were completely lost in SphK2-null mice. Hypoxic preconditioning-induced attenuation of postischemic BBB disruption in wild types, evidenced by reduced extravascular immunoglobulin G intensity, suggests direct protection of BBB integrity. Measurement of BBB junctional protein status in response to HPC revealed SphK2-dependent increases in triton-insoluble claudin-5 and VE-cadherin, which may serve to strengthen the BBB before stroke. Postischemic loss of VE-cadherin, occludin, and zona occludens-1 in SphK2-null mice with prior HPC suggests that SphK2-dependent protection of these adherens and tight junction proteins is compulsory for HPC to establish a vasculoprotective phenotype. Further elucidation of the mediators of this endogenous, HPC-activated lipid signaling pathway, and their role in protecting the ischemic BBB, may provide new therapeutic targets for cerebrovascular protection in stroke patients.

scholarly journals The Influence of Electronic Acupuncture At A Specific Frequency In Facilitating The Passage of NGF Through The Blood-Brain Barrier And Its Effect On Learning And Memory In MCAO/R Rats

2021 ◽  
Author(s):  
Yibin Zhao ◽  
Xuqing Mao ◽  
Hao Wang ◽  
Lin Gan ◽  
Shanshan Zhang ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Blood Brain Barrier ◽  
Therapeutic Effect ◽  
Fluorescein Isothiocyanate ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Pathological Conditions ◽  
Blood Brain ◽  
Specific Frequency ◽  
The Brain

Abstract The blood-brain barrier (BBB) maintains the balance of the internal environment of the brain and strictly controls substance exchange between the brain and blood dynamically but stably. Transient increases in the permeability of the BBB plays an important role in helping macromolecular drugs enter the brain to exert their pharmacological effects. Previous research has revealed that electronic acupuncture (EA) stimulation at a specific frequency can enhance the permeability of the BBB and induce the entry of 20 kDa fluorescein isothiocyanate-dextran (FITC-dextran) into the cerebral cortex, but whether it can also allow drugs to pass the BBB remains unknown. We hypothesized that EA at a specific frequency could open the BBB and induce the entry of nerve growth factor (NGF) into the brain to exert its therapeutic effect. To simulate the clinical apoplexy sequelae observed in patients and determine the basic timing of BBB repair under pathological conditions, we employed the middle cerebral artery occlusion (MCAO) model and assessed changes in the permeability and structure of the BBB by measuring both the intensity of Evans blue (EB) staining and the cerebral infarction volume and evaluating the ultrastructure of the BBB. Then, we used a laser spectrometer and immunofluorescence to observe entry of NGF into the brain. Finally, we assessed the learning and memory ability of rats and used the DeadEnd TM Fluorometric TUNEL System to assess apoptosis in the hippocampus. Our results showed that the BBB was essentially repaired three weeks after MCAO, indicating that EA stimulation at a specific frequency can enhance BBB permeability and induce NGF uptake by prefrontal neurons. In the presence of EA stimulation, entry of NGF into the brain promoted learning and memory in rats and inhibited the apoptosis of neurons in the hippocampus. In this study, the MCAO model was used to determine the timing of BBB repair under pathological conditions and assess the EA stimulation-induced entry of NGF into the brain to exert its therapeutic effect. EA could serve as a new strategy for delivering therapeutics to the central nervous system (CNS), given that EA stimulation at a specific frequency was shown to increase the permeability of the BBB. Further study of the mechanism underlying the opening of the BBB and its timing is needed.

scholarly journals THER-11. PEPTIDE-MEDIATED PERMEABILIZATION OF THE BLOOD-BRAIN BARRIER IMPROVES DRUG DELIVERY TO BRAIN METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i13-i13
Author(s):  
Synnøve Nymark Aasen ◽  
Heidi Espedal ◽  
Christopher Holte ◽  
Olivier Keunen ◽  
Tine Veronika Karlsen ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Plasma Membranes ◽  
Combined Treatment ◽  
Brain Barrier ◽  
Therapeutic Window ◽  
Dce Mri ◽  
Blood Brain ◽  
The Brain ◽  
Bbb Opening

Abstract BACKGROUND: Melanoma patients have a high risk of developing brain metastases, which is associated with a poor prognosis. The blood-brain barrier (BBB) inhibits sufficient drug delivery into metastatic lesions. We investigated the ability of a synthetic peptide (K16ApoE) to permeabilize the BBB for more effective drug treatment. METHODS: DCE-MRI was performed to study the therapeutic window of BBB opening facilitated by K16ApoE. In vivoand in vitroassays were used to determine K16ApoE toxicity and also to obtain mechanistic insight into its action on the BBB. The therapeutic impact of K16ApoE on melanoma metastases was determined together with dabrafenib, which is otherwise known not to cross an intact BBB. RESULTS: DCE-MRI exhibited an effective K16ApoE-mediated BBB opening for up to 1h. Mechanistic studies displayed a dose-dependent effect of K16ApoE caused by induction of endocytosis. At higher concentrations, the peptide also showed unspecific disturbances on plasma membranes. Combined treatment with K16ApoE and dabrafenib reduced the brain metastatic burden in mice compared to dabrafenib. We also showed by PET/CT that the peptide facilitated the delivery of compounds up to 150 kDa into the brain. CONCLUSIONS: We demonstrate a transient opening of the BBB, caused by K16ApoE, that facilitates improved drug-delivery into the brain. This improves the efficacy of drugs that otherwise do not cross the intact BBB.

scholarly journals Blood-brain barrier shuttle peptides enhance AAV transduction in the brain after systemic administration

Biomaterials ◽  
2018 ◽  
Vol 176 ◽  
pp. 71-83 ◽  
Author(s):  
Xintao Zhang ◽  
Ting He ◽  
Zheng Chai ◽  
R. Jude Samulski ◽  
Chengwen Li
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Administration ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

scholarly journals DL-3n-Butylphthalide Improves Blood–Brain Barrier Integrity in Rat After Middle Cerebral Artery Occlusion

2021 ◽  
Vol 14 ◽  
Author(s):  
Muyassar Mamtilahun ◽  
Zhenyu Wei ◽  
Chuan Qin ◽  
Yongting Wang ◽  
Yaohui Tang ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Aqp4 Expression ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

Objective: DL-3n-butylphthalide (NBP) has beneficial effects in different stages of ischemic stroke. Our previous studies have demonstrated that NBP promoted angiogenesis in the perifocal region of the ischemic brain. However, the molecular mechanism of NBP for blood–brain barrier protection in acute ischemic stroke was unclear. Here, we explored the neuroprotective effects of NBP on blood–brain barrier integrity in the acute phase of ischemic stroke in a rat model.Methods: Adult male Sprague–Dawley rats (n = 82) underwent 2 h of transient middle cerebral artery occlusion and received 90 mg/kg of NBP for 3 days. Brain edema, infarct volume, surface blood flow, and neurological severity score were evaluated. Blood–brain barrier integrity was evaluated by Evans blue leakage and changes in tight junction proteins. We further examined AQP4 and eNOS expression, MMP-9 enzyme activity, and possible signaling pathways for the role of NBP after ischemic stroke.Results: NBP treatment significantly increased eNOS expression and surface blood flow in the brain, reduced brain edema and infarct volume, and improved neurological severity score compared to the control group (p < 0.05). Furthermore, NBP attenuated Evans blue and IgG leakage and increased tight junction protein expression compared to the control after 1 and 3 days of ischemic stroke (p < 0.05). Finally, NBP decreased AQP4 expression, MMP-9 enzyme activity, and increased MAPK expression during acute ischemic stroke.Conclusion: NBP protected blood–brain barrier integrity and attenuated brain injury in the acute phase of ischemic stroke by decreasing AQP4 expression and MMP-9 enzyme activity. The MAPK signaling pathway may be associated in this process.

Sign in / Sign up

Export Citation Format

Share Document