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Background The interaction of the receptor for advanced glycation end product (RAGE) on blood-brain-barrier(BBB) with amyloid β (Aβ) plays an important role in the occurrence and development of AD. RP1 is a RAGEspecific binding peptide, which was discovered in our previous experiments, and it has been proved to beeffective on AD cell model, however, its effects on BBB tight junctions (TJs) and on Aβ transport into the brain isunclear.Methods Immunofluorescence experiment was used to identify whether RP1 bound with RAGE specifically.BEnd3-immortalized mouse brain microvascular endothelial cells were used to construct a BBB model. TEER andFD40 tests were used to confirm the stability of the BBB model, and the colocalization of the RP1 and RAGE onthe surface bEnd3 cells was observed with confocal microscopy.Results We confirmed that RP1 can bind to RAGE specifically in vitro. Functional analyses indicated that RP1 caneffectively alleviate the destroy of TJs of BBB and the decrease of permeability of BBB caused by Aβ. Furthermore,RP1 can competitively inhibit the interaction of Aβ with the RAGE in vitro, and effectively inhibit Aβ transport intothe brain.Conclusion RP1 can inhibit BBB damage induced by Aβ and block RAGE-Aβ interaction effectively, and RP1 canbe a candidate of RAGE inhibitors contributing to AD treatment
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¹⁸F-AV-1451 is a tau PET ligand that has high affinity for paired helical filament tau. However, various off-target bindings unrelated to tau have also been reported. Herein, we report a case of 83-year-old woman, who showed abnormal uptake of AV-1451 that was shown to be subacute infarction. Clinicians should recognize that increased uptake of AV-1451 may be related to stroke.
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Aged, 80 and over , Female , Humans , Infarction , StrokeABSTRACT
Objective To determine the effect of treadmill exercise on expression of matrix metalloproteinase-2 (MMP-2) in rats follow-ing traumatic brain injury (TBI). Methods Fifty-five male adult Sprague-Dawley rats were randomly assigned to sham (n=15), control (n=20) and exercise (n=20) groups, the later two groups subjected to unilateral cortical contusion injury (CCI). All the rats were assessed with foot-fault test 6, 12, 18 and 24 days after CCI. Evans blue perfusion was used to evaluate the integrity of the blood-brain-barrier (BBB) 48 hours after CCI. Protein expression of MMP-2 was determined with Western blotting one week after CCI. Results The score of foot-fault test improved more in the exercise group than in the control group 12, 18 and 24 days after CCI (F>4.793, P<0.05). Evans blue extravasa-tion was less in the exercise group than in the control group (t=-8.091, P<0.001), as well as the expression of MMP-2 (t=-13.12, P<0.001). Conclusion Early treadmill exercise can improve the motor function in rats with TBI, which may associate with inhibition of MMP-2 ex-pression to protect BBB integrity.
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Objective To develop a steady-state brain distribution model in rats and to assess the blood brain barrier(BBB) penetration of antipyrine, atenolol and a group of ZZB candidate compounds. Methods Antipyrine, atenolol and ZZB compounds were administered to rats by an initial iv bolus dose (loading dose) followed by iv infusion at a constant rate for 30-40 min to reach steady-state plasma kinetics. The blood and brain tissue samples were then collected. The steady-state concentrations of the samples were measured by LC-MS/MS. The steady-state ratio of brain to plasma concentration (Kp) was calculated. The drugs and candidate compounds were also tested with Caco-2 cell model and the apparent bidirectional transport permeability coefficient (Papp) was obtained. Results Antipyrine and atenolol were known as drugs with high and low BBB penetration properties respectively. The mean brain concentrations of antipyrine and atenolol at steady-state were(2561 ± 125) and(20.1±0.8)ng/g with the Kp values of 0.93 ± 0.04 and 0.015 ± 0.002, respectively. The Kp value of antipyrine was about 60 folds higher than that of atenolol. Despite the similar structures of ZZB compounds, the Kp values were varied in the range from 0.044 to 6.41. The Kp values were not correlated with Papp values yielded from Caco-2 cell model. Conclusion The established rat steady-state brain distribution model is simple, reliable and could significantly reduce the animal use. It is a practical in vivo model for assessment of BBB penetration of drugs.
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Objective To explore the mechanism by which enterovirus71 (EV71) crossing the blood-brain barrier (BBB). Methods BBB models were established by human brain microvascular endothelial cells (HBMECs) in vitro and were randomly assigned to control and EV71-in!ected groups. The cytotoxic effect o! EV71 on HBMECs was examined by morphological observation, immunoflurescence, transmission electron microscope and real-time PCR. In addition, the cytoskeletal alterations in HBMECswere observed by laser confocal method. Results EV71 infection could lead to cytopathic changes of HBMECs. Immunofluorescent staining confirmed the presence of EV71 antigen (red fluorescence) and 20-30 nm EV71 particles in EV71-infected HBMECs, but not in mock infected cells. Viral replication in HBMECs was shown by real-time PCR in a time-dependent manner (P<0. 01). EV71 infected cell lost the normal morphology and polarity, with disarranged actin filaments. Conclusion For the first time we prove that EV71 can infect HBMECs and can replicate in the cells, and can induce cytoskeleton changes in some HBMECs.
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Cannabinoid 1 receptor (CB1R) is one of most important targets for the treatment of obesity. However, the clinical application of CB1R antagonist rimonabant is restricted because of the central nervous system-related unwanted liabilities. Peripherally restricted CB1R antagonist with limited blood-brain-barrier penetration may maintain the antiobesity efficacy of rimonabant without unwanted side effects. This strategy has become the new hot spot for the development of antiobesity drugs. In this paper, we review the recent progress in peripherally restricted CB1 receptor antagonist .
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Cannabinoid 1 receptor (CB1R) is one of most important targets for the treatment of obesity. However, the clinical application of CB1R antagonist rimonabant is restricted because of the central nervous system-related unwanted liabilities. Peripherally restricted CB1R antagonist with limited blood-brain-barrier penetration may maintain the antiobesity efficacy of rimonabant without unwanted side effects. This strategy has become the new hot spot for the development of antiobesity drugs. In this paper, we review the recent progress in peripherally restricted CB1 receptor antagonist.
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<p><b>OBJECTIVE</b>To study the effect of electromagnetic pulse (EMP) exposure on permeability of in vitro blood-brain-barrier (BBB) model.</p><p><b>METHODS</b>An in vitro BBB model, established by co-culturing brain microvascular endothelial cells (BMVEC) and astroglial cells (AC) isolated from rat brain, was exposed to EMP at 100 kV/m and 400 kV/m, respectively. Permeability of the model was assayed by measuring the transendothelial electrical resistance (TEER) and the horseradish peroxidase (HRP) transmission at different time points. Levels of BBB tight junction-related proteins were measured at 0, 1, 2, 4, 8, 12, 16, 20, 24 h after EMP exposure by Western blotting.</p><p><b>RESULTS</b>The TEER level was lower in BBB model group than in control group at 12 h after EMP, exposure which returned to its normal level at 24 h. The 24 h recovery process was triphasic and biphasic respectively after EMP exposure at 100 kV/m and 400 kV/m. Following exposure to 400 kV/m EMP, the HRP permeability increased at 1-12 h and returned to its normal level at 24 h. Western blotting showed that the claudin-5 and ZO-1 protein levels were changed after EMP exposure.</p><p><b>CONCLUSION</b>EMP exposure at 100 kV/m and 400 kV/m can increase the permeability of in vitro BBB model and BBB tight junction-related proteins such as ZO-1 and claudin-5 may change EMP-induced BBB permeability.</p>
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Animals , Female , Rats , Blood-Brain Barrier , Radiation Effects , Capillary Permeability , Radiation Effects , Cells, Cultured , Electromagnetic Fields , Rats, Sprague-DawleyABSTRACT
We have done a study for the real-time changes of blood-brain-barrier disruption(BBBD) with brain cortical microdialysis induced by intra-carotid mannitol infusion and of cortical blood flow with laser Doppler flowmetry. A microdialysis probe was established on the right parietal cortex with 99mTc-DTPA(500 Da) as a marker, and two laser Doppler probes on the bilateral frontal cortex. Intra-carotid administration of mannitol was followed in 3 rats and intra-arterial infusion of isotonic saline in 3 control rats. Cortical blood flows were increased dramatically by about 270% to 310% from the preinfusion state within 5 minutes after mannitol infusion as compared to an average of 150% increase in saline controls. BBBd-induced extravascular leakage of 99mTc-DTPA sampled by microdialysis and estimated by high pressure liquid chromatography increased dramatically within 2 minutes, maximally about 10 times that of the pre-infusion state within 5-10 minutes after infusion, and decreased rapidly about next 20 minutes but was still more than 4 times the pre-infusion state, and slowed to near preinfusion state during the next 40-60 minutes. This result suggests the real changes of BBBD estimated by brain cortical microdialysis were relatively comparable to previous radioisotope measurement and the first 20 minutes was significantly valuable for administration of certain molecules using BBBD induced by intra-arterial mannitol infusion.