Endogenous FGF21 attenuates blood-brain barrier disruption in penumbra after delayed recanalization in MCAO rats through FGFR1/PI3K/Akt pathway / 中南大学学报(医学版)

OBJECTIVES@#Restoration of blood circulation within "time window" is the principal treating goal for treating acute ischemic stroke. Previous studies revealed that delayed recanalization might cause serious ischemia/reperfusion injury. However, plenty of evidences showed delayed recanalization improved neurological outcomes in acute ischemic stroke. This study aims to explore the role of delayed recanalization on blood-brain barrier (BBB) in the penumbra (surrounding ischemic core) and neurological outcomes after middle cerebral artery occlusion (MCAO).@*METHODS@#Recanalization was performed on the 3rd day after MCAO. BBB disruption was tested by Western blotting, Evans blue dye, and immunofluorescence staining. Infarct volume and neurological outcomes were evaluated on the 7th day after MCAO. The expression of fibroblast growth factor 21 (FGF21), fibroblast growth factor receptor 1 (FGFR1), phosphatidylinositol-3-kinase (PI3K), and serine/threonine kinase (Akt) in the penumbra were observed by immunofluorescence staining and/or Western blotting.@*RESULTS@#The extraversion of Evans blue, IgG, and albumin increased surrounding ischemic core after MCAO, but significantly decreased after recanalization. The expression of Claudin-5, Occludin, and zona occludens 1 (ZO-1) decreased surrounding ischemic core after MCAO, but significantly increased after recanalization. Infarct volume reduced and neurological outcomes improved following recanalization (on the 7th day after MCAO). The expressions of Claudin-5, Occludin, and ZO-1 decreased surrounding ischemic core following MCAO, which were up-regulated corresponding to the increases of FGF21, p-FGFR1, PI3K, and p-Akt after recanalization. Intra-cerebroventricular injection of FGFR1 inhibitor SU5402 down-regulated the expression of PI3K, p-Akt, Occludin, Claudin-5, and ZO-1 in the penumbra, which weakened the beneficial effects of recanalization on neurological outcomes after MCAO.@*CONCLUSIONS@#Delayed recanalization on the 3rd day after MCAO increases endogenous FGF21 in the penumbra and activates FGFR1/PI3K/Akt pathway, which attenuates BBB disruption in the penumbra and improves neurobehavior in MCAO rats.

Contrast Medium-Induced Transient Neurologic Deteriorations Following Cerebral angiography and Coil Embolization for Unruptured Aneurysm: Report of Two Cases / 대한뇌혈관외과학회지

Cerebral angiography with contrast medium (CM) is a key method for diagnosis and interventional treatment of intracranial cerebral vascular lesions. Cerebral angiography causes few neurologic complications. There have been rare reports of complications related to disruption of the blood-brain barrier due to the administration of nonionic CM. We observed two patients with transient neurologic complications following cerebral angiography and coil embolization for unruptured aneurysm.

The Effects of Propofol on Blood-Brain Barrier Disruption with Mannitol Infusion in Cervical Sympathetic Nerve Blocked Rats / 대한구급학회지

BACKGROUND: Blood brain barrier disruption (BBBD)increases therapeutic agents delivery to brain diseases.Increasing the delivery of therapeutic drugs to the brainimproves out come f or patients with brain tumors.Cervical sympathetic chain block can increase the degree of mannitol induced blood brain barrier disruption in rats.Anesthetic agents may modify hyperosmolar blood brain barrier disruption.Therefore we evaluated the effecfs of pentobarbital and propofol on mannitol induced blood brain barrier disruption(BBBD)in cervical sympathetic nerve blocked rats. METHODS: 14 male Sprague-Dawley rats were divided into 2 groups.Intravenous pentobarbital (group 1,n=7)and propofol (group 2,n=7)were administrated.Rats was blocked with 0.5% bupivacaine on right cervical sympathetic chain.All rats received 37degrees C,25%mannitol (1.75 g/kg) via right carotid artery.BBBD was estimated by Evans blue staining in cerebral hemisphere. RESULTS: Both groups showed BBBD in right side hemisphere and there was no significant difference between group 1 and group 2 in right side hemisphere. CONCLUSIONS: The results suggest that propofol could be used to be anesthetics for BBBD in cervical sympathetic blocked rats.

The Effects of Intravenous Anesthetics on Blood-Brain Barrier Disruption Induced with Mannitol in Rats / 대한마취과학회지

BACKGROUND: In the anesthetic state, various anesthetic agents may effect on hyperosmolar blood-brain barrier disruption. Therefore, the effects of intravenous anesthetics, pentobarbital, ketamine and propofol, on the mannitol induced blood brain barrier disruption (BBBD) of 21 Spague-Dawly rats were evaluated. METHODS: Intravenous anesthetics, pentobarbital (group 1), propofol (group 2) and ketamine (group 3), were administrated before right intracarotid artery infusion of mannitol in three groups. BBBD was estimated by the calculation of the ratio of radioactivity between plasma and brain tissue using 99MTC-human serum albumin and Evans blue staining in cerebral hemisphere. Also cerebral blood flow (CBF) was monitored with laser doppler flowmetry. RESULTS: Percent albuminal space of right and left cerebral hemisphere was showed 9.01 +/- 3.47%, 1.65 +/- 1.25% in group 1, 8.02 +/- 2.19%, 1.61 +/- 1.06% in group 2 and 5.63 +/- 1.79%, 1.10 +/- 0.94% in group 3 respectively. Evans blue dye staining was showed 2+~3+ in the right and 0 in the left cerebral hemisphere in all groups. Right cerebral hemisphere showed significantly more blood brain barrier disruption than left cerebral hemisphere in all groups (p<0.01). And there was no significant difference in BBBD among three groups. However, the degree of BBBD of group 3 was drop down to nearly 70-80% of group 1 and 2. The CBF of group 3 was significantly higher than that of group 1 and group 2 after intracarotid infusion of mannitol (p<0.05). CONCLUSIONS: The results suggest that pentobarbital, propofol and ketamine could be used to be anesthetics for BBBD in rats, but some caution should be paid to use ketamine in mannitol induced BBBD.

Real-time Estimation of Mannitol-Induced Blood-Brain-Barrier Disruption by Microdialysis

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.

Is the Phenomenon of Blood-Brain Barrier Disruption Induced with Mannitol All-or-None?

We evaluated the effect of mannitol-induced blood-brain-barrier disruption(BBBD) in 20 rats of the routine-dose mannitol group(1.75g/kg), 7 rats of the small-dose mannitol group(0.87g/kg), and 10 rats of the saline control group. Radioactivity ratios of brain section to plama in the routine dose mannitol group revealed a wide variation of 0.0134 to 0.1747 which was compared to the small dose mannitol group of 0.0107-0.0275 in the plasma albumin space and to the saline control group of 0.0051-0.0174. This result suggest that mannitol-induced BBBD may not be threshold event of all-or-none phenopomenon, but progressive graded reaction with various sensitivity.