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Inhibition of protein kinase C? reverses increased blood-brain barrier permeability during hyperglycemic stroke and prevents edema formation in vivo.

ABSTRACT: We investigated the effect of circulating factors and protein kinase C? on blood-brain barrier permeability and edema during hyperglycemic stroke.Male Wistar rats that were hyperglycemic by streptozotocin (50 mg/kg) for 5 to 6 days underwent middle cerebral artery occlusion (MCAO) for 2 hours with 2 hours of reperfusion. Blood-brain barrier permeability was measured in middle cerebral arteries that were ischemic (MCAO) or nonischemic (CTL) and perfused with plasma (20% in buffer) from MCAO or CTL animals. A separate set of MCAO vessels was perfused with the protein kinase C? inhibitor CGP53353 (0.5 ?mol/L) and permeability measured. Lastly, hyperglycemic rats were treated intravenously with CGP53353 (10 or 100 ?g/kg or vehicle 15 minutes before reperfusion and edema formation measured by wet:dry weights (n=6/group).MCAO vessels had increased permeability compared with controls regardless of the plasma perfusate. Permeability (water flux, ?m(3)×10(8)) of CTL vessel/CTL plasma (n=8), CTL vessel/MCAO plasma (n=7), MCAO vessel/CTL plasma (n=6), and MCAO vessel/MCAO plasma (n=6) was 0.98±0.11, 1.13±0.07, 1.36±0.02, and 1.34±0.06; P<0.01). Inhibition of protein kinase C? in MCAO vessels (n=6) reversed the increase in permeability (0.92±0.1; P<0.01). In vivo, hyperglycemia increased edema versus normoglycemia after MCAO (water content=78.84%±0.11% versus 81.38%±0.21%; P<0.01). Inhibition of protein kinase C? with 10 or 100 ?g/kg CGP53353 during reperfusion prevented the increased edema in hyperglycemic animals (water content=79.54%±0.56% and 79.99%±0.43%; P<0.01 versus vehicle).These results suggest that the pronounced vasogenic edema that occurs during hyperglycemic stroke is mediated in large part by activation of protein kinase C?.

SUBMITTER: Cipolla MJ

PROVIDER: S-EPMC3202059 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Inhibition of protein kinase Cβ reverses increased blood-brain barrier permeability during hyperglycemic stroke and prevents edema formation in vivo.

Cipolla Marilyn J MJ Huang Quillan Q Sweet Julie G JG

Stroke 20110818 11

<h4>Background and purpose</h4>We investigated the effect of circulating factors and protein kinase Cβ on blood-brain barrier permeability and edema during hyperglycemic stroke.<h4>Methods</h4>Male Wistar rats that were hyperglycemic by streptozotocin (50 mg/kg) for 5 to 6 days underwent middle cerebral artery occlusion (MCAO) for 2 hours with 2 hours of reperfusion. Blood-brain barrier permeability was measured in middle cerebral arteries that were ischemic (MCAO) or nonischemic (CTL) and perfu ...[more]

PMID: 21852606

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Project description:Background Plasma gelsolin (pGSN) is an important part of the blood actin buffer that prevents negative consequences of possible F-actin deposition in the microcirculation and has various functions during host immune response. Recent reports reveal that severe COVID-19 correlates with reduced levels of pGSN. Therefore, using an in vitro system, we investigated whether pGSN could attenuate increased permeability of the blood–brain barrier (BBB) during its exposure to the portion of the SARS-CoV-2 spike protein containing the receptor binding domain (S1 subunit). Materials and methods Two- and three-dimensional models of the human BBB were constructed using the human cerebral microvascular endothelial cell line hCMEC/D3 and exposed to physiologically relevant shear stress to mimic perfusion in the central nervous system (CNS). Trans-endothelial electrical resistance (TEER) as well as immunostaining and Western blotting of tight junction (TJ) proteins assessed barrier integrity in the presence of the SARS-CoV-2 spike protein and pGSN. The IncuCyte Live Imaging system evaluated the motility of the endothelial cells. Magnetic bead-based ELISA was used to determine cytokine secretion. Additionally, quantitative real-time PCR (qRT-PCR) revealed gene expression of proteins from signaling pathways that are associated with the immune response. Results pGSN reversed S1-induced BBB permeability in both 2D and 3D BBB models in the presence of shear stress. BBB models exposed to pGSN also exhibited attenuated pro-inflammatory signaling pathways (PI3K, AKT, MAPK, NF-κB), reduced cytokine secretion (IL-6, IL-8, TNF-α), and increased expression of proteins that form intercellular TJ (ZO-1, occludin, claudin-5). Conclusion Due to its anti-inflammatory and protective effects on the brain endothelium, pGSN has the potential to be an alternative therapeutic target for patients with severe SARS-CoV-2 infection, especially those suffering neurological complications of COVID-19. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02642-4.

Dataset Information

Inhibition of protein kinase C? reverses increased blood-brain barrier permeability during hyperglycemic stroke and prevents edema formation in vivo.

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Inhibition of protein kinase Cβ reverses increased blood-brain barrier permeability during hyperglycemic stroke and prevents edema formation in vivo.

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