Protein Kinase C Activation Modulates Reversible Increase in Cortical Blood–Brain Barrier Permeability and Tight Junction Protein Expression during Hypoxia and Posthypoxic Reoxygenation

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.

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“…Following hypoxia, claudin-5 expression increases (Willis et al, 2010), consistent with our finding following HPC.…”

Section: Discussionsupporting

confidence: 91%

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

Wacker

Freie

Perfater

et al. 2012

J Cereb Blood Flow Metab

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“…However, how LTD 4 mediates the reduction of ZO-1 remains to be elucidated. Previous studies indicated that activation of PKC and p38 signaling pathways may lead to ZO-1 disruption and increase of BBB permeability (51,52). Other reports also revealed that endogenous CysLTs may increase intracellular calcium level and activate protein kinase C, p38, and PI3K (53).…”

Section: Discussionmentioning

confidence: 99%

Antiasthmatic Drugs Targeting the Cysteinyl Leukotriene Receptor 1 Alleviate Central Nervous System Inflammatory Cell Infiltration and Pathogenesis of Experimental Autoimmune Encephalomyelitis

Wang

et al. 2011

The Journal of Immunology

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Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators and are considered to play a key role in inflammatory diseases such as asthma. Antagonists targeting the receptor of CysLTs (CysLT1) are currently used as antiasthmatic drugs. CysLTs have also been implicated in other inflammatory reactions. In this study, we report that in experimental autoimmune encephalomyelitis animals, CysLT1 is upregulated in immune tissue and the spinal cord, and CysLT levels in the blood and cerebrospinal fluid are also higher than in normal mice. Two clinically used antiasthma drugs, montelukast and zafirlukast, both targeting CysLT1, effectively block the CNS infiltration of inflammatory cells and thus reduce the incidence, peak severity, and cumulative clinical scores. Further study indicated that CysLT1 signaling does not affect the differentiation of pathogenic T helper cells. It might affect the pathogenesis of experimental autoimmune encephalomyelitis by increasing the secretion of IL-17 from myelin oligodendrocyte glycoprotein-specific T cells, increasing the permeability of the blood–brain barrier and inducing chemotaxis of T cells. These effects can be blocked by CysLT1 antagonists. Our findings indicate that the antiasthmatic drugs against CysLT1 can also be used to treat multiple sclerosis.

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“…Our global model of cerebral hypoxia has been used previously to study changes in BBB architecture and intracellular signaling after hypoxic insult. 22,[32][33][34] However, it has not been used to examine regulation and functional expression of putative BBB drug transporters until the present study.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

Thompson

Sanchez-Covarrubias

Slosky

et al. 2014

J Cereb Blood Flow Metab

121

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Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood-brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O 2 , 60 minutes followed by 21% O 2 , 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor-b (TGF-b)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-b/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.

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Protein Kinase C Activation Modulates Reversible Increase in Cortical Blood–Brain Barrier Permeability and Tight Junction Protein Expression during Hypoxia and Posthypoxic Reoxygenation

Cited by 98 publications

References 42 publications

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

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

Antiasthmatic Drugs Targeting the Cysteinyl Leukotriene Receptor 1 Alleviate Central Nervous System Inflammatory Cell Infiltration and Pathogenesis of Experimental Autoimmune Encephalomyelitis

Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

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