Selective Activation of Cannabinoid Receptor 2 in Leukocytes Suppresses Their Engagement of the Brain Endothelium and Protects the Blood-Brain Barrier

Rom, Slava; Zuluaga-Ramirez, Viviana; Dykstra, Holly; Reichenbach, Nancy L.; Pacher, Pál; Persidsky, Yuri

doi:10.1016/j.ajpath.2013.07.033

Cited by 62 publications

(81 citation statements)

References 55 publications

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“…The following PARP inhibitors were used in this study: 5-aminoisoquinolinone (AIQ) and [N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride (PJ34) purchased from Enzo Life Sciences (Farmingdale, NY, USA); AZD2281 (AZD, Olaparib) purchased from Selleck Chemicals (Houston, TX, USA), and 5'-deoxy- 9,10 BMVEC were treated with PARP inhibitors (AIQ or AZD at 10 μmol/L, EB47 or PJ34 at 2 μmol/L) for 1 hour (unless otherwise stated) and then with TNFα (50 ng/ml) for 4 hours.…”

Section: Reagents and Cellsmentioning

confidence: 99%

“…IVM for in vivo leukocyte adhesion was performed on animals with cranial windows. 8,9 Prior to IVM, animals were IC injected with TNFα (0.5 μg per mouse) for 2 hours. IC injections were performed using an inner cannula (Plastics One), which is customized to have a 1 mm projection after passing through the guide cannula already implanted in the animal.…”

Section: Animals and Ivmmentioning

confidence: 99%

“…Treatments were removed from the BMVEC prior to addition of freshly isolated human calcein-AM labeled monocytes; adhesion assays were performed as described. 9,10 Fluorescence of adherent monocytes was measured using a Synergy 2 plate reader (BioTek, Winooski, VT, USA). Results are presented as the fold difference in adhesion (mean ± s.e.m.)…”

Section: Monocyte Adhesion Assaysmentioning

confidence: 99%

“…Western blots were performed as described. 9,16 Flow Cytometry Analysis of surface expression of adhesion molecules was performed using the conjugated antibodies ICAM-1-APC and vascular cell adhesion molecule 1 (VCAM-1)-FITC (BD Biosciences, San Jose, CA) as described. 18 Data were acquired with a FACS BD Canto II flow cytometer (BD Biosciences) and analyzed with FlowJo software (Tree Star, Ashland, OR, USA).…”

Section: Pcr Array and Qpcrmentioning

confidence: 99%

“…In this study, we tested whether inhibition of PARP would reduce leukocyte adhesion in vivo in an animal model of localized aseptic meningitis (induced by intracerebral injection of tumor necrosis factor alpha (TNFα)), utilizing intravital videomicroscopy (IVM) for surveillance of cerebral vascular changes and leukocyte-endothelial interactions. 8,9 Inactivation of PARP resulted in a significant decrease in leukocyte adhesion to and migration across the CNS endothelium in vivo. In addition, we showed that PARP inhibition caused reduction in leukocyte adhesion and migration in an in vitro blood-brain barrier (BBB) model, thereby preserving barrier functions.…”

Section: Introductionmentioning

confidence: 99%

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Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

Rom

Zuluaga-Ramirez

Dykstra

et al. 2014

J Cereb Blood Flow Metab

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Blood-brain barrier (BBB) dysfunction seen in neuroinflammation contributes to mortality and morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. Identification of molecular targets maintaining barrier function is of clinical relevance. We used a novel in vivo model of localized aseptic meningitis where tumor necrosis factor alpha (TNFα) was introduced intracerebrally and surveyed cerebral vascular changes and leukocyte-endothelium interactions by intravital videomicroscopy. Poly (ADP-ribose) polymerase-1 (PARP) inhibition significantly reduced leukocyte adhesion to and migration across brain endothelium in cortical microvessels. PARP inactivation diminished BBB permeability in an in vivo model of systemic inflammation. PARP suppression in primary human brain microvascular endothelial cells (BMVEC), an in vitro model of BBB, enhanced barrier integrity and augmented expression of tight junction proteins. PARP inhibition in BMVEC diminished human monocyte adhesion to TNFα-activated BMVEC (up to 65%) and migration (80-100%) across BBB models. PARP suppression decreased expression of adhesion molecules and decreased activity of GTPases (controlling BBB integrity and monocyte migration across the BBB). PARP inhibitors down-regulated expression of inflammatory genes and dampened secretion of pro-inflammatory factors increased by TNFα in BMVEC. These results point to PARP suppression as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation. PARP-1 is a member of a family of NAD-dependent enzymes that is responsible for~80% of cellular poly(ADP-ribose) formation. 1 Poly(ADP-ribosyl)ation is a post-translational modification of proteins with widespread effects on diverse cellular functions including gene expression, differentiation and cell death. 2 As a scaffold protein and as an enzyme, PARP-1 (further referred to in the text as PARP) is a key component of the transcriptional machinery that controls chromatin architecture, histone shuttling, and spatial organization of transcription-regulating supramolecular complexes, 2 thereby regulating inflammationassociated genes.In this article, for the first time, we show mechanisms of the modulatory effects of PARP inhibition in brain endothelium. Previous studies have demonstrated anti-inflammatory effects of PARP suppression in animal models of traumatic brain injury, multiple sclerosis (MS), meningitis, and stroke, [3][4][5] where PARP inhibitors reduced edema, leukocyte infiltration and neuroinflammation, and decreased intercellular adhesion molecule 1 (ICAM-1) expression. 4,6 PARP inhibitors have now reached the stage of

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Section: Reagents and Cellsmentioning

confidence: 99%

Section: Animals and Ivmmentioning

confidence: 99%

Section: Monocyte Adhesion Assaysmentioning

confidence: 99%

Section: Pcr Array and Qpcrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

Rom

Zuluaga-Ramirez

Dykstra

et al. 2014

J Cereb Blood Flow Metab

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Effects of cannabinoids and their receptors on viral infections

Tahamtan

Tavakoli-Yaraki

Rygiel

et al. 2015

Journal of Medical Virology

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Cannabinoids, the active ingredient in marijuana, and their derivatives have received remarkable attention in the last two decades because they can affect tumor growth and metastasis. There is a large body of evidence from in vivo and in vitro models showing that cannabinoids and their receptors influence the immune system, viral pathogenesis, and viral replication. The present study reviews current insights into the role of cannabinoids and their receptors on viral infections. The results reported here indicate that cannabinoids and their receptors have different sequels for viral infection. Although activation or inhibition of cannabinoid receptors in the majority of viral infections are proper targets for development of safe and effective treatments, caution is required before using pharmaceutical cannabinoids as a treatment agent for patients with viral infections.

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Genetic Manipulation of the Endocannabinoid System

Zimmer

2015

Handbook of Experimental Pharmacology

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The physiological and pathophysiological functions of the endocannabinoid system have been studied extensively using transgenic and targeted knockout mouse models. The first gene deletions of the cannabinoid CB(1) receptor were described in the late 1990s, soon followed by CB(2) and FAAH mutations in early 2000. These mouse models helped to elucidate the fundamental role of endocannabinoids as retrograde transmitters in the CNS and in the discovery of many unexpected endocannabinoid functions, for example, in the skin, bone and liver. We now have knockout mouse models for almost every receptor and enzyme of the endocannabinoid system. Conditional mutant mice were mostly developed for the CB(1) receptor, which is widely expressed on many different neurons, astrocytes and microglia, as well as on many cells outside the CNS. These mouse strains include "floxed" CB(1) alleles and mice with a conditional re-expression of CB(1). The availability of these mice made it possible to decipher the function of CB(1) in specific neuronal circuits and cell populations or to discriminate between central and peripheral effects. Many of the genetic mouse models were also used in combination with viral expression systems. The purpose of this review is to provide a comprehensive overview of the existing genetic models and to summarize some of the most important discoveries that were made with these animals.

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Selective Activation of Cannabinoid Receptor 2 in Leukocytes Suppresses Their Engagement of the Brain Endothelium and Protects the Blood-Brain Barrier

Cited by 62 publications

References 55 publications

Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

Effects of cannabinoids and their receptors on viral infections

Genetic Manipulation of the Endocannabinoid System

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