Treatment with BBB022A or rolipram stabilizes the blood-brain barrier in experimental autoimmune encephalomyelitis: an additional mechanism for the therapeutic effect of type IV phosphodiesterase inhibitors

Folcik, Virginia A; Smith, Terence; O'Bryant, Sage; Kawczak, Julie A.; Zhu, Bin; Sakurai, Hideki; Kajiwara, Atsushi; Staddon, James M.; Głąbiński, Andrzej; Chernosky, Ann; Tani, Masanao; Johnson, Justin M.; Tuohy, Vincent K.; Rubin, Lee L.; Ransohoff, Richard M.

doi:10.1016/s0165-5728(99)00063-6

Cited by 53 publications

(36 citation statements)

References 28 publications

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“…These results are in accordance with previous results using rolipram as a therapeutic agent in spinal cord injury and transient global ischemia where lower doses were also more effective (Block et al, 1997, Nikulina et al, 2004. Rolipram has also been found to improve outcome in experimental allergic encephalomyelitis, Alzheimer disease, multiple sclerosis, ischemia, and striatal excitotoxicity (Genain et al, 1995, Navikas et al, 1998, Folcik et al, 1999, Gong et al, 2004, Demarch et al, 2007, Sasaki et al, 2007. Our results and the many studies assessing rolipram in models of neurological disorders suggest that use of a PDE IV antagonist may be a promising avenue of research as we search for a successful pharmacological therapy for TBI patients.…”

Section: Discussionsupporting

confidence: 90%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

133

151

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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Section: Discussionsupporting

confidence: 90%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

133

151

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“…Activation/suppression of APCs and regulation of the cytokine environment are known to be controlled by cAMP levels (Fassbender et al, 2010;Kambayashi et al, 2001). Therefore the upregulation of PDE4B2 mRNA that we report here, in areas with high amount of cellular infiltrates and around the microvessels, together with the role of cAMP in the antigen presentation process (Fallarino et al, 2010) The amelioration of the clinical signs and delayed onset of EAE described after PDE4 inhibition (Folcik et al, 1999;Martinez et al, 1999;Moore et al, 2006;Sommer et al, 1995) T-cell populations that have a crucial role in the EAE model are Th1-and Th17-positive cells (Komiyama et al, 2006;Tzartos et al, 2008;Zamvil and Steinman 1990). These immune cells infiltrate and attack oligodendrocytes, activate resident microglia and astrocytes, leading to demyelination and axonal damage in the EAE model (Lassmann et al, 2001;Soulika et al, 2009).…”

Section: Discussionmentioning

confidence: 72%

“…In the EAE model, amelioration of the clinical signs and delayed onset is observed after PDE4 inhibition with rolipram (Folcik et al, 1999;Moore et al, 2006;Sommer et al, 1995). The PDE4B gene has been related to the inflammatory response in mouse monocytes and macrophages (Jin et al, 2005a) and previous publications by our group have shown that the PDE4B mRNA splice variant PDE4B2 is upregulated in cellular infiltrates of EAE rat brains (Reyes-Irisarri et al, 2007).…”

Section: Introductionmentioning

confidence: 93%

Critical role for PDE4 subfamilies in the development of experimental autoimmune encephalomyelitis

Sanabra

Johansson

Mengod

2013

Journal of Chemical Neuroanatomy

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“…There is increasing evidence that PDEs may control the BBB through modulating cAMP or cGMP levels. Elevation of intracellular cAMP levels increases the electrical resistance of endothelial monolayers by stabilizing intercellular junctional complexes 7 and thus reduces BBB permeability. Decreased cAMP and increased calcium levels are linked to increased permeability in the endothelial cells.…”

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confidence: 99%

Defining the Phosphodiesterase Superfamily Members in Rat Brain Microvessels

Cui

Patterson

et al. 2011

ACS Chem. Neurosci.

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C yclic nucleotide phosphodiesterases (PDEs) are enzymes that regulate the cellular levels of the second messengers, cAMP and cGMP, by controlling their rates of degradation. The functions of the PDEs include modulation of vascular tone and permeability to ensure an appropriate blood supply and molecular delivery to local tissues. Eleven PDE families have been identified, each having several different isoforms and splice variants. 1 On the other hand, expression of individual PDE family members may be tissue-specific. Following the well-accepted definition for nomenclature, a PDE family member written in lower case letters in italics refers to the nucleotide while those written in nonitalicized capital letters refer to the protein. 1 Expression of the cGMP-stimulated PDE2A is differential in human venous and capillary endothelial cells. 2 PDE4a and PDE4b express at both transcriptional and translational levels; simultaneously, pde4d mRNA is detectable but PDE4D protein cannot be identified with the isoform-specific antibody in rat pulmonary microvascular endothelial cells. 3 Activities of the cAMP PDE and the cGMP PDE were identified in bovine brain microvessels three decades ago, 4 and more recently the expression of PDE1 and PDE5 was characterized in guinea pig basilar arteries. 5 Nevertheless, there is limited information concerning detailed expressions of the PDE superfamily components in brain microvessels.The brain-blood-barrier (BBB) maintains the homeostasis of the brain. Studies using dyes and electron-dense tracers indicate that the primary BBB occurs at the level of the intracerebral microvasculature. 6 Vascular endothelial cells at the bloodÀbrain interface are sealed together at their edges by tight junctions and make up the walls of microvessels. The tight junctions of these cells are composed of smaller transmembrane protein subunits, frequently biochemical dimers. There is increasing evidence that PDEs may control the BBB through modulating cAMP or cGMP levels. Elevation of intracellular cAMP levels increases the electrical resistance of endothelial monolayers by stabilizing intercellular junctional complexes 7 and thus reduces BBB permeability. Decreased cAMP and increased calcium levels are linked to increased permeability in the endothelial cells. 8À10 Conversely, agents that increase endothelial cAMP levels prevent barrier injury in the lung injury models. 11,12 Evidence from other organs, such as kidney, suggests PDE involvement in osmotic water permeability. PDE function underlies arginine vasopressin-regulated water reabsorption in the principal cells of the renal collecting duct by terminating protein kinase A (PKA) signaling through hydrolysis of localized cAMP. 13 A recent report indicates that PDE4D tethers EPAC1 in a vascular endothelial cadherin (VE-Cad)-based signaling complex and controls cAMP-mediated vascular permeability. 14 Received: May 24, 2011 Accepted: June 27, 2011ABSTRACT: Eleven phosphodiesterase (PDE) families are known, each having several different isoforms and splice...

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Treatment with BBB022A or rolipram stabilizes the blood-brain barrier in experimental autoimmune encephalomyelitis: an additional mechanism for the therapeutic effect of type IV phosphodiesterase inhibitors

Cited by 53 publications

References 28 publications

Modulation of the cAMP signaling pathway after traumatic brain injury

Modulation of the cAMP signaling pathway after traumatic brain injury

Critical role for PDE4 subfamilies in the development of experimental autoimmune encephalomyelitis

Defining the Phosphodiesterase Superfamily Members in Rat Brain Microvessels

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