Adenosine A2A receptor agonist ameliorates EAE and correlates with Th1 cytokine‐induced blood brain barrier dysfunction via suppression of MLCK signaling pathway

4区 · 医学

ArticleOA

作者: Liu, Ying ; Alahiri, Marwan ; Xie, Boxun ; Sadiq, Saud A. ; Ulloa, Bianca

AbstractIntroductionMultiple sclerosis (MS) disease activity is associated with blood‐brain barrier (BBB) disruption, which is mediated by inflammatory cytokines released by CD4+ lymphocytes. To assess the effects of adenosine A2A receptors on BBB permeability in vitro and in vivo.MethodsA2A receptor expression was detected by immunostaining in experimental autoimmune encephalomyelitis (EAE) C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG)35–55, and human MS brain. F‐actin and the tight junction protein Claudin‐5 were assessed in endothelial cells treated with an A2A receptor specific agonist (CGS‐21680) after Th1 cytokine stimulation. EAE mice were divided into control and CGS‐21680 (50 µg/kg, i.p., daily) groups. Disease scores were recorded daily to evaluate neurological impairment. The effects of A2A receptor on inflammation and demyelination were assessed after euthanasia by immunostaining or histology; BBB permeability was measured by sodium fluoride (Na‐F) and FITC‐dextran amounts.ResultsEndothelial A2A receptor was detected in demyelination areas of MS brain samples. In EAE lesions, A2A receptor was expressed in the endothelium in association with immune cell infiltration. Treatment with CGS‐21680 counteracted the effects of Th1 cytokines on endothelial cells in vitro, preventing the reduction of tight junction protein expression and stress fiber formation. The effects of A2A receptor activation were correlated with MLCK phosphorylation signaling repression. In EAE, A2A receptor agonist decreased BBB permeability and inhibited EAE neurologic deficiency in mice.ConclusionsA2A receptor activation at EAE onset helps reduce the effects of Th1 stimulation on BBB permeability, indicating that A2A receptor mediates BBB function in CNS demyelinated disease.

2017-10-01·Progress in Neuro-Psychopharmacology and Biological Psychiatry2区 · 医学

Toll-like receptors, NF-κB, and IL-27 mediate adenosine A2A receptor signaling in BTBR T + Itpr3 tf /J mice

2区 · 医学

Article

作者: Bakheet, Saleh A ; Ansari, Mushtaq A ; Attia, Sabry M ; Nadeem, Ahmed ; Al-Ayadhi, Laila Yousef ; Ahmad, Sheikh F

Autism is a predominant neurodevelopmental disorder characterized by impaired communication, social deficits, and repetitive behaviors. Recent research has proposed that the impairment of innate immunity may play an important role in autism. Toll-like receptors (TLRs) are potential therapeutic targets against neuroinflammation. The BTBR T⁺ Itpr3^tf/J (BTBR) mouse is a well-known model of autism, showing repetitive behaviors such as cognitive inflexibility and increased grooming as compared to C57BL/6 (B6) mice. Adenosine A2A receptor (A2AR) signaling is involved in inflammation, brain injury, and lymphocyte infiltration into the CNS, but the role of A2AR in autism remains unknown. We investigated the effect of A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on the expression levels of TLRs, IL-27, NF-κB p65, and IκBα in BTBR mice. Treatment of BTBR mice with SCH increased the percentage of splenic CD14⁺TLR2⁺ cells, CD14⁺TLR3⁺ cells, CD14⁺TLR4⁺ cells, and decreased the percentage of CD14⁺IL-27⁺ cells, as compared to the untreated BTBR mice. Our results reveal that BTBR mice treated with CGS had reversal of SCH-induced immunological responses. Moreover, mRNA and protein expression analyses confirmed increased expression of TLR2, TLR3, TLR4, and NF-κB p65 in brain tissue, and decreased IL-27 and IκBα expression following SCH treatment, as compared to the untreated-BTBR and CGS-treated BTBR mice. Together, these results suggest that the A2AR agonist corrects neuroimmune dysfunction observed in BTBR mice, and thus has the potential as a therapeutic approach in autism.

2017-10-01·Journal of Neuroimmunology3区 · 医学

Adenosine A2A receptor signaling affects IL-21/IL-22 cytokines and GATA3/T-bet transcription factor expression in CD4 + T cells from a BTBR T + Itpr3tf/J mouse model of autism

3区 · 医学

Article

作者: Bakheet, Saleh A ; Attia, Sabry M ; Almutairi, Mashal M ; Ansari, Mushtaq A ; Nadeem, Ahmed ; Ahmad, Sheikh F

Autism is a complex heterogeneous neurodevelopmental disorder; previous studies have identified altered immune responses among individuals diagnosed with autism. An imbalance in the production of pro- and anti-inflammatory cytokines and transcription factors plays a role in neurodevelopmental behavioral and autism disorders. BTBR T⁺ Itpr3tf/J (BTBR) mice are used as a model for autism, as they exhibit social deficits, communication deficits, and repetitive behaviors compared with C57BL/6J (B6) mice. The adenosine A2A receptor (A2AR) appears to be a potential target for the improvement of behavioral, inflammatory, immune, and neurological disorders. We investigated the effects of the A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on IL-21, IL-22, T-bet, T-box transcription factor (T-bet), GATA3 (GATA Binding Protein 3), and CD152 (CTLA-4) expression in BTBR mice. Our results showed that BTBR mice treated with SCH had increased CD4⁺IL-21⁺, CD4⁺IL-22⁺, CD4⁺GATA3⁺, and CD4⁺T-bet⁺ and decreased CD4⁺CTLA-4⁺ expression in spleen cells compared with BTBR control mice. Moreover, CGS efficiently decreased CD4⁺IL-21⁺, CD4⁺IL-22⁺, CD4⁺GATA3⁺, and CD4⁺T-bet⁺ and increased CD4⁺CTLA-4 production in spleen cells compared with SCH-treated and BTBR control mice. Additionally, SCH treatment significantly increased the mRNA and protein expression levels of IL-21, IL-22, GATA3, and T-bet in brain tissue compared with CGS-treated and BTBR control mice. The augmented levels of IL-21/IL-22 and GATA3/T-bet could be due to altered A2AR signaling. Our results indicate that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of autistic and neuroimmune dysfunctions.

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