Effect of Novel A<sub>2A</sub>Adenosine Receptor Agonist ATL 313 on<i>Clostridium difficile</i>Toxin A-Induced Murine Ileal Enteritis

Cavalcante, Ingrid Chaves; Castro, M. V.; Barreto, A. R. F.; Sullivan, Gail W.; Vale, Mariana Lima; Almeida, Paulo Roberto Carvalho de; Linden, Joel; Rieger, Jayson M.; Cunha, Fernando; Guerrant, Richard L.; Ribeiro, Ronaldo A.; Brito, Gerly A.C.

doi:10.1128/iai.74.5.2606-2612.2006

Cited by 66 publications

(82 citation statements)

References 41 publications

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“…The selective A 2a receptor agonist ATL 313 (0.5-5 nM) also reduced Clostridium difficile TxA-induced secretion and edema, prevented the mucosal damage and neutrophil infiltration, TxA-induced cell death, TNF-α production, as well as increased ileal ADA activity, in murine ileal loops exposed to TxA. Effects were reversed by the selective A 2a receptor antagonist ZM241385 (5 nM) [15].…”

Section: Reflex-driven Intestinal Diarrhea and Clinical Relevance Of mentioning

confidence: 70%

“…Recent studies provided convincing evidence that activation of an A 2a receptor attenuates intestinal inflammation in animal models of IBD and may serve as a novel therapy for IBD [15,77,82]. In general, adenosine has diverse functions in the GI tract in the regulation of secretion, motility, innate mucosal immunity, is protective against experimental IBD, and is important in mediating inflammatory responses at sites of injury, and has anti-inflammatory effects in epithelial cells.…”

Section: Reflex-driven Intestinal Diarrhea and Clinical Relevance Of mentioning

confidence: 99%

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Purinergic receptors and gastrointestinal secretomotor function

Christofi

2008

Purinergic Signalling

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Secretomotor reflexes in the gastrointestinal (GI) tract are important in the lubrication and movement of digested products, absorption of nutrients, or the diarrhea that occurs in diseases to flush out unwanted microbes. Mechanical or chemical stimulation of mucosal sensory enterochromaffin (EC) cells triggers release of serotonin (5-HT) (among other mediators) and initiates local reflexes by activating intrinsic primary afferent neurons of the submucous plexus. Signals are conveyed to interneurons or secretomotor neurons to stimulate chloride and fluid secretion. Inputs from myenteric neurons modulate secretory rates and reflexes, and special neural circuits exist to coordinate secretion with motility. Cellular components of secretomotor reflexes variably express purinergic receptors for adenosine (A1, A2a, A2b, or A3 receptors) or the nucleotides adenosine 5′-triphosphate (ATP), adenosine diphosphate (ADP), uridine 5′-triphosphate (UTP), or uridine diphosphate (UDP) (P2X 1-7 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 12 receptors). This review focuses on the emerging concepts in our understanding of purinergic regulation at these receptors, and in particular of mechanosensory reflexes. Purinergic inhibitory (A 1 , A 3 , P2Y 12 ) or excitatory (A 2 , P2Y 1 ) receptors modulate mechanosensitive 5-HT release. Excitatory (P2Y 1 , other P2Y, P2X) or inhibitory (A 1 , A 3 ) receptors are involved in mechanically evoked secretory reflexes or "neurogenic diarrhea." Distinct neural (pre-or postsynaptic) and non-neural distribution profiles of P2X 2 , P2X 3 , P2X 5 , P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , or P2Y 12 receptors, and for some their effects on neurotransmission, suggests their role in GI secretomotor function. Luminal A 2b , P2Y 2 , P2Y 4 , and P2Y 6 receptors are involved in fluid and Cl -, HCO 3 -, K + , or mucin secretion. Abnormal receptor expression in GI diseases may be of clinical relevance. Adenosine A 2a or A 3 receptors are emerging as therapeutic targets in inflammatory bowel diseases (IBD) and gastroprotection; they can also prevent purinergic receptor abnormalities and diarrhea. Purines are emerging as fundamental regulators of enteric secretomotor reflexes in health and disease.

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Section: Reflex-driven Intestinal Diarrhea and Clinical Relevance Of mentioning

confidence: 70%

Section: Reflex-driven Intestinal Diarrhea and Clinical Relevance Of mentioning

confidence: 99%

Purinergic receptors and gastrointestinal secretomotor function

Christofi

2008

Purinergic Signalling

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“…Other studies have shown that stimulation of A 2A receptors can reduce inflammation in the intestinal mucosa in rabbits and mice [111] and reduce tissue injury and inflammation in mice with toxin A-induced enteritis [112]. A recent study utilized a high-density oligonucleotide microarray analysis to study TNBS-induced colitis [113].…”

Section: Intestinal Pathologies and Purinergic Signalingmentioning

confidence: 99%

Purinergic receptors and synaptic transmission in enteric neurons

Ren

Bertrand

2007

Purinergic Signalling

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Purines such as ATP and adenosine participate in synaptic transmission in the enteric nervous system as neurotransmitters or neuromodulators. Purinergic receptors are localized on the cell bodies or nerve terminals of different functional classes of enteric neurons and, with other receptors, form unique receptor complements. Activation of purinergic receptors can regulate neuronal activity by depolarization, by regulating intracellular calcium, or by modulating second messenger pathways. Purinergic signaling between enteric neurons plays an important role in regulating specific enteric reflexes and overall gastrointestinal function. In the present article, we review evidence for purine receptors in the enteric nervous system, including P1 (adenosine) receptors and P2 (ATP) receptors. We will explore the role they play in mediating fast and slow synaptic transmission and in presynaptic inhibition of transmission. Finally, we will examine the molecular properties of the native receptors, their signaling mechanisms, and their role in gastrointestinal pathology. Keywords

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“…Other studies have demonstrated that adenosine acting on the A2a receptor of T-lymphocytes can selectively suppress the expression of pro-inflammatory cytokines while sparing antiinflammatory activity mediated by IL-10 and TGF-b [29] . The tissue injury and inflammation in mice with enteritis induced by Clostridium difficile toxin A can be alleviated by a new A2a receptor agonist, ATL 313, through the mechanism of inhibiting neutrophil infiltration, TNF-a production and adenosine deaminase activity [30] . Adenosine can down-regulate neutrophil functions by decreasing their adhesion, degranulation, and oxidant activities [25] .…”

Section: Inflammation In Ibdmentioning

confidence: 99%

“…A1 and A3 receptors are usually coupled with Gi proteins that inhibit adenylate cyclase, whereas the A2aR and A2bR receptors are coupled with Gs proteins that activate adenylate cyclase. Several studies have demonstrated that adenosine attenuates intestinal inflammation predominantly through the effects of the A2aR receptor of neutrophils and T-lymphocytes [29,30,48] . However, Yang et al [49] found that activation of the A2bR can also have anti-inflammatory effects, using a gene knockout method to delete this gene in order to show a proinflammatory phenotype.…”

Section: Physiology Of Adenosine Metabolism By Intestinal Epithelium mentioning

confidence: 99%

Adenosine: An immune modulator of inflammatory bowel diseases

Ye¹,

Rajendran²

2009

WJG

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Inflammatory bowel disease (IBD) is a common and lifelong disabling gastrointestinal disease. Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response. Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models. High extracellular adenosine suppresses and resolves chronic inflammation in IBD models. High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis. Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation.Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells, respectively. Increased extracellular adenosine levels activate the A2a receptor, which would reduce cytokines responsible for chronic inflammation.

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Effect of Novel A_2AAdenosine Receptor Agonist ATL 313 onClostridium difficileToxin A-Induced Murine Ileal Enteritis

Cited by 66 publications

References 41 publications

Purinergic receptors and gastrointestinal secretomotor function

Purinergic receptors and gastrointestinal secretomotor function

Purinergic receptors and synaptic transmission in enteric neurons

Adenosine: An immune modulator of inflammatory bowel diseases

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Effect of Novel A2AAdenosine Receptor Agonist ATL 313 onClostridium difficileToxin A-Induced Murine Ileal Enteritis

Cited by 66 publications

References 41 publications

Purinergic receptors and gastrointestinal secretomotor function

Purinergic receptors and gastrointestinal secretomotor function

Purinergic receptors and synaptic transmission in enteric neurons

Adenosine: An immune modulator of inflammatory bowel diseases

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Product

Resources

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Effect of Novel A_2AAdenosine Receptor Agonist ATL 313 onClostridium difficileToxin A-Induced Murine Ileal Enteritis