title: Suppression of inflammatory events associated to intestinal ischemia-reperfusion by 5-HT1A blockade in mice.
abstract: Intestinal ischemia and reperfusion (I/R) is a potentially life-threatening disease, ensuing from various clinical conditions. Experimentally, either protective or detrimental roles have been attributed to 5-HT in the functional and morphological injury caused by mesenteric I/R. Recently, we proved the involvement of 5-HT2A receptors in the intestinal dysmotility and leukocyte recruitment induced by 45min occlusion of the superior mesenteric artery (SMA) followed by 24h reperfusion in mice. Starting from these premises, the aim of our present work was to investigate the role played by endogenous 5-HT in the same experimental model where 45min SMA clamping was followed by 5h reflow. To this end, we first observed that ischemic preconditioning before I/R injury (IPC+I/R) reverted the increase in 5-HT tissue content and in inflammatory parameters induced by I/R in mice. Second, the effects produced by intravenous administration of 5-HT1A ligands (partial agonist buspirone 10mgkg(-1), antagonist WAY100135 0.5-5mgkg(-1)), 5-HT2A antagonist sarpogrelate (10mgkg(-1)), 5-HT3 antagonist alosetron (0.1mgkg(-1)), 5-HT4 antagonist GR125487 (5mgkg(-1)) and 5-HT re-uptake inhibitor fluoxetine (10mgkg(-1)) on I/R-induced inflammatory response were investigated in I/R mice and compared to those obtained in sham-operated animals (S). Our results confirmed the significant role played by 5-HT2A receptors not only in the late but also in the early I/R-induced microcirculatory dysfunction and showed that blockade of 5-HT1A receptors protected against the intestinal leukocyte recruitment, plasma extravasation and reactive oxygen species formation triggered by SMA occlusion and reflow. The ability of α7 nicotinic receptor (α7nAchR) antagonist methyllycaconitine (5mgkg(-1)) to counteract the beneficial action provided by buspirone on I/R-induced neutrophil infiltration suggests that the anti-inflammatory effect produced by 5-HT1A receptor antagonism could be partly ascribed to the indirect activation of α7nAch receptors.
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy. Electronic address: simona.bertoni@unipr.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Arcaro
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vivo
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rapalli
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.affiliation: Dipartimento di Scienze Medico-Veterinarie, University of Parma, via del Taglio 10, 43126 Parma, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cantoni
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Saccani
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Flammini
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Domenichini
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.affiliation: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D005260:Female; D051547:Heme Oxygenase-1 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins / Q000097:blood; D051379:Mice; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors
chemical_list: D053583:Interleukin-1beta; D008565:Membrane Proteins; D018733:Nicotinic Antagonists; D010879:Piperazines; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D044282:Receptor, Serotonin, 5-HT1A; C081293:WAY 100135; C054634:methyllycaconitine; D012701:Serotonin; D008315:Malondialdehyde; D009195:Peroxidase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D002065:Buspirone; D000157:Aconitine
keywords: 5-HT(1A) receptor; Buspirone; Ischemic preconditioning; Mesenteric ischemia/reperfusion; Serotonin; α7 nicotinic receptor