Skip to main content
Top
Published in: Digestive Diseases and Sciences 9/2015

01-09-2015 | Original Article

The Effect of Ischemia and Reperfusion on Enteric Glial Cells and Contractile Activity in the Ileum

Authors: Cristina Eusébio Mendes, Kelly Palombit, Cátia Vieira, Isabel Silva, Paulo Correia-de-Sá, Patricia Castelucci

Published in: Digestive Diseases and Sciences | Issue 9/2015

Login to get access

Abstract

Background

We investigated the effects of ischemia followed by different periods of reperfusion (I/R) on immunoreactive S100β-positive glial and Hu-immunoreactive neurons co-expressing the P2X2 receptor in the myenteric plexus of the rat ileum.

Methods

The ileal artery was occluded for 35 min with an atraumatic vascular clamp. The animals were killed 24 h, 72 h, and 1 week after ischemia. Sham animals were not submitted to ileal artery occlusion. The relative density, size, and co-localization of P2X2 receptor-expressing cells in relation to S100β-immunoreactive glial and Hu-immunoreactive neuronal cells were evaluated. Additionally, we analyzed the effects of I/R on gastrointestinal transit and ileum contractile activity.

Results

The cellular density of P2X2 receptor and neuronal Hu immunoreactivity/cm2 decreased after I/R, whereas glial S100β immunoreactivity/cm2 increased. No significant differences between sham and I/R groups were observed regarding the perikarya area of Hu-positive neurons. The area of S100β-immunoreactive glial cells increased by 24.1 % 1 week after I/R compared with the 24 h group. Methylene blue progression along the small intestine decreased (P < 0.05) from 24.5 ± 2.3 % in the sham group to 17.2 ± 2.0 % 1 week post-ischemia. We noted a significant (P < 0.05) decrease in the maximal contraction amplitude triggered by electrical field stimulation in the presence of ATP in preparations submitted to 24 h of I/R.

Conclusions

Changes in the P2X2 receptor density parallel myenteric neuronal loss following I/R of the rat ileum. This, together with the increase in the activated (oversized) glial cells, may contribute to decreased GI motility after I/R.
Literature
1.
go back to reference Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol. 2012;9:286–294.CrossRefPubMed Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol. 2012;9:286–294.CrossRefPubMed
3.
go back to reference Gulbransen BD, Sharkey KA. Novel functional roles for enteric glia in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol. 2012;9:625–632.CrossRefPubMed Gulbransen BD, Sharkey KA. Novel functional roles for enteric glia in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol. 2012;9:625–632.CrossRefPubMed
4.
go back to reference Dogiel, AS. Über den Bau der Ganglien in den Geflechtendes Darmesund der Gallenblase des Menschen und der Säugestiere [German]. Arch Anat Physiol Leypizig. Anat Abt Jg. 1899;130–158. Dogiel, AS. Über den Bau der Ganglien in den Geflechtendes Darmesund der Gallenblase des Menschen und der Säugestiere [German]. Arch Anat Physiol Leypizig. Anat Abt Jg. 1899;130–158.
7.
go back to reference Hanani M, Reichenbach A. Morphology of horseradish peroxidase (HRP)-injected glial cells in the myenteric plexus of the guinea-pig. Cell Tissue Res. 1994;278:153–160.CrossRefPubMed Hanani M, Reichenbach A. Morphology of horseradish peroxidase (HRP)-injected glial cells in the myenteric plexus of the guinea-pig. Cell Tissue Res. 1994;278:153–160.CrossRefPubMed
8.
go back to reference Abbrachio MP, Burnstock G, Verkhratsky A, Zimmermann H. Purinergic signaling in the nervous system: an overview. Trends Neurosci. 2009;32:19–29.CrossRef Abbrachio MP, Burnstock G, Verkhratsky A, Zimmermann H. Purinergic signaling in the nervous system: an overview. Trends Neurosci. 2009;32:19–29.CrossRef
9.
go back to reference Vulchanova L, Arvidsson U, Riedl M, et al. Differential distribution of two ATP-gated ion channels (P2x receptors) determined by immunohistochemistry. Proc Natl Acad Sci. 1996;93:8063–8067.PubMedCentralCrossRefPubMed Vulchanova L, Arvidsson U, Riedl M, et al. Differential distribution of two ATP-gated ion channels (P2x receptors) determined by immunohistochemistry. Proc Natl Acad Sci. 1996;93:8063–8067.PubMedCentralCrossRefPubMed
10.
go back to reference Castelucci P, Robbins HL, Poole DP, Furness JB. The distribution of purine P2X2 receptors in the guinea pig enteric nervous system. Histochem Cell Biol. 2002;117:415–422.CrossRefPubMed Castelucci P, Robbins HL, Poole DP, Furness JB. The distribution of purine P2X2 receptors in the guinea pig enteric nervous system. Histochem Cell Biol. 2002;117:415–422.CrossRefPubMed
11.
go back to reference Hu HZ, Gao N, Lin Z, Liu S, et al. P2X7 receptors in the enteric nervous system of guinea-pig small intestine. J Comp Neurol. 2001;440:299–310.CrossRefPubMed Hu HZ, Gao N, Lin Z, Liu S, et al. P2X7 receptors in the enteric nervous system of guinea-pig small intestine. J Comp Neurol. 2001;440:299–310.CrossRefPubMed
12.
go back to reference Poole DP, Castelucci P, Robbins HL, Chiocchetti R, Furness JB. The distribution of P2X3 purine receptor subunits in the guinea-pig enteric nervous system. Auton Neurosci.. 2002;101:39–47.CrossRefPubMed Poole DP, Castelucci P, Robbins HL, Chiocchetti R, Furness JB. The distribution of P2X3 purine receptor subunits in the guinea-pig enteric nervous system. Auton Neurosci.. 2002;101:39–47.CrossRefPubMed
13.
go back to reference Van Nassauw L, Brouns I, Adraensen D, et al. Neurochemical identification of enteric neurons expressing P2X(3) receptors in the guinea-pig ileum. Histochem Cell Biol. 2002;118:193–203.PubMed Van Nassauw L, Brouns I, Adraensen D, et al. Neurochemical identification of enteric neurons expressing P2X(3) receptors in the guinea-pig ileum. Histochem Cell Biol. 2002;118:193–203.PubMed
14.
go back to reference Xiang Z, Burnstock G. Distribution of P2Y2 receptors in the guinea pig enteric nervous system and its coexistence with P2X2 and P2X3 receptors, neuropeptide Y, nitric oxide synthase and calretinin. Histochem Cell Biol. 2005;124:379–390.CrossRefPubMed Xiang Z, Burnstock G. Distribution of P2Y2 receptors in the guinea pig enteric nervous system and its coexistence with P2X2 and P2X3 receptors, neuropeptide Y, nitric oxide synthase and calretinin. Histochem Cell Biol. 2005;124:379–390.CrossRefPubMed
15.
go back to reference Xiang Z, Burnstock G. P2X2 and P2X3 purinoceptors in the rat enteric nervous system. Histochem Cell Biol. 2004;12:169–179.CrossRef Xiang Z, Burnstock G. P2X2 and P2X3 purinoceptors in the rat enteric nervous system. Histochem Cell Biol. 2004;12:169–179.CrossRef
16.
go back to reference Yu Q, Zhao Z, Sun J, et al. Expression of P2X6 receptors in the enteric nervous system of the rat gastrointestinal tract. Histochem Cell Biol. 2010;133:177–188.CrossRefPubMed Yu Q, Zhao Z, Sun J, et al. Expression of P2X6 receptors in the enteric nervous system of the rat gastrointestinal tract. Histochem Cell Biol. 2010;133:177–188.CrossRefPubMed
17.
go back to reference Giaroni C, Knight GE, Ruan H-Z, et al. P2 receptors in the murine gastrointestinal tract. Neuropharmacology. 2002;43:1313–1323.CrossRefPubMed Giaroni C, Knight GE, Ruan H-Z, et al. P2 receptors in the murine gastrointestinal tract. Neuropharmacology. 2002;43:1313–1323.CrossRefPubMed
18.
go back to reference Castelucci P, Robbins HL, Furness JB. P2X(2) purine receptor immunoreactivity of intraganglionic laminar endings in the mouse gastrointestinal tract. Cell Tissue Res. 2003;312:167–174.PubMed Castelucci P, Robbins HL, Furness JB. P2X(2) purine receptor immunoreactivity of intraganglionic laminar endings in the mouse gastrointestinal tract. Cell Tissue Res. 2003;312:167–174.PubMed
19.
go back to reference Vanderwinden JM, Timmermans JP, Schiffmann SN. Glial cells, but not interstitial cells, express P2X7, an ionotropic purinergic receptor, in rat gastrointestinal musculature. Cell Tissue Res. 2003;312:149–154.PubMed Vanderwinden JM, Timmermans JP, Schiffmann SN. Glial cells, but not interstitial cells, express P2X7, an ionotropic purinergic receptor, in rat gastrointestinal musculature. Cell Tissue Res. 2003;312:149–154.PubMed
20.
go back to reference Van Nassauw L, Brouns I, Adraensen D, et al. Region-specific distribution of the P2Y4 receptor in enteric glial cells and interstitial cells of Cajal within the guinea-pig gastrointestinal tract. Auton Neurosc: Basic Clin.. 2006;126:299–306.CrossRef Van Nassauw L, Brouns I, Adraensen D, et al. Region-specific distribution of the P2Y4 receptor in enteric glial cells and interstitial cells of Cajal within the guinea-pig gastrointestinal tract. Auton Neurosc: Basic Clin.. 2006;126:299–306.CrossRef
21.
go back to reference Piao DX, Jiang CH, Kosata M, et al. Cytoplasmic delayed neuronal death in the myenteric plexus of the rat small intestine after ischemia. Arch Histol Cytol. 1999;62:383–392.CrossRefPubMed Piao DX, Jiang CH, Kosata M, et al. Cytoplasmic delayed neuronal death in the myenteric plexus of the rat small intestine after ischemia. Arch Histol Cytol. 1999;62:383–392.CrossRefPubMed
22.
go back to reference Lindestrom L, Ekblad E. Structural and neuronal changes in rat ileum after ischemia with reperfusion. Dig Dis Sci. 2004;49:1212–1222.CrossRefPubMed Lindestrom L, Ekblad E. Structural and neuronal changes in rat ileum after ischemia with reperfusion. Dig Dis Sci. 2004;49:1212–1222.CrossRefPubMed
23.
go back to reference Calcina F, Barocelli E, Bertoni S, et al. Effect of N-methyl-d-aspartate receptor blockade on neuronal plasticity and gastrointestinal transit delay induced by ischemia/reperfusion in rats. Neuroscience. 2005;134:39–49.CrossRefPubMed Calcina F, Barocelli E, Bertoni S, et al. Effect of N-methyl-d-aspartate receptor blockade on neuronal plasticity and gastrointestinal transit delay induced by ischemia/reperfusion in rats. Neuroscience. 2005;134:39–49.CrossRefPubMed
24.
go back to reference Rivera LR, Thacker M, Castelucci P, et al. The reactions of specific neuron types to intestinal ischemia in the guinea pig enteric nervous system. Acta Neuropathol. 2009;118:261–270.CrossRefPubMed Rivera LR, Thacker M, Castelucci P, et al. The reactions of specific neuron types to intestinal ischemia in the guinea pig enteric nervous system. Acta Neuropathol. 2009;118:261–270.CrossRefPubMed
25.
go back to reference Thacker M, Rivera LR, Cho HJ, Furness JB. The relationship between glial distortion and neuronal changes following intestinal ischemia and reperfusion. Neurogastroenterol Motil. 2011;1:1–10. Thacker M, Rivera LR, Cho HJ, Furness JB. The relationship between glial distortion and neuronal changes following intestinal ischemia and reperfusion. Neurogastroenterol Motil. 2011;1:1–10.
26.
go back to reference Paulino AS, Palombit K, Cavriani G, et al. Effects of ischemia and reperfusion on P2X2 receptor expressing neurons of the rat ileum enteric nervous system. Dig Dis Sci. 2011;56:2262–2277.CrossRefPubMed Paulino AS, Palombit K, Cavriani G, et al. Effects of ischemia and reperfusion on P2X2 receptor expressing neurons of the rat ileum enteric nervous system. Dig Dis Sci. 2011;56:2262–2277.CrossRefPubMed
27.
go back to reference Palombit K, Mendes CE, Tavares-de-Lima W, et al. Effects of ischemia and reperfusion on subpopulations of rat enteric neurons expressing the P2X7 receptor. Dig Dis Sci. 2013;58:3429–3439.CrossRefPubMed Palombit K, Mendes CE, Tavares-de-Lima W, et al. Effects of ischemia and reperfusion on subpopulations of rat enteric neurons expressing the P2X7 receptor. Dig Dis Sci. 2013;58:3429–3439.CrossRefPubMed
28.
go back to reference Vieira C, Magalhães-Cardoso MT, et al. Feed-forward inhibition of CD73 and upregulation of adenosine deaminase contribute to the loss of adenosine neuromodulation in postinflammatory ileitis. Mediators Inflamm. 2014;2014:254640.PubMedCentralCrossRefPubMed Vieira C, Magalhães-Cardoso MT, et al. Feed-forward inhibition of CD73 and upregulation of adenosine deaminase contribute to the loss of adenosine neuromodulation in postinflammatory ileitis. Mediators Inflamm. 2014;2014:254640.PubMedCentralCrossRefPubMed
29.
go back to reference Vieira C, Duarte-Araújo M, Adães S, Magalhães-Cardoso T, Correia-de-Sá P. Muscarinic M3 facilitation of acetylcholine release from rat myenteric neurons depends on adenosine outflow leading to activation of excitatory A2A receptors. Neurogastroenterol Motil. 2009;21:1118–e95.CrossRefPubMed Vieira C, Duarte-Araújo M, Adães S, Magalhães-Cardoso T, Correia-de-Sá P. Muscarinic M3 facilitation of acetylcholine release from rat myenteric neurons depends on adenosine outflow leading to activation of excitatory A2A receptors. Neurogastroenterol Motil. 2009;21:1118–e95.CrossRefPubMed
30.
go back to reference Misawa R, Girotti PA, Mizuno MS, et al. Effects of protein deprivation and re-feeding on P2X2 receptors in enteric neurons. World J Gastroenterol. 2010;16:3651–3663.PubMedCentralCrossRefPubMed Misawa R, Girotti PA, Mizuno MS, et al. Effects of protein deprivation and re-feeding on P2X2 receptors in enteric neurons. World J Gastroenterol. 2010;16:3651–3663.PubMedCentralCrossRefPubMed
31.
go back to reference Girotti PA, Misawa R, Palombit K, et al. Differential effects of undernourishment on the differentiation and maturation of rat enteric neurons. Cell Tissue Res. 2013;353:367–380.CrossRefPubMed Girotti PA, Misawa R, Palombit K, et al. Differential effects of undernourishment on the differentiation and maturation of rat enteric neurons. Cell Tissue Res. 2013;353:367–380.CrossRefPubMed
32.
go back to reference Mizuno MS, Crisma AR, Borelli P, Castelucci P. Expression of the P2X2 receptor in different classes of ileum myenteric neurons in the female obese ob/ob mouse. World J Gastroenterol. 2012;18:4693–4703.PubMedCentralCrossRefPubMed Mizuno MS, Crisma AR, Borelli P, Castelucci P. Expression of the P2X2 receptor in different classes of ileum myenteric neurons in the female obese ob/ob mouse. World J Gastroenterol. 2012;18:4693–4703.PubMedCentralCrossRefPubMed
33.
go back to reference Mizuno MS, Crisma AR, Borelli P, et al. Distribution of the P2X2 receptor and chemical coding in ileal enteric neurons of obese male mice (ob/ob). World J Gastroenterol. 2014;14:20(38):13911–13919. Mizuno MS, Crisma AR, Borelli P, et al. Distribution of the P2X2 receptor and chemical coding in ileal enteric neurons of obese male mice (ob/ob). World J Gastroenterol. 2014;14:20(38):13911–13919.
34.
go back to reference Ren J, Bian X, DeVries M, Schnegelsberg B, et al. P2X2 subunits contribute to fast synaptic excitation in myenteric neurons of the mouse small intestine. J Physiol. 2003;552:809–821.PubMedCentralCrossRefPubMed Ren J, Bian X, DeVries M, Schnegelsberg B, et al. P2X2 subunits contribute to fast synaptic excitation in myenteric neurons of the mouse small intestine. J Physiol. 2003;552:809–821.PubMedCentralCrossRefPubMed
36.
37.
go back to reference Ohta T, Kubota A, Murakami M, Otsuguro K-I, Ito S. P2X2 receptors are essential for [Ca2+]i increases in response to ATP in cultured rat myenteric neurons. Am J Physiol (Gastrointest Liver Physiol). 2005;289:935–948.CrossRef Ohta T, Kubota A, Murakami M, Otsuguro K-I, Ito S. P2X2 receptors are essential for [Ca2+]i increases in response to ATP in cultured rat myenteric neurons. Am J Physiol (Gastrointest Liver Physiol). 2005;289:935–948.CrossRef
38.
go back to reference De Giorgio R, Bovara M, Barbara G, et al. Anti-HuD-induced neuronal apoptosis underlying paraneoplastic gut dysmotility. Gastroenterology. 2003;125:70–79.CrossRefPubMed De Giorgio R, Bovara M, Barbara G, et al. Anti-HuD-induced neuronal apoptosis underlying paraneoplastic gut dysmotility. Gastroenterology. 2003;125:70–79.CrossRefPubMed
39.
go back to reference Lawson VA, Furness JB, Klemm HM, et al. The brain to gut pathway: a possible route of prion transmission. Gut. 2010;59:1643–1651.CrossRefPubMed Lawson VA, Furness JB, Klemm HM, et al. The brain to gut pathway: a possible route of prion transmission. Gut. 2010;59:1643–1651.CrossRefPubMed
40.
go back to reference Rivera LR, Pontell L, Cho HJ, et al. Knock out of neuronal nitric oxide synthase exacerbates intestinal ischemia/reperfusion injury in mice. Cell Tissue Res. 2012;349:565–576.CrossRefPubMed Rivera LR, Pontell L, Cho HJ, et al. Knock out of neuronal nitric oxide synthase exacerbates intestinal ischemia/reperfusion injury in mice. Cell Tissue Res. 2012;349:565–576.CrossRefPubMed
41.
go back to reference Castelucci P, de Souza RR, de Angelis RC, et al. Effects of pre- and postnatal protein deprivation and postnatal refeeding on myenteric neurons of the rat large intestine: a quantitative morphological study. Cell Tissue Res. 2002;310:1–7.CrossRefPubMed Castelucci P, de Souza RR, de Angelis RC, et al. Effects of pre- and postnatal protein deprivation and postnatal refeeding on myenteric neurons of the rat large intestine: a quantitative morphological study. Cell Tissue Res. 2002;310:1–7.CrossRefPubMed
42.
go back to reference Galligan JJ. Pharmacology of synaptic transmission in the enteric nervous system. Curr Opin Pharmacol. 2002;2:623–629.CrossRefPubMed Galligan JJ. Pharmacology of synaptic transmission in the enteric nervous system. Curr Opin Pharmacol. 2002;2:623–629.CrossRefPubMed
43.
go back to reference Boesmans W, Cirillo C, Van den Abbeel V, et al. Neurotransmitters involved in fast excitatory neurotransmission directly activate enteric glial cells. Neurogastroenterol Motil. 2013;25:151–160.CrossRef Boesmans W, Cirillo C, Van den Abbeel V, et al. Neurotransmitters involved in fast excitatory neurotransmission directly activate enteric glial cells. Neurogastroenterol Motil. 2013;25:151–160.CrossRef
44.
go back to reference Gulbransen BD, Sharkey KA. Purinergic neuron-to-glia signaling in the enteric nervous system. Gastroenterology. 2009;136:1349–1358.CrossRefPubMed Gulbransen BD, Sharkey KA. Purinergic neuron-to-glia signaling in the enteric nervous system. Gastroenterology. 2009;136:1349–1358.CrossRefPubMed
45.
go back to reference Von Boyen GB, Schulte N, Pflüger C, et al. Distribution of enteric glia and GDNF during gut inflammation. BMC Gastroenterol. 2011;11:3.CrossRef Von Boyen GB, Schulte N, Pflüger C, et al. Distribution of enteric glia and GDNF during gut inflammation. BMC Gastroenterol. 2011;11:3.CrossRef
46.
go back to reference Ferri GL, Probert L, Cocchia D, et al. Evidence for the presence of S-100 protein in the glial component of the human enteric nervous system. Nature. 1982;297:409–410.CrossRefPubMed Ferri GL, Probert L, Cocchia D, et al. Evidence for the presence of S-100 protein in the glial component of the human enteric nervous system. Nature. 1982;297:409–410.CrossRefPubMed
47.
go back to reference Marosti AR, da Silva MV, Palombit K, Mendes CE, Tavares-de-Lima W, Castelucci P. Differential effects of intestinal ischemia and reperfusion in rat enteric neurons and glial cells expressing P2X2 receptors. Histol Histopathol. 2015;30:489–501.PubMed Marosti AR, da Silva MV, Palombit K, Mendes CE, Tavares-de-Lima W, Castelucci P. Differential effects of intestinal ischemia and reperfusion in rat enteric neurons and glial cells expressing P2X2 receptors. Histol Histopathol. 2015;30:489–501.PubMed
48.
go back to reference Duarte-Araújo M, Nascimento C, Timóteo MA, et al. Relative contribution of ecto-ATPase and ecto-ATPDase pathways to the biphasic effect of ATP on acetylcholine release from myenteric motoneurons. Br J Pharmacol. 2009;156:519–533.PubMedCentralCrossRefPubMed Duarte-Araújo M, Nascimento C, Timóteo MA, et al. Relative contribution of ecto-ATPase and ecto-ATPDase pathways to the biphasic effect of ATP on acetylcholine release from myenteric motoneurons. Br J Pharmacol. 2009;156:519–533.PubMedCentralCrossRefPubMed
49.
go back to reference Reese JH, Cooper JR. Modulation of the release of acetylcholine from ileal synaptosomes by adenosine and adenosine 5′-triphosphate. J Pharmacol Exp Ther. 1982;223:612–616.PubMed Reese JH, Cooper JR. Modulation of the release of acetylcholine from ileal synaptosomes by adenosine and adenosine 5′-triphosphate. J Pharmacol Exp Ther. 1982;223:612–616.PubMed
50.
go back to reference Barthó L, Undi S, Benkó R, et al. Multiple motor effects of ATP and their inhibition by P purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid in the small intestine of the guinea-pig. Basic Clin Pharmacol Toxicol. 2006;98:488–495.CrossRefPubMed Barthó L, Undi S, Benkó R, et al. Multiple motor effects of ATP and their inhibition by P purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid in the small intestine of the guinea-pig. Basic Clin Pharmacol Toxicol. 2006;98:488–495.CrossRefPubMed
51.
go back to reference Undi S, Benkó R, Wolf M, et al. Purinergic nerves mediate the non-nitrergic relaxation of the human ileum in response to electrical field stimulation. Brain Res Bull. 2006;71:242–244.CrossRefPubMed Undi S, Benkó R, Wolf M, et al. Purinergic nerves mediate the non-nitrergic relaxation of the human ileum in response to electrical field stimulation. Brain Res Bull. 2006;71:242–244.CrossRefPubMed
Metadata
Title
The Effect of Ischemia and Reperfusion on Enteric Glial Cells and Contractile Activity in the Ileum
Authors
Cristina Eusébio Mendes
Kelly Palombit
Cátia Vieira
Isabel Silva
Paulo Correia-de-Sá
Patricia Castelucci
Publication date
01-09-2015
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 9/2015
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-015-3663-3

Other articles of this Issue 9/2015

Digestive Diseases and Sciences 9/2015 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine