GASTRO-INTESTINAL NEUROPHARMACOLOGY
Head of the research unit:
Prof. Dr. R. Lefebvre, MD, PhD
Email: romain.lefebvre@UGent.be
Scientific staff:
D. Babu, Master in Pharmacy
S. Cosyns, Master of Biomedical sciences
F. de Vin, Bio-engineer, PhD Applied Biological Sciences
E. Priem, Master of Biomedical sciences
S. Weninger, Master in microbiology and genetics
Technical staff:
B. Blanckaert, Industrial engineer electronics
S.M. Choi, Industrial engineer chemistry
I. Van Colen, Industrial engineer chemistry
E. Van Deynse, Industrial engineer chemistry
V. Geers, Voluntary laboratory assistant
Research areas
The major functions of the gastro-intestinal tract, absorption, secretion and motility,
are controlled by intrinsic and extrinsic neurons. The intrinsic or enteric
nervous system is essential for the control of the smooth muscle activity.
The most important neurons are the cholinergic ones, that release the
contractile neurotransmitter acetylcholine, and the non-adrenergic
non-cholinergic (NANC) neurons, that release one or more inhibitory
neurotransmitters such as nitric oxide (NO).
A first research area deals with the physiological and pharmacological relevance of soluble guanylate cyclase (sGC) in the gastro-intestinal tract. sGC is a heterodimer consisting of an a and a b subunit. Both subunits have 2 isoforms : a1 and a2, b1 and b2. The 2 physiological relevant dimers are a1b1 and a2b in the gastro-intestinal tract, mainly a1b1 is present. sGC is the most important target of NO in the gastro-intestinal tract although also other targets have been described. The relative importance of sGCa1b1 , versus sGCa2b1 , and the role of sGC in the effect of NO on gastro-intestinal motility is investigated in vitro and in vivo (gastric emptying, intestinal transit) by use of sGCa1 knockout and sGCb1 mutant mice.
A second area deals with the influence of carbon monoxide (CO) and CO-releasing molecules (CORMS) in the gastro-intestinal tract. CO is endogenously produced by the hemoxygenase (HO) enzyme family. HO-2 is constitutively expressed, while HO-1 is expressed in stress and inflammation. Besides of CO, HO also produces biliverdin, that is metabolised to bilirubin through biliverdin reductase; both biliverdin and bilirubin are powerful anti-oxydants. The influence of CO and CORMS on gastro-intestinal motility and their mechanism of action is investigated, as well as the interaction between the HO-biliverdin reductase system and nitrergic neurotransmission. The anti-inflammatory effect and the mechanism of action of CORMS is investigated in the inflammatory phase of postoperative ileus.
A third research area deals with the influence of serotonin on gastro-intestinal motility. Serotonin has both contractile as well as relaxant influences on the smooth muscle cells of the gastro-intestinal tract, either directly via receptors on the smooth muscle cells or indirectly via receptors on enteric neurones. The receptor subtype involved in the effect of serotonin on stomach and intestine are evaluated in different species. In particular, 5-HT4 receptors are investigated. These receptors are present on cholinergic nerve endings in the gastro-intestinal tract, stimulating acetylcholine release, but they are also present on atrial cells. The pharmacological characteristics of the 5-HT4 receptors at these 2 sites are compared.
Representative recent publications
- Lefebvre R.A., Ferrero S., Van Colen I., Dhaese I., Camerini G., Fulcheri E., Remorgida V. : Influence of 5-HT4 receptor activation on acetylcholine release in human large intestine with endometriosis. Neurogastroenterol. Motil. 22, 557-563, 2010.
- De Maeyer J.H., Schuurkes J.A., Lefebvre R.A. : Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach. Brit. J. Pharmacol. 156, 362-376, 2009.
- De Backer O., Elinck E., Blanckaert B., Leybaert L., Motterlini R., Lefebvre R.A. : Water-soluble CO-releasing molecules reduce the development of postoperative ileus via modulation of MAPK/HO-1 signalling and reduction of oxidative stress. Gut, 58, 347-356, 2009.
- Vanneste G., Van Nassauw L., Kalfin R., Van Colen I., Elinck E., Van Crombruggen K., Timmermans J.-P. and Lefebvre R.A. : Jejunal cholinergic, nitrergic and soluble guanylate cyclase activity in postoperative ileus. Surgery, 144, 410-426, 2008.
- De Maeyer J.H., Aerssens J., Verhasselt P. and Lefebvre R.A. : Alternative splicing and exon duplication generates 10 unique porcine 5-HT4 receptor splice variants including a functional homofusion variant. Physiol. Genomics, 34, 22-33, 2008.
- Vanneste G., Dhaese I., Sips P., Buys E., Brouckaert P. and Lefebvre R.A. : Gastric motility in soluble guanylate cyclase alfa 1 knock-out mice. J. Physiol. 584, 907-920, 2007.
- De Backer O. and Lefebvre R.A. : Mechanisms of relaxation by carbon monoxide molecule-2 in murine gastric fundus and jejunum. Eur. J. Pharmacol. 572, 197-206, 2007.
- De Maeyer J.H., Straetemans R., Schuurkes J.A.J. and Lefebvre R.A. : Porcine left atrial and sinoatrial 5-HT4 receptor-induced responses: fading of the response and influence of development. Brit. J. Pharmacol. 147, 140-157, 2006.
- Leclere P.G., Prins N.H., Schuurkes J.A.J. and Lefebvre R.A. : 5-HT4 receptors located on cholinergic nerves in human colon circular muscle. Neurogastroenterol. Motil. 17, 366-375, 2005.
Ph.D. Theses
- I. Dhaese, 28.05.2010
Role of soluble guanylate cyclase isoforms and of hydrogen sulfide in gastrointestinal motility. - O. De Backer, 14.09.2009
Haem oxygenase in the gastrointestinal tract - Physiological role and therapeutic possibilities. - G. Vanneste, 8.12.2008
Role of soluble granulate cyclase in the effect of nitric oxide on gastrointestinal motility in physiological conditions and in postoperative inflammation. - J. De Maeyer, 14.11.2008
Organ dependent efficacy of 5-HT4 receptor agonists - A pharmacological and molecular study on porcine atrium and stomach. - C. Delesalle, 18.03.2008 (copromotor with Prof. Dr. P. Deprez, Department of Large Animal Internal Medicine, Faculty of Veterinary Medicine, Ghent)
Ileus in the colic horse : prognostic factors and the role of serotonin and serotonergic receptors.
(Cooperation with Department of Large Animal Internal Medicine, Faculty of Veterinary Medicine, Ghent, Prof. P. Deprez) - K. Van Crombruggen, 17.12.2007
Colonic motility under normal and inflammatory conditions : nitrergic-purinergic control and role of soluble guanylate cyclase. - P. Janssen, 05.07.2004
Serotoninergic control of gastric motility. A comparative study in cat, dog and pig. - L. Van Geldre, 04.06.2004
Investigation of pre- and postsynaptic characteristics of nitrergic neurotransmission in the gastrointestinal tract. - P. Leclere, 20.06.2002
Regulation of cholinergic neurotransmission in the porcine and human gastrointestinal tract. - E. Colpaert, 16.05.2002
Role of antioxidants in the protection of het nitrergic neurotransmitter. - J. Dick, 26.10.2001
Interaction between nitric oxide and vasoactive intestinal polypeptide in the regulation of gastric motility.
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