title: Pathways involved in gut mucosal barrier dysfunction induced in adult rats by maternal deprivation: corticotrophin-releasing factor and nerve growth factor interplay.
abstract: Neonatal maternal deprivation (NMD) increases gut paracellular permeability (GPP) through mast cells and nerve growth factor (NGF), and modifies corticotrophin-releasing factor (CRF) and corticosterone levels. CRF, corticosterone and mast cells are involved in stress-induced mucosal barrier impairment. Consequently, this study aimed to specify whether corticosteronaemia and colonic expression of both preproCRF and CRF are modified by NMD, and to determine if altered expression may participate in the elevated GPP in connection with NGF and mast cells. Male Wistar rat pups were either separated from postnatal days 2-14, or left undisturbed with their dam. At 12 weeks of age, adult rats were treated with mifepristone (an antagonist of corticoid receptors), alpha-helical CRF((9-41)) (a non-specific CRF receptor antagonist), or SSR-125543 (CRF-R(1) receptor antagonist). We also determined corticosteronaemia and both colonic preproCRF and CRF expression. Then, control rats were treated by CRF, doxantrazole (mast cell stabilizer), BRX-537A (a mast cell activator) and anti-NGF antibody. NMD did not modify colonic CRF level but increased colonic preproCRF expression and corticosteronaemia. Peripheral CRF, via CRF-R(1) receptor, but not corticosterone, was involved in the elevated GPP observed in these rats, through a mast-cell-mediated mechanism, since the increase of GPP induced by exogenous CRF was abolished by doxantrazole. Anti-NGF antibody treatment also reduced the elevated GPP induced by CRF or BRX-537A. CRF acts through CRF-R(1) receptors to stimulate NGF release from mast cells, which participates in the elevated GPP observed in NMD adult rats. This suggests that early traumatic experience induced neuro-endocrine dysfunction, involved in alterations of gut mucosal barrier.
authors.affiliation: Neuro-Gastroenterology and Nutrition Unit, INRA, 180 chemin de Tournefeuille, BP.3, 31931 Toulouse Cedex 9, France.
authors.forename: Frederick
authors.initials: F
authors.lastname: Barreau
authors.forename: Christel
authors.initials: C
authors.lastname: Cartier
authors.forename: Mathilde
authors.initials: M
authors.lastname: Leveque
authors.forename: Laurent
authors.initials: L
authors.lastname: Ferrier
authors.forename: Raphael
authors.initials: R
authors.lastname: Moriez
authors.forename: Valerie
authors.initials: V
authors.lastname: Laroute
authors.forename: Andras
authors.initials: A
authors.lastname: Rosztoczy
authors.forename: Jean
authors.initials: J
authors.lastname: Fioramonti
authors.forename: Lionel
authors.initials: L
authors.lastname: Bueno
mesh_terms: D000818:Animals; D003106:Colon / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008426:Maternal Deprivation; D015735:Mifepristone / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D010539:Permeability; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
chemical_list: C451725:4-(2-chloro-4-methoxy-5-methylphenyl)-N(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine; D006727:Hormone Antagonists; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; D013844:Thiazoles; D015735:Mifepristone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D020932:Nerve Growth Factor; C045089:corticotropin releasing hormone (9-41)