title: Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation.
abstract: Prenatal infection is a major stressful experience leading to enhanced susceptibility for mental illnesses in humans. We recently reported in rats, that oxidative stress and glutathione (GSH) shortage occurred in fetal male brain after lipopolysaccharide (LPS) to the dams and that these responses might be involved in the neurodevelopmental deficits observed in adolescent offspring. Furthermore, pretreatment with N-acetylcysteine (NAC) before LPS avoided both delayed synaptic plasticity and mnesic performance deficits. Since NAC is one of the few medications permitted in pregnant women, this study evaluated the ability of NAC to serve as a protective therapy even after the LPS challenge. Pregnant rats received a single ip injection of E. coli LPS, two days before delivery, and were given NAC in their tap water after the LPS. GSH was evaluated at the time of its expected drop in the hippocampus of male fetuses, whereas long-term potentiation (LTP) in the CA1 area of the hippocampus and spatial memory in the water-maze were recorded in 28-day-old male offspring. Post-treatment with NAC, four hours after the LPS challenge fully prevented the drop in the GSH hippocampal content. LTP, as well as spatial learning were completely protected. NAC administration at delivery also partially restored the LTP whereas post-treatment two days later was inefficient. Another set of dams were supplemented with alpha-tocopherol prior to LPS exposure, enhancing the alpha-tocopherol levels in fetal hippocampus. This treatment did not prevent the LPS-induced synaptic plasticity impairment. These results point to fetal hippocampal GSH as a major target of the detrimental effects of in utero LPS challenge. The therapeutic window of NAC extends up to birth, suggesting that this drug might be clinically useful even after an immuno-inflammatory episode.
authors.affiliation: Oxidative Stress and Neuroprotection, IBMM, CNRS UMR-5247, UM-1 and UM-2, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lanté
authors.forename: Johann
authors.initials: J
authors.lastname: Meunier
authors.forename: Janique
authors.initials: J
authors.lastname: Guiramand
authors.forename: Marie-Céleste
authors.initials: MC
authors.lastname: De Jesus Ferreira
authors.forename: Gilles
authors.initials: G
authors.lastname: Cambonie
authors.forename: Rose
authors.initials: R
authors.lastname: Aimar
authors.forename: Catherine
authors.initials: C
authors.lastname: Cohen-Solal
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
authors.forename: Michel
authors.initials: M
authors.lastname: Vignes
authors.forename: Gérard
authors.initials: G
authors.lastname: Barbanel
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D005978:Glutathione / Q000032:analysis / Q000172:deficiency; D006624:Hippocampus / Q000737:chemistry / Q000196:embryology / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018811:Maternal Exposure; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy* / Q000276:immunology; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; C482199:lipopolysaccharide, E coli O55-B5; D005978:Glutathione; D024502:alpha-Tocopherol; D000111:Acetylcysteine