title: Stress is critical for LPS-induced activation of microglia and damage in the rat hippocampus.
abstract: The hippocampus is insensitive to strong inflammatory stimulus under normal conditions and one of the most severely affected areas in Alzheimer's disease. We have analyzed the effect of chronic stress for 9 days in the hippocampus unilaterally injected with LPS. In non-stressed rats, LPS injection failed to activate microglia although a subset of degenerating cells in the CA1 area was evident. This effect was not accompanied by loss of Neu-N positive neurons in the CA1 area. In stressed rats, LPS injection had a dramatic effect in activating microglia along with astrogliosis and BDNF mRNA induction. NeuN immunostaining demonstrated a loss of about 50% of CA1 pyramidal neurons under these conditions. Fluoro jade B histochemistry demonstrated the presence of degenerating cells in most of CA1 area. Mechanistically, combination of chronic stress and LPS resulted in prominent activation of MAPKs including JNK, p38 and ERK clearly different from LPS injection in controls. Further, LPS+stress induced a dramatic decrease in phosphorylated levels of both Akt and CREB, which fully supports a consistent deleterious state in the hippocampal system under these conditions. Treatment with RU486, a potent inhibitor of glucocorticoid receptor activation, significantly protected animals against the deleterious effects observed in LPS-stressed animals.
authors.affiliation: Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/Prof. García González, 2, 41012 Sevilla, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Espinosa-Oliva
authors.forename: R M
authors.initials: RM
authors.lastname: de Pablos
authors.forename: R F
authors.initials: RF
authors.lastname: Villarán
authors.forename: S
authors.initials: S
authors.lastname: Argüelles
authors.forename: J L
authors.initials: JL
authors.lastname: Venero
authors.forename: A
authors.initials: A
authors.lastname: Machado
authors.forename: J
authors.initials: J
authors.lastname: Cano
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000187:drug effects*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009930:Organic Chemicals; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011374:Progesterone / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013315:Stress, Psychological / Q000097:blood / Q000473:pathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C026915:6-iodo-5-hydroxy-eicosatrienoic acid, delta-lactone; D001095:Arachidonic Acids; D019208:Brain-Derived Neurotrophic Factor; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D009930:Organic Chemicals; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C435731:fluoro jade; D011374:Progesterone; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010751:Phosphopyruvate Hydratase; D003345:Corticosterone