title: The γ-secretase blocker DAPT impairs recovery from lipopolysaccharide-induced inflammation in rat brain.
abstract: γ-Secretase is an important contributing enzyme in Alzheimer's disease and is therefore an important therapeutic target. However, the impact of γ-secretase inhibition is not well studied in acute neuroinflammation induced by systemic infection. In this study the influence of γ-secretase on the expression of some proinflammatory markers was assessed in the acute phase as well as the subsiding phase of neuroinflammation. Cerebral γ-secretase cleavage activity was measured by a fluorometric assay after lipopolysaccharide (LPS) intraperitoneal administration. Time profiles of TNF-α and COX-II expression were then determined to detect the time points relevant to the maximal inflammatory responses and the subsequent recovery phase. γ-Secretase activity coincident with TNF-α protein expression returned to its basal level till 8-12 h after systemic challenge with low dose LPS while COX-II over expression lasted for 48-72 h later. Pharmacological inhibition of γ-secretase with local or systemic administration of DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) was performed to indicate the results on the developmental and sinking phases of inflammatory responses in 6 and 72 h post LPS respectively. Our results demonstrate that both local and systemic modulation of γ-secretase hyper-activity with DAPT increase the duration of TNF-α, COX-II, and NFκB induction. We consistently found mild augmented apoptosis in animals treated with DAPT as determined by measuring cleaved caspase-3 expression and by TUNEL assay 72 h following LPS injection. These results suggest that γ-secretase modulation interferes with certain immune regulatory pathways which may restrict some inflammatory transcription factors such as NFκB.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy and Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Golestan, PO Box 6287, Ahvaz, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Nasoohi
authors.forename: A A
authors.initials: AA
authors.lastname: Hemmati
authors.forename: F
authors.initials: F
authors.lastname: Moradi
authors.forename: A
authors.initials: A
authors.lastname: Ahmadiani
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D053829:Amyloid Precursor Protein Secretases