Cyclooxygenase-2 (COX-2) and Presenilin-1 (PS1) Genes Exhibit Enhanced Transcription in Experimental Epileptogenesis
Abstract number :
K.05
Submission category :
Year :
2000
Submission ID :
382
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Walter J Lukiw, Nicolas G Bazan, Louisiana State Univ Sch of Medicine, New Orleans, LA; LSU Neuroscience Ctr, New Orleans, LA.
RATIONALE: Presenilin-1 (PS1), an integral transmembrane protein, and cyclooxygenase-2 (COX-2), a membrane-associated oxidoreductase, are implicated in accelerated A 42 generation and the propagation of neuroinflammatory cascades in Alzheimer's disease. This laboratory has previously shown that PS1 and COX-2 are coinduced (a) in gerbil hippocampus 72 hr after a single (6 min) episode of transient cerebral ischemia, (b) in hypoxic rat pup retina undergoing neovascularization and (c) in normal human neural progenitor cells in primary culture after treatment with A 42 (20 uM, 3 hr), NMDA (100 uM, 20 min) or IL-1 (10 ng/ml, 20 min). Under each of these conditions, PS1 and COX-2 RNA abundance displayed strikingly similar induction kinetics (r2>0.9, p<0.05, ANOVA). METHODS: In this study, computer assisted DNA sequence analysis of the TATA-containing COX-2 and PS1 gene promoters revealed important similarities in their repertoire of transcription factor- (TF-) DNA recognition sites in 5' regulatory regions, including DNA binding sites for the proinflammatory TF triad AP1, NF-kappaB and GAS(STAT1). Next, AP1-, NF-kappaB- and GAS(STAT1)-DNA-binding activities were examined in adult rat hippocampus at various times (0, 1, 3, 6 hr, 1, 3, 7 da and 2, 4, 8 wk) following a single intraperitoneal injection of kainic acid (KA; 10mg/kg). RESULTS: As in previously studied brain injury models, AP1-, NF-kappaB- and GAS(STAT1)-DNA binding correlated temporally with COX-2 and PS1 RNA message levels. Each TF displayed phasic DNA-binding profiles over the short term (0-3 hr), medium term (3-6 hr) and also after long term (4-8 wk) time periods. This correlated to maximal increases of COX-2 and PS1 messenger RNA at 3 and 24 hr post KA treatment. CONCLUSIONS: These data suggest that the developmentally regulated COX-2 and PS1 genes may share co-regulated transcriptional control in a variety of brain cell damage models and neurological conditions and that COX-2 and PS1 gene expression may represent early genetic components of a proinflammatory brain injury response. (Supported by NIH NS23002).