No abstract

Mouse null mutants of transcription factor ATF-2 were generated by the gene targeting method. They died shortly after birth and displayed symptoms of severe respiratory distress with lungs filled with meconium. These features are similar to those of a severe type of human meconium aspiration syndrome. The increased expression of the hypoxia inducible genes suggests that hypoxia occurs in the mutant embryos and that it may lead to strong gasping respiration with consequent aspiration of the amniotic fluid containing meconium. A reduced number of cytotrophoblast cells in the mutant placenta was found and may be responsible for an insufficient supply of oxygen prior to birth. Using the cDNA subtraction and microarray-based expression monitoring method, the expression level of the platelet-derived growth factor receptor ␣ gene, which plays an important role in the proliferation of trophoblasts, was found to be low in the cytotrophoblasts of the mutant placenta. In addition, ATF-2 can trans-activate the PDGF receptor ␣ gene promoter in the co-transfection assay. These results indicate the important role of ATF-2 in the formation of the placenta and the relationship between placental anomalies and neonatal respiratory distress. The ATF-2 null mutants should enhance our understanding of the mechanism of severe neonatal respiratory distress. Meconium aspiration syndrome (MAS)1 is a common neonatal problem that results in acute and chronic respiratory morbidity (for review, see Refs. 1 and 2). Unfortunately, our understanding of this entity is incomplete. Aspiration of meconium particles may occur before, during, or after delivery and is associated with deep inspiratory movements because of fetal respiratory depression. Aspiration of meconium may cause mechanical obstruction of the airways, chemical pneumonitis, and surfactant inactivation. Although MAS can be prevented in the majority of infants by appropriate suctioning at birth or by early administration of surfactant, the severe form of MAS is still a neonatal problem that remains to be resolved (3).A number of transcription factors of the ATF/CREB family, all of which contain a DNA-binding domain consisting of a cluster of basic amino acids and a leucine zipper region (b-zip), have been identified (for review, see Ref. 4). They bind to the cAMP response element (CRE) as homodimers or heterodimers formed through the leucine zipper. Among the numerous transcription factors of the ATF/CREB family, three factors, ATF-2 (also called CRE-BP1), ATF-a, and CRE-BPa form a subgroup (5-9). These factors are capable of forming homodimers or heterodimers with c-Jun (10). A common characteristic of this group of factors is their activation by the stress-activated protein kinases such as the Jun amino-terminal kinase and p38 (11-13). The stress-activated protein kinases phosphorylate this group of factors at sites close to the NH 2 -terminal transcriptional activation domain containing the metal finger structure and stimulate their trans-activating capacity. Because a group of fac...

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Present study was designed to investigate modulation of experimental dementia by Pitavastatin and donepezil. Learning and memory of the swiss albino mice were studied on Morris water-maze. Celecoxib orally (p.o.)/Streptozotocin (STZ) intracerebroventricular administrations were used to induce experimental dementia. Brain acetyl cholinesterase activity was measured by EllMann's method to assess cholinergic activity of the brain. Brain thio barbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively, to assess total oxidative stress in brain. Total serum cholesterol level was measured by Allain's method. Celecoxib/STZ treatments produced a significant loss of learning and memory. Pitavastatin/Donepezil successfully attenuated this Celecoxib/STZ induced dementia. Higher levels of brain acetyl-cholinesterase (AChE) activity, TBARS and lower level of GSH were observed in Celecoxib/STZ treated animals, which were significantly attenuated by Donepezil. Pitavastatin also attenuated the Celecoxib/STZ induced high levels of TBARS & low levels of GSH without effecting AChE activity and total serum cholesterol levels. Celecoxib induced dementia noted in the present study may be attributed to its stimulatory effect on amyloid beta-42, brain AChE activity, and oxidative stress. Sub-diabetogenic STZ induced memory deficits closely related to Alzheimer's disease. Reversal of Celecoxib/STZ induced memory deficits by Pitavastatin may be due to its antioxidative, anti beta amyloid aggregatory property, and by Donepezil, due to its anticholinesterase and neuroprotective actions.