title: Corticotropin-Releasing Factor Receptor-1  Antagonism Reduces Oxidative Damage  in an Alzheimer’s Disease Transgenic Mouse  Model.
abstract: Reports from Alzheimer’s disease (AD) biomarker work have shown a strong link between oxidative stress and AD neuropathology. The nonenzymatic antioxidant, glutathione (GSH), plays a crucial role in defense against reactive oxygen species and maintenance of GSH redox homeostasis. In particular, our previous studies on GSH redox imbalance have implicated oxidative stress induced by excessive reactive oxygen species as a major mediator of AD-like events, with the presence of S- glutathionylated proteins (Pr-SSG) appearing prior to overt AD neuropathology. Furthermore, evidence suggests that oxidative stress may be associated with dysfunction of the hypothalamic-pituitary-adrenal axis, leading to activation of inflammatory pathways and increased production of corticotropin-releasing factor (CRF). Therefore, to investigate whether oxidative insults can be attenuated by reduction of central CRF signaling, we administered the type-1 CRF receptor (CRFR1) selective antagonist, R121919, to AD-transgenic mice beginning in the preclinical/prepathologic period (30-day-old) for 150 days, a time point where behavioral impairments and pathologic progression should be measureable. Our results indicate that R121919 treatment can significantly reduce Pr-SSG levels and increase glutathione peroxide activity, suggesting that interference of CRFR1 signaling may be useful as a preventative therapy for combating oxidative stress in AD.
authors: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA. chz002@ucsd.edu
authors: Cheng
authors: C
authors: Zhang
authors: Ching-Chang
authors: CC
authors: Kuo
authors: Setareh H
authors: SH
authors: Moghadam
authors: Louise
authors: L
authors: Monte
authors: Kenner C
authors: KC
authors: Rice
authors: Robert A
authors: RA
authors: Rissman
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D011743:Pyrimidines; C412383:R 121919; D003346:Corticotropin-Releasing Hormone; D005979:Glutathione Peroxidase; D005978:Glutathione; D019803:Glutathione Disulfide
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