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Corticotropin-releasing factor receptor-1 antagonism reduces oxidative damage in an Alzheimer’s disease transgenic mouse model


Year of Publication:
Contact PI Name:
Robert A. Rissman
Contact PI Affiliation:
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
Cheng Zhang, Ching-Chang Kuo, Setareh H. Moghadam, Louise Monte, Kenner C. Rice
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Art Quilt Initiative
National Institute on Drug Abuse (NIDA)
Alzheimer's Association
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Study Goal and Principal Findings:

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 timepoint 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Corticotropin-Releasing Factor Receptor 1 (CRFR1)
Therapeutic Notes:
Corticotropin-Releasing Factor Receptor 1 (CRFR1) has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Glutathione (GSH)
Oxidized Glutathione
Protein S-Glutathionylation
Glutathione Peroxidase (GPx)
Receptor Antagonism