Skip to main content
U.S. flag

An official website of the United States government

Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer’s disease

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2013
Contact PI Name:
Eva Carro
Contact PI Affiliation:
Neuroscience Group, Instituto de Investigacion Hospital, Madrid, Spain
Co-Authors:
Rocio Perez-Gonzalez, Consuelo Pascual, Desiree Antequera, Marta Bolos, Miriam Redondo, Daniel I. Perez, Virginia Pérez-Grijalba, Agnieszka Krzyzanowska, Manuel Sarasa, Carmen Gil, Isidro Ferrer, Ana Martinez
Primary Reference (PubMED ID):
23582662
Funding Source:
Fundación Investigación Médica Mutua Madrileña
Spanish Ministry of Science and Innovation
Spanish Network on Multiple Sclerosis (REEM)
Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED)
Instituto de Salud Carlos III
Study Goal and Principal Findings:

In this study the investigators tested the quinazoline, S14, a BBB permeable PDE7 inhibitor, for efficacy in an APP/PS1 mouse model of AD.  Daily treatment (i.p. or p.o. route of delivery) of the mice for 4 weeks with S14 showed: (1) significant attenuation in behavioral impairment; (2) decreased brain Abeta deposition; (3) enhanced astrocyte-mediated Abeta degradation; and (4) decreased tau phosphorylation. These effects were found to be mediated via the cyclic adenosine monophosphate/cyclic adenosine monophosphate response element-binding protein signaling pathway, and inactivation of glycogen synthase kinase GSK3-beta.  In addition the authors examined the specific profile of S14 on different PDEs, its genotoxicity safety and in vivo pharmacokinetics. These studies found that S14 is a nongenotoxic, selective brain permeable PDE7 inhibitor.The data support the use of PDE7 inhibitors, and specifically S14 with safe mutagenicity and good brain penetration, as an effective therapeutic agents for the prevention and treatment of AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
S14
PubMed
Patents
Therapeutic Target:
Phosphodiesterase Type 7 (PDE7)
Open Targets
Pharos

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1
Model Name:
PS/APP
ALZFORUM
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
Biomarkers
Dose
Formulation
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

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
T Maze
Histopathology
beta Amyloid Load
Activated Astrocytes
Activated Microglia
Biochemical
CREB/phospho-CREB
phospho-Tau
Brain-beta Amyloid Oligomers
GSK3 beta/phospho-GSK3 beta
Caspase Activation
Pharmacokinetics
Brain/Plasma Ratio
Area Under the Curve (AUC)
Tmax
Cmax
Drug Concentration-Brain
Drug Concentration-Plasma
Toxicology
Ames Test
Cell Biology
Neuroprotection-Amyloid Neurotoxicity
beta Amyloid Peptide Clearance
Pharmacology
Target Selectivity
Share:
Print: