Nilvadipine antagonizes both Abeta vasoactivity in isolated arteries, and the reduced cerebral blood flow in APPsw transgenic mice


BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2004
Contact PI Name:
Daniel Paris
Contact PI Affiliation:
The Roskamp Institute, Sarasota, Florida, USA
Co-Authors:
Amita Quadros, James Humphrey, Nikunj Patel, Robert Crescentini, Fiona Crawford, Michael Mullan
Primary Reference (PubMED ID):
Funding Source:
Fujisawa Pharmaceutical
Study Goal and Principal Findings:

The development of Alzheimer's disease (AD) is generally thought to correlate with cerebral accumulation of Abeta. It has previously been shown that Abeta peptides enhance vasoconstriction in isolated arteries and oppose certain vasorelaxants. Moreover, exogenous application of Abeta peptides causes cerebral vasoconstriction in rodents and in transgenic mouse models of AD that overexpress Abeta there is reduced cerebral blood flow. In the present study, was investigated the effect of nilvadipine, a dihydropyridine-type calcium channel blocker, on Abeta induced vasoconstriction in isolated arteries and in vivo on cerebral blood flow (CBF) of an AD transgenic mouse model overexpressing Abeta (Tg APPsw line 2576). Nilvadipine completely inhibited the vasoactivity elicited by Abeta in rat aortae and in human middle cerebral arteries. The effect of a short treatment duration (2 weeks) with nilvadipine on regional CBF was investigated in 13-month-old Tg APPsw mice and control littermates using a laser Doppler imager. Additionally, CBF was also measured in 20-month-old Tg APPsw mice and control littermates that were chronically treated with nilvadipine for 7 months. Untreated Tg APPsw mice showed a reduction of regional CBF compared to their untreated control littermates. Nilvadipine restored cortical perfusion levels in Tg APPsw to values similar to those observed in control littermates without notably affecting the CBF of control mice. All together, these data suggest that nilvadipine might be useful for the treatment of oligemia associated with AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Nilvadipine
Therapeutic Target:
L-Type Calcium Channel/Dihydropyridine (DHP) Channel

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
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
Biochemical
Endothelin 1 (ET1)
Biomarker
Cerebral Blood Flow (CBF)
Imaging
Cerebral Blood Flow (CBF)
Physiology
Cerebral Blood Flow (CBF)
Blood Pressure

Source URL: http://alzped.nia.nih.gov/nilvadipine-antagonizes-both