Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice

Bibliographic

Year of Publication: 
2013
Contact PI Name: 
Laura Calzà
Contact PI Affiliation: 
Health Science and Technologies Interdepartmental Center for Industrial Research, University of Bologna, Bologna, Italy
Co-Authors: 
S. Sivilia, L. Lorenzini, A. Giuliani, M. Gusciglio, M. Fernandez, V.A. Baldassarro, C. Mangano, L. Ferraro, V. Pietrini, M.F. Baroc, A.R. Viscomi, S. Ottonello, G. Villetti, B.P. Imbimbo, L. Giardino
Primary Reference (PubMED ID): 
Funding Source:
Study Goal and Principal Findings: 

The study investigated effects of CHF5074 on AD neuropathology, spine density/morphology, cell cycle, microglia activity, and cognitive impairment in Tg2576 mice. CHF5074 is a nonsteroidal anti-inflammatory derivative devoid of cyclooxygenase inhibitory activity. In vitro, CHF5074 behaves as a γ secretase modulator preferentially inhibiting Aβ42 production.  CHF5074 has been shown to inhibit brain plaque deposition and to attenuate or reverse contextual and spatial memory deficit in different transgenic mouse models of AD, also reversing long-term potentiation deficit in the hippocampus. However, recent data have shown that CHF5074 is able to promote axon growth and astrocyte plasticity by modulating Rho-GTPase-dependent signaling. In this study, the effects of a long-term (13-month) treatment with CHF5074 on indicators of brain functionality and neurodegeneration in transgenic Tg2576 mice were assessed and compared with those induced by a prototypical γ-secretase inhibitor (DAPT).Tg2576 mice fed with standard diet displayed an impairment of recognition memory. This deficit was completely reverted by the higher dose of CHF5074, while no effects were observed in DAPT-treated mice. Similarly, amyloid plaque burden, microglia activation and aberrant cell cycle events were significantly affected by CHF5074, but not DAPT, treatment. Both CHF5074 and DAPT reduced intraneuronal Aβ content, also increasing Aβ40 and Aβ42 plasma levels. This comparative analysis revealed a profoundly diverse range of clinically relevant effects differentiating the multifunctional anti-inflammatory derivative CHF5074 from the γ-secretase inhibitor DAPT and highlighted unique mechanisms and potential targets that may be crucial for neuroprotection in mouse models of AD.

Therapeutic Agent

Therapeutic Information: 
Therapy Type:
Therapy Type:

Animal Model

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

Experimental Design

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

Experiment Notes

The estimated ingested doses of CHF5074 were about 20 and 60 mg/kg/day (behaviourally effective dose when given chronically for 9 months); the estimated ingested dose of DAPT was about 60 mg/kg/day.

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Behavioral
  • Novel Object Recognition Test (NORT)
  • Histopathology
  • beta Amyloid Load
  • Biochemical
  • Brain-beta Amyloid Oligomers
  • Brain-beta Amyloid Peptide-Total
  • Plasma-beta Amyloid Peptide 40
  • Plasma-beta Amyloid Peptide 42
  • Immunochemistry
  • Activated Microglia
  • Activated Astrocytes
  • Intracellular beta Amyloid Peptide
  • Cyclin A
  • Mature Neurons
  • Microscopy
  • Dendritic Spine Density
  • Dendritic Spine Morphology
  • Biomarker
  • Plasma-beta Amyloid Peptide 40
  • Plasma-beta Amyloid Peptide 42
  • Toxicology
  • Mortality