In-vivo histamine H3 receptor antagonism activates cellular signaling suggestive of symptomatic and disease modifying efficacy in Alzheimer’s disease

Bibliographic

Year of Publication: 
2011
Contact PI Name: 
Scott R. Bitner
Contact PI Affiliation: 
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA
Co-Authors: 
Stella Markosyan, Arthur L. Nikkel, Jorge D. Brioni
Primary Reference (PubMED ID): 
Funding Source:
Study Goal and Principal Findings: 

In previous studies the authors demonstrated that that pharmacological activation of specific signaling pathways in the whole animal can be used to mechanistically assess efficacy of potential AD therapeutics. Specifically,  the authors found that phosphorylation-activation of CREB a transcription factor germane to cognitive function, and phosphorylation-inhibition of glycogen synthase kinase3β (GSK3β), a primary tau kinase in AD, can be utilized as biochemical endpoints of symptomatic and disease modifying efficacy, respectively, in preclinical assessment of potential AD therapeutics.  The overall goal of this study was to examine the H3-antagonist-ABT-239, in both normal and transgenic (Tg)-AD mice for induction of CREB and S9-GSK3β phosphorylation, as measured immunohistochemically. Similar signaling experiments in normal CD-1mice were conducted with the AChE inhibitor donepezil. To provide a more primary endpoint of AD pathophysiology, effects of ABT-239 were also examined for reversal of tau hyperphosphorylation in the Tg TAPP tauopathy mouse model. In CD-1 moice ABT-239 drug treatment increased cortical CREB and S9-GSK3β phosphorylation. In contrast donepezil treatment, of CD-1 mice, increased CREB phosphorylation, but did not increase pS9-GSK3β expression. In Tg2576 mice continuous (s.c). infusion of ABT-239 normalized reduced cortical CREB and hippocampal S9-GSK3β phosphorylation. In the TAPP model ABT-239 infusion reversed tau hyperphosphorylation in the spinal cord and hippocampus of TAPP AD-transgenic mice.These results suggest that ABT-239 leads to biochemical signaling that promotes cognitive performance as well as attenuation of tau hyperphosphorylation, raising the intriguing possibility that H3 antagonists have potential for both symptomatic and disease modifying benefit in the treatment of AD.

Therapeutic Agent

Therapeutic Information: 
Therapy Type:
Therapy Type:

Animal Model

Model Information: 
Species:
Model Type:
Strain/Genetic Background: 
B6;SJL Mixed Background
Species:
Model Type:
Strain/Genetic Background: 
C57BL/6, DBA/2, SJL, SW
Species:
Model Type:
Strain/Genetic Background: 
CD-1

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

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Immunochemistry
  • phospho-Tau
  • phospho-cAMP Response Element-Binding Protein (phospho-CREB)