Bibliographic
Year of Publication:
2008
Contact PI Name:
Eduardo Arilla-Ferreiro
Primary Reference (PubMED ID):
Funding Source:
Centro de Investigación Biomédica en Red Physiopathology of Obesity and Nutrition (CIBEROBN)
Direccion General de Investigacion del Ministerio de Ciencia y Tecnologia Spain
Study Goal and Principal Findings:
Minocycline is a semi-synthetic second-generation tetracycline known to improve cognition in amyloid precursor protein transgenic mice. Whether it can protect the somatostatin (SRIF) receptor-effector system, also involved in learning and memory, from alterations induced by chronic i.c.v. infusion of β-amyloid peptide (Aβ)(25-35) is presently unknown. Hence, in the present study, we tested the effects of minocycline on the SRIF signaling pathway in the rat temporal cortex. To this end, male Wistar rats were injected with minocycline (45 mg/kg body weight) i.p. twice on the first day of treatment. On the following day and during 14 days, Aβ(25-35) was administered i.c.v. via an osmotic minipump connected to a cannula implanted in the left lateral ventricle (300 pmol/day). Minocycline (22.5 mg/kg, i.p.) was injected once again the last 2 days of the Aβ(25-35) infusion. The animals were killed by decapitation 24 h after the last drug injection. Our results show that minocycline prevents the decrease in SRIF receptor density and somatostatin receptor (sst) 2 expression and the attenuated capacity of SRIF to inhibit adenylyl cyclase (AC) activity, alterations present in the temporal cortex of Aβ(25-35)-treated rats. Furthermore, minocycline blocks the Aβ(25-35)-induced decrease in phosphorylated cyclic AMP (cAMP) response element binding protein (p-CREB) content and G-protein-coupled receptor kinase 2 (GRK) protein expression in this brain area. Altogether, the present data demonstrate that minocycline in vivo provides protection against Aβ-induced impairment of the SRIF signal transduction pathway in the rat temporal cortex and suggest that it may have a potential as a therapeutic agent in human Alzheimer’s disease, although further studies are warranted.
Therapeutic Agent
Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Minocycline
Therapeutic Target:
Multi Target
Animal Model
Model Information:
Species:
Rat
Model Type:
beta Amyloid Peptide Injection
Model Name:
Wistar (beta Amyloid 25-35 Peptide Injection Model)
Strain/Genetic Background:
Not Applicable
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
Experiment Notes
Age of Animal: In studies using rats, typically the rat weight is reported rather than age. A male Wistar rat weighing 200-250g is between 6-8 weeks old.
Outcomes
Outcome Measured
Outcome Parameters
Biochemical
Adenylyl Cyclase Activity
cAMP Response Element-Binding Protein (CREB)
phospho-cAMP Response Element-Binding Protein (phospho-CREB)
G Protein-Coupled Receptor Kinase 2 (GRK2)
Gi Protein alpha Subunit
Somatostatin (SST) Receptor
Somatostatin (SST) Receptor mRNA
Pharmacology
Binding Affinity
Competitive Inhibition