Skip to main content
U.S. flag

An official website of the United States government

The alpha7 nicotinic receptor agonist 4OH-GTS-21 protects axotomized septohippocampal cholinergic neurons in wild type but not amyloid-overexpressing transgenic mice


Year of Publication:
Contact PI Name:
Edwin M. Meyer
Contact PI Affiliation:
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA
M.A. King, J. Liu, J. Siemann, M. Altmann, C. Meyers, J.A. Hughes
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
McKnight Brain Institute at the University of Florida
Study Goal and Principal Findings:

While activation of alpha7 nicotinic receptors protects neurons from a variety of apoptotic insults in vitro, little is known about this neuroprotective action in vivo, especially under amyloidogenic conditions that mimic Alzheimer's disease. Therefore were investigated the effects of 4OH-GTS-21, a selective partial agonist for these receptors, on septohippocampal cholinergic and GABAergic neuron survival following fimbria fornix (FFX) lesions in three strains of mice: C57BL/6J wild type mice; human presenilin-1 mutant M146L (PS1) transgenic mice; and mice expressing both mutant PS1 and Swedish mutant K670N/M671L amyloid precursor protein (APP). Initial studies to demonstrated that 4OH-GTS-21 is likely brain permeant based on its ability to improve passive avoidance and Morris water task behaviors in nucleus basalis-lesioned rats. In FFX-lesioned mice, twice per day i.p. injections of 1 mg/kg of 4OH-GTS-21 for 2 weeks promoted the survival and prevented the atrophy of septal cholinergic neurons. Septal parvalbumin-staining GABAergic neurons were not protected by this treatment, although they also express alpha7 nicotinic receptors, suggesting an indirect, nerve growth factor (NGF)-mediated mechanism. No protection of cholinergic neurons was observed in similarly treated PS1 or APP/PS1 transgenic mice. 4OH-GTS-21 treatment actually reduced cholinergic neuronal size in APP/PS1 mice. Hippocampal amyloid deposition was not affected by FFX lesions or treatment with this alpha7 nicotinic receptor agonist in APP/PS1 mice under these conditions. These results indicate that brain alpha7 nicotinic receptors are potential targets for protecting at-risk brain neurons in Alzheimer's disease, perhaps via their effects on NGF receptors; however, this protection may be sensitive under some conditions to environmental factors such as inhibitory amyloid-peptides.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Nicotinic Cholinergic Receptor alpha 7 Subunit

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
BL6/D2xSwiss Webster
Model Type:
Strain/Genetic Background:
BL6/D2xSwiss Webster
Model Type:
Strain/Genetic Background:
Model Type:
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
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


Outcome Measured
Outcome Parameters
Passive Avoidance Test
Morris Water Maze
Choline Acetyltransferase (ChAT)
Cell Survival
Brain-beta Amyloid Deposits
Cell Volume
Cell Survival
Cell Volume