The alpha7 nicotinic receptor agonist 4OH-GTS-21 protects axotomized septohippocampal cholinergic neurons in wild type but not amyloid-overexpressing transgenic mice.
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. We therefore 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.
Ren
K
K
Department of Pharmaceutics, 1600 Southwest Archer Drive, Box 100494, University of Florida, Gainesville, FL 32610, USA.
King
M A
MA
Liu
J
J
Siemann
J
J
Altman
M
M
Meyers
C
C
Hughes
J A
JA
Meyer
E M
EM
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000691:Anabasine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019771:Axotomy; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020712:Fornix, Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C116666:3-(4-hydroxy-2-methoxybenzylidene)anabaseine; D000682:Amyloid; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D017475:Receptors, Nerve Growth Factor; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid; D000691:Anabasine