Positive modulation of α7 nAChR responses in rat hippocampal interneurons to full agonists and the α7-selective partial agonists, 4OH-GTS-21 and S 24795

Abstract

SummaryOne approach for the identification of therapeutic agents for Alzheimer's disease has focused on the research of α7 nAChR-selective agonists such as the partial agonists 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21) and, more recently, 2-[2-(4-bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795). An alternative approach for targeting α7 nAChR has been the development of positive modulators for this receptor. In this study we examined the interactions between full or partial agonists and positive modulators of α7 nAChRs in situ in brain tissue. Three positive modulators were used, 5-hydroxyindole (5-HI), 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596), and genistein. Whole-cell recordings were performed in stratum radiatum interneurons from rat brain slices. Hippocampal interneurons were stimulated by ACh, choline, S 24795, or 4OH-GTS-21, before and after bath perfusion with the positive modulators. 5-HI was not effective at potentiating 200 μM 4OH-GTS-21-evoked responses, however 5-HI induced a sustained potentiation of responses evoked by 30 μM 4OH-GTS-21. When 1 mM ACh and 200 μM 4OH-GTS-21 were applied alternately α7-mediated responses to both agonists were reduced, suggesting that high concentration of 4OH-GTS-21 produces residual inhibition or desensitization and that 5-HI is not effective at overcoming receptor desensitization. Similar results were obtained with α7 receptors expressed in Xenopus oocytes. Interestingly, responses evoked by S 24795 were potentiated by 5-HI but not by genistein. Additionally, PNU-120596 was able to potentiate α7-mediated responses, regardless of the nature of the agonist. We demonstrated that the potentiation of α7 nAChR response would depend on the nature and the effective concentration of the agonist involved and its particular interaction with the positive modulator.

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

“…An alternative approach to treating memory and attention deficits that does not cause the tachyphylaxis induced by α7 nAChR agonists is the use of nonagonist positive modulators of these receptors [60], including partial agonists such as S24795 and GTS-21 [61] or positive allosteric modulators (PAMs) [62] such as PNU-120596 [63,64] and galantamine [65,66]. For example, PAMs can facilitate ACh neurotransmission by binding to receptor regions other than the active site, changing the receptor conformation, and in some cases preventing agonist-induced desensitization [13].…”

Positive and negative modulation of nicotinic receptors

“…Among them, we can name the anthelmintic agent morantel (Seo et al, 2009), the tyrosine kinase inhibitor genistein López-Hernández et al, 2009), the urea derivative NS-1738 [1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea] (Timmermann et al, 2007;Bertrand et al, 2008), the GABA A receptor positive modulator compound 6 (also called CCMI or XY4083) [N-(4-chlorophenyl)-a-[[(4-chloro-phenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide] (Ng et al, 2007), (2-amino-5-keto)thiazole compounds (e.g., LY-2087101) , and the G-protein-coupled 5-HT 2B/2C receptor antagonist SB-206553 (3,5-dihydro-5- (Dunlop et al, 2009). There are several PAMs that in principle are type I modulators, but we do not have enough information to determine whether they can behave as type II modulators.…”

“…Among type II PAMs, we can name PNU-120596 [N-(5-chloro-2,4-dimethoxyphenyl)-N 0 -(5-methyl-3-isoxazolyl)-urea] (Hurst et al, 2005;Young et al, 2008;Barron et al, 2009;Dunlop et al, 2009;López-Hernández et al, 2009), the pyrrole-sulfonamide derivative A-867744 [4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide] (Faghih et al, 2009), the tetrahydroquinoline derivative TQS (4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta[c]quinoline-8-sulfonic acid amide) , the anthelmintic agent ivermectin (Krause et al, 1998), the indolic alkaloid desformylflustrabromine Kim et al, 2007;Weltzin and Schulte, 2010), and the morphine derivative codeine (Storch et al, 1995). Type II modulators exert a much greater effect on AChR activation than agonists alone and decrease desensitization.…”

Differential Modulation of Brain Nicotinic Acetylcholine Receptor Function by Cytisine, Varenicline, and Two Novel Bispidine Compounds: Emergent Properties of a Hybrid Molecule

“…Rat Brain Slice Recording. Preparation of rat brain slices and whole-cell patch-clamp recordings were carried out as described previously (López-Hernández et al, 2009). All procedures involving animals were approved by the University of Florida Institutional Animal Care and Use Committee and were in accord with the National Fig.…”

“…To investigate and compare these agents on native nAChR subtypes in the brain, we focused on two neuronal types: the primary neurons in the lateral geniculate nucleus (LGN), which we previously showed to express primarily a4* receptors , and the a7-expressing interneurons of the hippocampal stratum radiatum (SR) (López-Hernández et al, 2009). In the absence of modulation by bath-applied drugs, the ACh-evoked responses in LGN neurons were stable, or in the case of the SR interneurons, showed a small run-up (Supplemental Fig.…”