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XB-ART-39550
Neuropharmacology. September 14, 2017;

Positive modulation of alpha7 nAChR responses in rat hippocampal interneurons to full agonists and the alpha7-selective partial agonists, 4OH-GTS-21 and S 24795.



Abstract
One approach for the identification of therapeutic agents for Alzheimer''s disease has focused on the research of a7 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 a7 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 a7 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 muM 4OH-GTS-21-evoked responses, however 5-HI induced a sustained potentiation of responses evoked by 30 muM 4OH-GTS-21. When 1mM ACh and 200 muM 4OH-GTS-21 were applied alternately a7-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 a7 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 a7-mediated responses, regardless of the nature of the agonist. We demonstrated that the potentiation of a7 nAChR response would depend on the nature and the effective concentration of the agonist involved and its particular interaction with the positive modulator.

PubMed ID: 19371574
Article link: Neuropharmacology.

Genes referenced: chrna4



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