NEW ANGELS COMPOUNDS DISCOVERED BY COMPUTATIONAL SCREENING REDUCE BETA AMYLOID-INDUCED CHOLINOTOXICITY IN VIVO
01/29/2020
Erzsebet Kovesdi1, 1, Szidonia Farkas1, Peter Faludi1, Kristof Laszlo1, Viola Vertes1, Norbert Jeszenoi1, Csaba Hetenyi2, Monika Balint2, Gergely Kovacs1, István M Abraham1
1 Molecular Neuroendocrinology Research Group, Institute of Physiology, Medical School, Centre for Neuroscience, Szentagothai Research Institute, University of Pecs, Pecs
2 Department of Pharmacology and Pharmacotherapy, Medical School, University of Pecs, Pecs
Our previous studies demonstrated that gonadal estradiol (E2)-induced non-genomic action on signal transduction pathways protects basal forebrain cholinergic (BFC) neurons via estrogen receptor α (ERα) in animal model of Alzheimer\’s disease. A recent advance of non-genomic estrogen research was the identification of synthetic estrogenic compounds “Activators of Non-Genomic Estrogen Like Signaling” (ANGELS). Although ANGELS are cytoprotective their neuroprotective potential is unknown. The aim of our study was to screen a steroid database for potential ANGELS compounds, and test their effect in the Aβ1-42-induced neurotoxicity on BFC neurons. The screening was performed by computational docking of the steroids to both the classical and alternative binding sites of ERα as it was described in our previous study (Balint et al, 2017). The top binders were shortlisted and seven of the 17 ANGELS candidate compounds were tested in vivo. Ovariectomized mice were microinjected with Aβ1-42 into the nucleus basalis magnocellularis (NBM) and they received single injection of ANGELS compounds. The Aβ1-42-induced cholinergic fiber loss in the somatosensory cortex (SC) and cholinergic cell loss in the NBM were determined with quantitative histochemistry and immunohistochemistry. From the tested compounds, A0520, A3270 and A6992 were the most effective, they significantly restored the loss of cholinergic cortical projections in SC. In contrast, these compounds did not affect the number of cholinergic cell bodies in NBM. Our discovery pathway combining the dual site computational screening with direct in vivo testing proved to be useful for selection of potential neuroprotective compounds against beta Aβ1-42 -induced neurotoxicity.