A microscopy-based small molecule screen in primary neurons reveals neuroprotective properties of the FDA-approved anti-
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RESEARCH
Open Access
A microscopy-based small molecule screen in primary neurons reveals neuroprotective properties of the FDA-approved anti-viral drug Elvitegravir Simon F. Merz1 , C. Peter Bengtson1 , Clara Tepohl1, Anna M. Hagenston1 , Hilmar Bading1 Carlos Bas-Orth1,2*
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Abstract Glutamate toxicity is a pathomechanism that contributes to neuronal cell death in a wide range of acute and chronic neurodegenerative and neuroinflammatory diseases. Activation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor and breakdown of the mitochondrial membrane potential are key events during glutamate toxicity. Due to its manifold functions in nervous system physiology, however, the NMDA receptor is not well suited as a drug target. To identify novel compounds that act downstream of toxic NMDA receptor signaling and can protect mitochondria from glutamate toxicity, we developed a cell viability screening assay in primary mouse cortical neurons. In a proof-of-principle screen we tested 146 natural products and 424 FDA-approved drugs for their ability to protect neurons against NMDA-induced cell death. We confirmed several known neuroprotective drugs that include Dutasteride, Enalapril, Finasteride, Haloperidol, and Oxybutynin, and we identified neuroprotective properties of Elvitegravir. Using live imaging of tetramethylrhodamine ethyl ester-labelled primary cortical neurons, we found that Elvitegravir, Dutasteride, and Oxybutynin attenuated the NMDA-induced breakdown of the mitochondrial membrane potential. Patch clamp electrophysiological recordings in NMDA receptorexpressing HEK293 cell lines and primary mouse hippocampal neurons revealed that Elvitegravir does not act at the NMDA receptor and does not affect the function of glutamatergic synapses. In summary, we have developed a cost-effective and easy-to-implement screening assay in primary neurons and identified Elvitegravir as a neuro- and mitoprotective drug that acts downstream of the NMDA receptor. Keywords: Excitotoxicity, Mitochondria, Neuroprotection, NMDA receptor, Glutamate toxicity, Dutasteride, Finasteride, Oxybutynin, Channelrhodopsin
* Correspondence: [email protected] 1 Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany 2 Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Heidelberg University, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is no
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