Phenotypic screening of small-molecule inhibitors: Implications for therapeutic discovery and drug target development in traumatic brain injury

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Abstract

The inability of central nervous system (CNS) neurons to regenerate damaged axons and dendrites following traumatic brain injury (TBI) creates a substantial obstacle for functional recovery. Apoptotic cell death, deposition of scar tissue, and growth-repressive molecules produced by glia further complicate the problem and make it challenging for re-growing axons to extend across injury sites. To date, there are no approved drugs for the treatment of TBI, accentuating the need for relevant leads. Cell-based and organotypic bioassays can better mimic outcomes within the native CNS microenvironment than target-based screening methods and thus should speed the discovery of therapeutic agents that induce axon or dendrite regeneration. Additionally, when used to screen focused chemical libraries such as small-molecule protein kinase inhibitors, these assays can help elucidate molecular mechanisms involved in neurite outgrowth and regeneration as well as identify novel drug targets. Here, we describe a phenotypic cellular (high content) screening assay that utilizes brainderived primary neurons for screening small-molecule chemical libraries.

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Al-Ali, H., Lemmon, V. P., & Bixby, J. L. (2016). Phenotypic screening of small-molecule inhibitors: Implications for therapeutic discovery and drug target development in traumatic brain injury. In Methods in Molecular Biology (Vol. 1462, pp. 677–688). Humana Press Inc. https://doi.org/10.1007/978-1-4939-3816-2_37

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