Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin

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dc.contributor.author Sleiman, Sama
dc.contributor.author Aleyasin, Hossein
dc.contributor.author Karuppagounder, Saravanan S.
dc.contributor.author Kumar, Amit
dc.contributor.author Basso, Manuela
dc.contributor.author Ma, Thong
dc.contributor.author Siddiq, Ambreena
dc.date.accessioned 2017-09-05T12:48:46Z
dc.date.available 2017-09-05T12:48:46Z
dc.date.copyright 2014 en_US
dc.identifier.issn 1557-7716 en_US
dc.identifier.uri http://hdl.handle.net/10725/6133
dc.description.abstract Aims: Pharmacological activation of the adaptive response to hypoxia is a therapeutic strategy of growing interest for neurological conditions, including stroke, Huntington's disease, and Parkinson's disease. We screened a drug library with known safety in humans using a hippocampal neuroblast line expressing a reporter of hypoxia-inducible factor (HIF)-dependent transcription. Results: Our screen identified more than 40 compounds with the ability to induce hypoxia response element-driven luciferase activity as well or better than deferoxamine, a canonical activator of hypoxic adaptation. Among the chemical entities identified, the antihelminthic benzimidazoles represented one pharmacophore that appeared multiple times in our screen. Secondary assays confirmed that antihelminthics stabilized the transcriptional activator HIF-1α and induced expression of a known HIF target gene, p21cip1/waf1, in post-mitotic cortical neurons. The on-target effect of these agents in stimulating hypoxic signaling was binding to free tubulin. Moreover, antihelminthic benzimidazoles also abrogated oxidative stress-induced death in vitro, and this on-target effect also involves binding to free tubulin. Innovation and Conclusions: These studies demonstrate that tubulin-binding drugs can activate a component of the hypoxic adaptive response, specifically the stabilization of HIF-1α and its downstream targets. Tubulin-binding drugs, including antihelminthic benzimidazoles, also abrogate oxidative neuronal death in primary neurons. Given their safety in humans and known ability to penetrate into the central nervous system, antihelminthic benzimidazoles may be considered viable candidates for treating diseases associated with oxidative neuronal death, including stroke. en_US
dc.language.iso en en_US
dc.title Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SAS en_US
dc.author.idnumber 201408170 en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal Antioxidants & Redox Signaling en_US
dc.journal.volume 22 en_US
dc.journal.issue 2 en_US
dc.article.pages 121-134 en_US
dc.identifier.doi http://dx.doi.org/ 10.1089/ars.2013.5595 en_US
dc.identifier.ctation Aleyasin, H., Karuppagounder, S. S., Kumar, A., Sleiman, S., Basso, M., Ma, T., ... & Haskew-Layton, R. (2015). Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin. Antioxidants & redox signaling, 22(2), 121-134. en_US
dc.author.email sama.sleiman@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url http://online.liebertpub.com/doi/abs/10.1089/ars.2013.5595 en_US
dc.author.affiliation Lebanese American University en_US

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