Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin
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 neurob...
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| Format: | article |
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2014
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| Online Access: | http://hdl.handle.net/10725/6133 http://dx.doi.org/ 10.1089/ars.2013.5595 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://online.liebertpub.com/doi/abs/10.1089/ars.2013.5595 |
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| _version_ | 1864513478574735360 |
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| author | Sleiman, Sama |
| author2 | Aleyasin, Hossein Karuppagounder, Saravanan S. Kumar, Amit Basso, Manuela Ma, Thong Siddiq, Ambreena |
| author2_role | author author author author author author |
| author_facet | Sleiman, Sama Aleyasin, Hossein Karuppagounder, Saravanan S. Kumar, Amit Basso, Manuela Ma, Thong Siddiq, Ambreena |
| author_role | author |
| dc.creator.none.fl_str_mv | Sleiman, Sama Aleyasin, Hossein Karuppagounder, Saravanan S. Kumar, Amit Basso, Manuela Ma, Thong Siddiq, Ambreena |
| dc.date.none.fl_str_mv | 2014 2017-09-05T12:48:46Z 2017-09-05T12:48:46Z 2017-09-05 |
| dc.identifier.none.fl_str_mv | 1557-7716 http://hdl.handle.net/10725/6133 http://dx.doi.org/ 10.1089/ars.2013.5595 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. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://online.liebertpub.com/doi/abs/10.1089/ars.2013.5595 |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Antioxidants & Redox Signaling |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_f5c84d29f826bfc0b47f4652e49cf2c3 |
| identifier_str_mv | 1557-7716 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. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/6133 |
| publishDate | 2014 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulinSleiman, SamaAleyasin, HosseinKaruppagounder, Saravanan S.Kumar, AmitBasso, ManuelaMa, ThongSiddiq, AmbreenaAims: 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.PublishedN/A2017-09-05T12:48:46Z2017-09-05T12:48:46Z20142017-09-05Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1557-7716http://hdl.handle.net/10725/6133http://dx.doi.org/ 10.1089/ars.2013.5595Aleyasin, 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.http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.phphttp://online.liebertpub.com/doi/abs/10.1089/ars.2013.5595enAntioxidants & Redox Signalinginfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/61332021-03-19T10:00:52Z |
| spellingShingle | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin Sleiman, Sama |
| status_str | publishedVersion |
| title | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin |
| title_full | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin |
| title_fullStr | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin |
| title_full_unstemmed | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin |
| title_short | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin |
| title_sort | Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin |
| url | http://hdl.handle.net/10725/6133 http://dx.doi.org/ 10.1089/ars.2013.5595 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://online.liebertpub.com/doi/abs/10.1089/ars.2013.5595 |