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

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, p21(cip1/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.

journal_name

Antioxid Redox Signal

journal_title

Antioxidants & redox signaling

authors

Aleyasin H,Karuppagounder SS,Kumar A,Sleiman S,Basso M,Ma T,Siddiq A,Chinta SJ,Brochier C,Langley B,Haskew-Layton R,Bane SL,Riggins GJ,Gazaryan I,Starkov AA,Andersen JK,Ratan RR

doi

10.1089/ars.2013.5595

subject

Has Abstract

pub_date

2015-01-10 00:00:00

pages

121-34

issue

eissn

1523-0864

issn

1557-7716

journal_volume

pub_type

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