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

Overview

MeSH

  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Survival
  • Cyclin-Dependent Kinase Inhibitor p21
  • Humans
  • Immunohistochemistry
  • Mebendazole
  • Mice

MeSH Major

  • Anthelmintics
  • Benzimidazoles
  • Hippocampus
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neurons
  • Tubulin

abstract

  • 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. 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. 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.

publication date

  • January 10, 2015

has subject area

  • Animals
  • Anthelmintics
  • Benzimidazoles
  • Blotting, Western
  • Cell Line
  • Cell Survival
  • Cyclin-Dependent Kinase Inhibitor p21
  • Hippocampus
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • Mebendazole
  • Mice
  • Neurons
  • Tubulin

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4281859

Digital Object Identifier (DOI)

  • 10.1089/ars.2013.5595

PubMed ID

  • 24766300

Additional Document Info

start page

  • 121

end page

  • 134

volume

  • 22

number

  • 2