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


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.
1 Burke-Cornell Medical Research Institute , White Plains, New York.
Hossein
H
Aleyasin
Saravanan S
SS
Karuppagounder
Amit
A
Kumar
Sama
S
Sleiman
Manuela
M
Basso
Thong
T
Ma
Ambreena
A
Siddiq
Shankar J
SJ
Chinta
Camille
C
Brochier
Brett
B
Langley
Renee
R
Haskew-Layton
Susan L
SL
Bane
Gregory J
GJ
Riggins
Irina
I
Gazaryan
Anatoly A
AA
Starkov
Julie K
JK
Andersen
Rajiv R
RR
Ratan
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008463:Mebendazole / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism*
D000871:Anthelmintics; D001562:Benzimidazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014404:Tubulin; D008463:Mebendazole