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2-Methoxyestradiol Attenuates Autophagy Activation After Global Ischemia

  • Xiao-Yu Xin (a1), Jing Pan (a1), Xiao-Qiang Wang (a2), Jian-Fang Ma (a1), Jian-Qing Ding (a1), Guo-Yuan Yang (a3) and Sheng-Di Chen (a1)...

Abstract

Background:

Hypoxia inducible factor 1 (HIF-1) is a key transcriptional factor activated during cerebral ischemia, which regulates a great number of downstream genes, including those associated with cell death. In the present study, we aimed to test the hypothesis that post-ischemic HIF-1α up-regulation might promote autophagy activation; thereby, HIF-1α inhibitor 2ME2 might prevent neurons from ischemic injury through inhibiting autophagy.

Methods:

Global ischemia was induced using the four-vessel occlusion model (4-VO) in Sprague-Dawley rats (male, 250-280g). 2-Methoxyestradiol (2ME2, 5mg/kg, i.p.) was administrated to down-regulate HIF-1α expression. Post-ischemic beclin-1 and LC3 protein expression was determined at different time points through Western blot assay. Neuronal injury was determined by cresyl violet staining and TUNEL staining in coronal histological sections.

Results:

The expression of beclin-1 and the ratio of LC3-II/LC3-I increased significantly at 12 and 24 h after ischemia. 2ME2 could remarkably inhibit the up-regulation of beclin-1 and the increase of LC3-II/LC3-I ratio during reperfusion. Moreover, 2ME2 and 3-MA exhibited powerful protective effects against ischemic/reperfusion induced neuronal injury.

Conclusions:

This study confirmed that autophagy participated in post-ischemic neuronal injury. 2ME2, a HIF-1α inhibitor, might significantly decrease autophagy activation after cerebral ischemia and relieve post-ischemic neuronal injury. Our findings demonstrate that autophagy could be a potential target for neuronal protection after cerebral ischemia.

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Copyright

Corresponding author

Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao, Tong University School of Medicine, Shanghai 200025, China.

References

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