The Neuroprotective Effect of Thalidomide against Ischemia through the Cereblon-mediated Repression of AMPK Activity

Naoya Sawamura, Mariko Yamada, Miku Fujiwara, Haruka Yamada, Hideki Hayashi, Norio Takagi, Toru Asahi

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Thalidomide was originally used as a sedative and found to be a teratogen, but now thalidomide and its derivatives are widely used to treat haematologic malignancies. Accumulated evidence suggests that thalidomide suppresses nerve cell death in neurologic model mice. However, detailed molecular mechanisms are unknown. Here we examined the molecular mechanism of thalidomide's neuroprotective effects, focusing on its target protein, cereblon (CRBN), and its binding protein, AMP-activated protein kinase (AMPK), which plays an important role in maintaining intracellular energy homeostasis in the brain. We used a cerebral ischemia rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Thalidomide treatment significantly decreased the infarct volume and neurological deficits of MCAO/R rats. AMPK was the key signalling protein in this mechanism. Furthermore, we considered that the AMPK-CRBN interaction was altered when neuroprotective action by thalidomide occurred in cells under ischemic conditions. Binding was strong between AMPK and CRBN in normal SH-SY5Y cells, but was weakened by the addition of H2O2. However, when thalidomide was administered at the same time as H2O2, the binding of AMPK and CRBN was partly restored. These results suggest that thalidomide inhibits the activity of AMPK via CRBN under oxidative stress and suppresses nerve cell death.

Original languageEnglish
Article number2459
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'The Neuroprotective Effect of Thalidomide against Ischemia through the Cereblon-mediated Repression of AMPK Activity'. Together they form a unique fingerprint.

  • Cite this