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

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.

Enhancement of neural stem cell survival, proliferation and differentiation by IGF-1 delivery in graphene oxide-incorporated PLGA electrospun nanofibrous mats

“…H 2 O 2 in medium mediates oxidative injury and inammation in vitro, thus simulating the tissue microenvironment aer nerve injury. [32][33][34] Our results showed that NSCs on the PLGA/GO nanobres had a better survival rate than PLGA alone, suggesting that GO was effective in preventing NSCs on the surface of the graphene-polymer hybrid scaffolds from reactive oxygen species (ROS)-mediated cell death. Previous research has demonstrated that GO protects mesenchymal stem cells (MSCs) and provides microenvironments suitable for long-term MSC survival in vivo and in vitro.…”

AMPK: The key to ischemia‐reperfusion injury

“…Thalidomide is a sedative. In oxidative stress of cerebral IRI, the activity of CRBN inhibits AMPK activation and thus nerve cell death (Sawamura et al, 2018). After cerebral IRI, the expression levels of Sesn2, p‐AMPK, PGC‐1α, and SOD2 were significantly increased.…”

Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase

“…Complimentary to ubiquitination of the α-subunit, the CRL4A-CRBN complex was subsequently shown to polyubiquitinate the γ1-subunit to promote its proteasomal degradation [ 127 ]. CRBN also suppressed deleterious α-T172 phosphorylation in a rat model of cerebral ischemia (middle cerebral artery occlusion/reperfusion) in response to thalidomide, a known CRBN modulator, and attenuated cardioprotective AMPK activation in mouse hearts in response to ischemia/reperfusion [ 141 , 142 ]. CRBN levels were found to be reduced, and AMPK levels increased, following exercise of a mouse model of type 1 diabetes, supporting a regulatory role for skeletal muscle CRBN in glucose homeostasis [ 143 ].…”