iTRAQ-derived quantitative proteomics uncovers the neuroprotective property of bexarotene in a mice model of cerebral ischemia–reperfusion injury

Bexarotene, a FDA-approved drug for cutaneous lymphoma, has been shown to exert brain protective effects. In previous study, we demonstrated that Bexarotene protects against cerebral ischemic stroke by suppressing the JNK/Caspase-3 signaling pathway. However, the molecular mechanisms by which Bexarotene-mediated neuroprotective are not fully understood. Based on the isobaric tags for relative and absolute quantification (iTRAQ)-derived proteomics and bioinformatics analysis, 4,454 differentially expressed proteins (DEPs) were identified in upstream of the JNK signaling pathway. Among them, 149 DEPs showed aberrant expression in the vehicle-versus Bexarotene-treated mice. DEPs were primarily enriched in the metabolism, calcium, and MAPK signaling pathways. The largest DEP increase was seen with heat shock protein HSP 70, whereas the largest DEP decrease was seen with JNK scaffold protein JIP3, both of which are involved in the MAPK network. Furthermore, we illustrated the Bexarotene obviously abolished oxygen and glucose deprivation/reperfusion (OGD/R)- induced LDH leakage, cells apoptosis, and the protein expression level of the JIP3,p-ASK1, p-JNK, and Cleaved Caspase3. Together, these results suggest a potential neuroprotective role of Bexarotene via inhibition of the JIP3/ASK1/JNK/Caspase 3 signaling pathway.