Celecoxib Exerts Neuroprotective Effects in β-Amyloid-Treated SH-SY5Y Cells Through the Regulation of Heme Oxygenase-1: Novel Insights for an Old Drug

The formation and aggregation of amyloid-beta-peptide (A beta) into soluble and insoluble species represent the pathological hallmarks of Alzheimer's disease (AD). Over the last few years, however, soluble A beta (sA beta) prevailed over fibrillar A beta (fA beta) as determinant of neurotoxicity. One of the main therapeutic strategies for challenging neurodegeneration is to fight against neuroinflammation and prevent free radical-induced damage: in this light, the heme oxygenase/biliverdin reductase (HO/BVR) system is considered a promising drug target. The aim of this work was to investigate whether or not celecoxib (CXB), a selective inhibitor of the pro-inflammatory cyclooxygenase-2, modulates the HO/BVR system and prevents lipid peroxidation in SH-SY5Y neuroblastoma cells. Both sA beta (6.25-50 nM) and fA beta (1.25-50 nM) dose-dependently over-expressed inducible HO (HO-1) after 24 h of incubation, reaching statistical significance at 25 and 6.25 nM, respectively. Interestingly, CXB (1-10 mu M, for 1 h) further enhanced A beta-induced HO-1 expression through the nuclear translocation of the transcriptional factor Nrf2. Furthermore, 10 mu M CXB counteracted the A beta-induced ROS production with a mechanism fully dependent on HO-1 up-regulation; nevertheless, 10 mu M CXB significantly counteracted only 25 nM sA beta-induced lipid peroxidation damage in SH-SY5Y neurons by modulating HO-1. Both carbon monoxide (CORM-2, 50 nM) and bilirubin (50 nM) significantly prevented ROS production in A beta-treated neurons and favored both the slowdown of the growth rate of A beta oligomers and the decrease in oligomer/fibril final size. In conclusion, these results suggest a novel mechanism through which CXB is neuroprotective in subjects with early AD or mild cognitive impairment.