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

Abstract

The formation and aggregation of amyloid-β-peptide (Aβ) into soluble and insoluble species represent the pathological hallmarks of Alzheimer’s disease (AD). Over the last few years, however, soluble Aβ (sAβ) prevailed over fibrillar Aβ (fAβ) 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 sAβ (6.25–50 nM) and fAβ (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 μM, for 1 h) further enhanced Aβ-induced HO-1 expression through the nuclear translocation of the transcriptional factor Nrf2. Furthermore, 10 μM CXB counteracted the Aβ-induced ROS production with a mechanism fully dependent on HO-1 up-regulation; nevertheless, 10 μM CXB significantly counteracted only 25 nM sAβ-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 Aβ-treated neurons and favored both the slowdown of the growth rate of Aβ 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.

Synthesize heterogeneous biological knowledge via representation learning for Alzheimer’s disease drug repurposing

“… 26 Celecoxib NSAID Osteoarthritis, Rheumatoid arthritis PTGS2, PDPK1, CDH11 + + + Mhillaj et al. 27 Mifepristone Hormone modulators Early pregnancy termination PGR, NR3C1, KLK3 + Pomara et al. 28 Trazodone Antidepressants Major depressive disorder HTR2A, HTR2C, SLC6A4 + + Ashford 29 Ibuprofen NSAID Pain, Osteoarthritis, Rheumatoid arthritis COX-1, COX-2, PTGS2 + + + Van Dam 30 Avagacestat (BMS-708163) Anti-amyloid NA γ-secretase + Tong et al.…”

Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions

“…Results reported by Mhillaj et al, confirmed CO and Bilirubin ability to reduce ROS formation induced by soluble amyloid-β-peptide and fibrillar amyloid-β-peptide, and demonstrated the capacity of CO and bilirubin to reduce growth rate of Aβ oligomers in AD [ 131 ].…”

Round Scad-Derived Octapeptide WCPFSRSF Confers Neuroprotection by Regulating Akt/Nrf2/NFκB Signaling

“…Evidence indicated that Nrf2 inhibited the microglial activation and thereby suppressed neuronal loss. 31 Furthermore, HO-1 also plays a vital role in the inflammatory response via the release of the anti-inflammatory gaseous molecule CO. 32 There is a crosstalk between Nrf2 and NFκB, and the balance between them is essential in the precession of neurodegenerative disease because these two molecules direct the opposite genes. 6 Glutamate also leads to inflammatory response, and thus, we checked whether WCPFSRSF regulated the NFκB pathway (Figure 5A).…”