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

Emanuela Mhillaj,Massimiliano Papi,Fabiola Paciello,Valentina Palmieri,Cesare Mancuso,Giordano Perini,Andrea Silvestrini,Anna Rita Fetoni,Luigia Trabace,Rolando Rolesi

doi:10.3389/fcell.2020.561179

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.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, memory loss, inability to perform daily activities, and is the leading cause of dementia
Several research groups described a marked induction of Heme oxygenase (HO)-1 in postmortem brain tissues as well as in plasma and lymphocytes from patients with AD or mild cognitive impairment (MCI), this latter being the transitional phase from healthy aging to AD (Calabrese et al, 2006; Di Domenico et al, 2012)
The rationale to explain HO1 induction in AD is related to the neuroprotective features of this early gene/protein whose ability to prevent heme toxicity, enhanced during excessive free radical generation, and to release the antinflammatory gaseous molecule carbon monoxide (CO) (Nitti et al, 2018), make this enzyme a pivotal player in the cell stress response (Mancuso et al, 2013; Motterlini and Foresti, 2017)

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, memory loss, inability to perform daily activities, and is the leading cause of dementia The deposition of both senile plaques and neurofibrillary tangles, formed by the aggregation of fibrillar amyloid-β-peptide (fAβ) and hyperphosphorylated tau protein, respectively, are considered the pathological hallmarks of AD (Hardy and Selkoe, 2002). Significant research in the last decade has advanced a novel hypothesis that highlights the role of soluble forms of Aβ (sAβ), including the soluble oligomers produced during Aβ aggregation, as determinants of neurotoxicity (Selkoe and Hardy, 2016; Mhillaj et al, 2017) In this regard, a strong association has been shown between abnormal cerebral levels of sAβ forms and loss of synaptic plasticity (Wilcox et al, 2011; Park et al, 2013), inhibition of long-term potentiation (LTP) (Walsh et al, 2002), alteration of glutamatergic synapses (Green and LaFerla, 2008; Canas et al, 2014) and cognitive impairment (Tucci et al, 2014; Balducci et al, 2016; Mhillaj et al, 2018b). Cyclooxygenase-2 (COX-2), by producing both free radicals and neuroinflammatory prostaglandins, plays a main role in AD pathogenesis and the administration of non-steroidal antinflammatory drugs (NSAIDs), including COX-2 inhibitors, has been considered a prophylactic approach to reduce the risk to develop AD (Hoozemans and O’Banion, 2005; Minghetti, 2007)

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