7-Ketocholesterol and 7β-hydroxycholesterol: In vitro and animal models used to characterize their activities and to identify molecules preventing their toxicity

Abstract

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.Distributed under a Creative Commons Attribution -NonCommercial -NoDerivatives| 4.0International License

Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases

“…It is now well established in many cells that 7KC is a potent inducer of apoptosis and autophagy [ 29 , 30 ]. We described in human promonocytic U937 cells, murine microglial BV-2 cells and murine oligodendrocyte 158N cells, that 7KC induces a mode of cell death associated with oxidative stress and some characteristics of apoptosis and autophagy, named oxiapoptophagy [ 29 , 30 ]. In murine neuroblastoma N2a cells, it was therefore important to characterize the mode of cell death induced under treatment with 7KC in the presence or absence of RSV, QCT, API (3.125 µM), or of α-tocopherol (400 µM), used as reference for cytoprotection.…”

“…Indeed, for the latter, molecules capable of opposing oxiapoptophagy could have a systemic effect and therefore a significant general impact on aging. In addition, as 7KC induces death by oxiapoptophagy in the three main cell types of the central nervous system (neuronal, microglial and glial cells) [ 29 , 30 ], identifying molecules which inhibit oxiapoptophagy should theorically allow neurodegeneration to be counteracted.…”

“…In our laboratory, in order to inhibit or reduce oxiapoptophagy induced by 7KC, the signaling pathways of which have been described and summarized by Vejux et al [ 29 ] and Brahmi et al [ 30 ], we have chosen a strategy based on the use of synthetic molecules, natural molecules or mixtures of molecules (oils, phenolic extracts) [ 30 , 100 , 101 ]. At the moment, few molecules are able to attenuate the cytotoxic effects of 7KC in vitro when treating cells either before the addition of 7KC, or simultaneously.…”

“…Among the synthetic molecules are two activators of the Nrf2 pathway, dimethyl fumarate and its major metabolite, monomethyl fumarate, which have shown cytoprotective effects in 158N cells not only on 7KC but also on 7β-hydroxycholesterol, which can also be formed by auto- oxidation of cholesterol as well as enzymatically from 7KC via the enzyme 11β-HSD1 [ 55 , 56 ]. Some lipids, such as α-tocopherol (the main component of Vitamin E constituted of four tocopherols and four tocotrienols), oleic acid (C18:1 n-9: the main fatty acid of olive oil) and docosahexaenoic acid (C22:6 n-3: abundant in oily and blue fishes as salmon, trout, sardines, herrings, mackerel and tuna) also have important cytoprotective activities against 7KC in different cell types, including nerve cells; they strongly reduce oxidative stress, mitochondrial dysfunction (loss of ΔΨm), peroxisomal changes, apoptosis and autophagy [ 29 , 30 , 93 , 102 ]. It has been clearly established that α-tocopherol prevents the accumulation of 7KC in the lipid rafts, inhibiting thus the cascade of events leading to cell death [ 68 , 103 , 104 ].…”

“…leading to the Fenton and Haber–Weiss reactions) [ 27 ]. Although the biogenesis pathway of 7KC by auto-oxidation is considered to be preponderant [ 28 ], 7KC can also be formed enzymatically by the enzyme 11β-HSD2 from 7β-hydroxycholesterol in some cells and from 7-dehydrocholesterol by the enzyme CYP7A1 [ 29 ]. Therefore, to oppose the detrimental effects of 7KC (oxidative stress, inflammation and cell death), it is judicious to find molecules opposing these cytotoxic effects, or strategies that contribute to its biodegradation [ 29 , 30 ], rather than by using enzyme inhibitors.…”