Protective Effect of Ergothioneine against 7-Ketocholesterol-Induced Mitochondrial Damage in hCMEC/D3 Human Brain Endothelial Cells

Abstract

Recent findings have suggested that the natural compound ergothioneine (ET), which is synthesised by certain fungi and bacteria, has considerable cytoprotective potential. We previously demonstrated the anti-inflammatory effects of ET on 7-ketocholesterol (7KC)-induced endothelial injury in human blood-brain barrier endothelial cells (hCMEC/D3). 7KC is an oxidised form of cholesterol present in atheromatous plaques and the sera of patients with hypercholesterolaemia and diabetes mellitus. The aim of this study was to elucidate the protective effect of ET on 7KC-induced mitochondrial damage. Exposure of human brain endothelial cells to 7KC led to a loss of cell viability, together with an increase in intracellular free calcium levels, increased cellular and mitochondrial reactive oxygen species, a decrease in mitochondrial membrane potential, reductions in ATP levels, and increases in mRNA expression of TFAM, Nrf2, IL-1β, IL-6 and IL-8. These effects were significantly decreased by ET. Protective effects of ET were diminished when endothelial cells were coincubated with verapamil hydrochloride (VHCL), a nonspecific inhibitor of the ET transporter OCTN1 (SLC22A4). This outcome demonstrates that ET-mediated protection against 7KC-induced mitochondrial damage occurred intracellularly and not through direct interaction with 7KC. OCTN1 mRNA expression itself was significantly increased in endothelial cells after 7KC treatment, consistent with the notion that stress and injury may increase ET uptake. Our results indicate that ET can protect against 7KC-induced mitochondrial injury in brain endothelial cells.

Insomnia in Forensic Detainees: Is Salience Network the Common Pathway for Sleep, Neuropsychiatric, and Neurodegenerative Disorders?

“…Astrocytes support the neurons by generating GPX-4 to avert neuronal death by ferroptosis. GPX-4 functions to repair oxidized lipids and oxysterols, including 7-ketocholesterol (7KCl), toxins that disrupt plasma and mitochondrial membranes, triggering neuronal death [ 118 ]. Ferroptosis has been associated with sleep deprivation, indicating that neurons likely import GPX-4 during sleep [ 119 ].…”

Ergothioneine Mediated Neuroprotection of Human iPSC derived-Dopaminergic Neurons.

“…It can cross the blood-brain barrier (BBB) and accumulate in the brain following oral administration to mice [24], and is also found in human brain [19,22,25]. ET has shown protective effects against oxidative damage by oxysterols in human brain endothelial cells [26,27], in animal models of stroke [28], cardiovascular disease [29,30], inflammation [31,32], cognitive impairment and dementia in mice [33][34][35], and aging [36]. ET levels in the blood are lower in PD patients [37].…”

Ergothioneine-Mediated Neuroprotection of Human iPSC-Derived Dopaminergic Neurons

“…It can cross the blood–brain barrier (BBB) and accumulate in the brain following oral administration to mice [ 24 ], and is also found in the human brain [ 19 , 22 , 25 ]. ET has shown protective effects against oxidative damage by oxysterols in human brain endothelial cells [ 26 , 27 ], in rodent models of stroke [ 28 ], cardiovascular disease [ 29 , 30 ], inflammation [ 31 , 32 ], cognitive impairment and dementia [ 33 , 34 , 35 ], and aging [ 36 ]. ET levels in the blood are lower in PD patients [ 37 ].…”