New Probucol Analogues Inhibit Ferroptosis, Improve Mitochondrial Parameters, and Induce Glutathione Peroxidase in HT22 Cells

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

“…In addition to ferrostatins and liproxstatins, additional inhibitors of ferroptosis have been identified. The hypocholesterolemic drug probucol and its analogs have been reported to suppress ferroptosis and to be effective in models of Glu toxicity (Bueno et al, 2020). Of note, necrostatin-1 (nec-1), which is a RIPK1 inhibitor that suppresses necroptosis, has an off-target effect in suppressing ferroptosis at high concentrations and thus must be used with care.…”

Novel Probucol Analogue, 4,4′-Diselanediylbis (2,6-Di-tert-Butylphenol), Prevents Oxidative Glutamate Neurotoxicity In Vitro and Confers Neuroprotection in a Rodent Model of Ischemic Stroke

“…In these cells, excess glutamate inhibits the cystine/glutamate antiporter system X c – and induces oxidative cell death. , To investigate the potential protective effects of probucol, C1 or C2 , cells were exposed during 24 h to three glutamate concentrations: 3 mM, which causes a slight decline in cell viability; 5 mM, which causes a moderate impairment in cell viability; and 10 mM, which is extremely deleterious and causes a 95% decrease in cell viability (Figure ). Although post hoc analysis showed that probucol treatment failed to protect against glutamate-induced cytotoxicity (Figure A,B), C1 or C2 displayed significant protective effects at concentrations of 0.3, 1, and 3 μM when exposed to 5 mM glutamate (Figure C–F). Notably, C2 induced protective effects at 1 μM against extremely deleterious 10 mM glutamate (Figure E,F).…”

“…Probucol is a hypocholesterolemic drug with a long history in the prevention and treatment of cardiovascular diseases . Our recent studies based on oxidative models of neuropathology have indicated that probucol also displays neuroprotective effects. − Particularly, we have recently focused on the design and synthesis of probucol analogues that can potentially present higher neuroprotective effects compared to the parental compound . Of note, some of these novel probucol analogues were able to inhibit glutamate-mediated oxidative toxicity under in vitro conditions, , despite the absence of in vivo findings.…”

“…Considering that oxidative glutamate toxicity can be a component of the ischemic cascade and probucol and analogues may exhibit neuroprotective effects by mitigating oxidative glutamate toxicity, at least under in vitro conditions, , this study aimed to investigate and compare the potential protective effects of probucol and two newly synthesized analogues [2,6-di- tert -butyl-4-selenocyanatophenol (Compound 1; C1 ) and 4,4′-diselanediylbis (2,6-di- tert -butylphenol) (Compound 2, C2 )] against in vitro oxidative glutamate toxicity in HT22 cells, an established NMDA receptor-independent model of neuronal cytotoxicity. , We show that although probucol displayed no beneficial effects, both analogues significantly protected against glutamate-induced cytotoxicity. The most promising and with no apparent toxic effects compound ( C2 ) was further investigated in an in vivo model of focal ischemic stroke in rats, based on the central injection of the potent vasoconstrictor endothelin-1 (ET-1) .…”

Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway

“…The inhibition of system x c − and the resulted oxidative damages of HT22 hippocampal neuronal cells by erastin- or glutamate-induced ferroptosis, which has been implied in the pathology of many neuronal diseases ( Bueno et al., 2020 ; Chu et al., 2020 ; Neitemeier et al., 2017 ). To evaluate the potential neuronal cytoprotective effects of myriocin, HT22 cells were pre-treated with 0.5 μM of myriocin for different time from 6 to 48 h followed by treatment with erastin (1 μM) or glutamate (15 mM) for 24 h. The viability of HT22 cells without the pre-treatment of myriocin was significantly decreased by erastin or glutamate, while myriocin pre-treatment for 12 h or more provided significant protection ( Figures 1 A and 1B).…”