CuII (atsm) inhibits ferroptosis: Implications for treatment of neurodegenerative disease.

Autor:	Southon, Adam, Szostak, Kathryn, Acevedo, Karla M., Dent, Krista A., Volitakis, Irene, Belaidi, Abdel A., Barnham, Kevin J., Crouch, Peter J., Ayton, Scott, Donnelly, Paul S., Bush, Ashley I.
Předmět:	AMYOTROPHIC lateral sclerosis NEURODEGENERATION THERAPEUTICS PARKINSON'S disease BIOAVAILABILITY CELL death CELL survival SULFUR compounds BIOLOGICAL models RESEARCH ANIMAL experimentation RESEARCH methodology MEDICAL cooperation EVALUATION research ORGANOMETALLIC compounds COMPARATIVE studies RESEARCH funding LIPID peroxidation (Biology) MICE
Zdroj:	British Journal of Pharmacology; Feb2020, Vol. 177 Issue 3, p656-667, 12p, 1 Diagram, 5 Graphs
Abstrakt:	Background and Purpose: Diacetyl-bis(4-methyl-3-thiosemicarbazonato)copperII (CuII (atsm)) ameliorates neurodegeneration and delays disease progression in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), yet the mechanism of action remains uncertain. Promising results were recently reported for separate Phase 1 studies in ALS patients and PD patients. Affected tissue in these disorders shares features of elevated Fe, low glutathione and increased lipid peroxidation consistent with ferroptosis, a novel form of regulated cell death. We therefore evaluated the ability of CuII (atsm) to inhibit ferroptosis.Experimental Approach: Ferroptosis was induced in neuronal cell models by inhibition of glutathione peroxidase-4 activity with RSL3 or by blocking cystine uptake with erastin. Cell viability and lipid peroxidation were assessed and the efficacy of CuII (atsm) was compared to the known antiferroptotic compound liproxstatin-1.Key Results: CuII (atsm) protected against lipid peroxidation and ferroptotic lethality in primary and immortalised neuronal cell models (EC50 : ≈130 nM, within an order of magnitude of liproxstatin-1). NiII (atsm) also prevented ferroptosis with similar potency, whereas ionic CuII did not. In cell-free systems, CuII (atsm) and NiII (atsm) inhibited FeII -induced lipid peroxidation, consistent with these compounds quenching lipid radicals.Conclusions and Implications: The antiferroptotic activity of CuII (atsm) could therefore be the disease-modifying mechanism being tested in ALS and PD trials. With potency in vitro approaching that of liproxstatin-1, CuII (atsm) possesses favourable properties such as oral bioavailability and entry into the brain that make it an attractive investigational product for clinical trials of ferroptosis-related diseases. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
Externí odkaz:	Zobrazit plný text záznamu Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.