Toxicity of cuprizone a Cu²⁺chelating agent on isolated mouse brain mitochondria: a justification for demyelination and subsequent behavioral dysfunction

Abstract

Multiple Sclerosis (MS) is a complex disease with an unknown etiology and no effective cure, despite decades of extensive research that led to the development of several partially effective treatments. In this study we aimed to investigate brain mitochondrial dysfunction in demyelination induced by cuprizone in mice. Cuprizone was used for induction of demyelination in mice through a diet containing 0.2% w/w cuprizone for 5 weeks. Behavioral tests for proving of MS was performed and then mitochondria from brain of animals were isolated and afterwards parameters of mitochondrial dysfunction examined. Results of mitochondrial dysfunction parameters such as mitochondrial swelling, production ROS, collapse of the membrane potential showed that isolated mitochondria from cuprizone treated mice have been damaged compared to those of untreated control mice. It is likely that demyelination induced mitochondrial damage led to increased mitochondrial ROS formation and progression of oxidative damages in neurons. It is suggested that cuprizone which is a Cu(2+) chelating agent causes impairment of electron transport chain (complex IV) and antioxidant system (SOD) in mitochondria leading to decreased ATP production and increased ROS formation.

Toxicity of lithium on isolated heart mitochondria and cardiomyocyte: A justification for its cardiotoxic adverse effect

“…After incubating isolated heart mitochondria with Li + (0, 75, 125, 250, and 500 μM) in respiration buffer containing 0.32 mM sucrose, 10 mM Tris, 20 mM Mops, 50 μM EGTA, 0.5 mM MgCl 2 , 0.1 mM KH 2 PO 4 , and 5 mM sodium succinate, the mitochondrial H 2 O 2 production was assayed by F‐2500 fluorescence spectrophotometer (HITACHI) using DCFH‐DA (final concentration, 10 μM) for a period of 60 min. Excitation and emission wavelengths were 485 and 530 nm, respectively …”

Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model

“…However, the mechanism by which cuprizone is thought to unfold its toxicity is via disturbing both mitochondrial functions as well as important detoxifying enzymes such as superoxide dismutase (Faizi et al, 2016). However, the mechanism by which cuprizone is thought to unfold its toxicity is via disturbing both mitochondrial functions as well as important detoxifying enzymes such as superoxide dismutase (Faizi et al, 2016).…”

Cuprizone‐induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damage‐inducible transcript 3

“…What activates the UPR in cuprizone‐intoxicated mice? It is suggested that the Cu 2+ chelating agent cuprizone causes mitochondria dysfunction leading to decreased ATP production and increased reactive oxygen species (ROS) formation (Faizi et al, ). In support of this assumption, we recently demonstrated that cuprizone induces the activation of the nuclear factor erythroid 2‐related factor 2 (Nrf2) pathways, which is the main transcriptional regulator of the anti‐oxidant stress defense (Draheim et al, ).…”