Water-Soluble Cuprizone Derivative: Synthesis, Characterization, and in Vitro Studies

Abstract

The cuprizone mouse model is one of the most accepted model systems for the investigation of oligodendrocyte degeneration, a process critically involved in the pathogenesis of diseases such as multiple sclerosis or schizophrenia. In order to substitute the in vivo experiments by in vitro approaches, the amine derivative BiMPi is introduced as a water-soluble alternative to cuprizone. Regarding superoxide dismutase activity, toxicity for oligodendrocytes, and disturbance of mitochondrial membrane potential, BiMPi shows similar in vitro effects as is observed in vivo for cuprizone.

Lipocalin 2 attenuates oligodendrocyte loss and immune cell infiltration in mouse models for multiple sclerosis

“…Whether a stabilization of oligodendroglial mitochondria‐function by LCN2 contributes to the observed increase in oligodendrocyte loss in the Lcn2 −/− animals has to be further investigated. Despite mitochondrial impairment, the above mentioned disturbances in cellular homeostasis caused by Cup intoxication additionally results in increased levels of oxidative stress, the induction of endoplasmic reticulum (ER) stress/unfolded protein responses (UPR), neuroinflammation, and finally the loss of myelin‐producing oligodendrocytes (Draheim et al, 2016; Fischbach et al, 2019; Fries et al, 2019). Secreted LCN2 binds to different receptors which are expressed by a variety of cells, including oligodendrocytes (Egashira et al, 2016).…”

“…It has been shown that cellular loss in this model involves the disturbance of mitochondrial functions and the inhibition of copper‐dependent detoxifying enzymes such as superoxide dismutase (SOD) (Acs et al, 2013; Fries et al, 2019). These disturbances in cellular homeostasis are thought to result in increased levels of oxidative stress, the induction of endoplasmic reticulum (ER) stress, neuroinflammation, and the loss of myelin‐producing oligodendrocytes (Draheim et al, 2016; Fischbach et al, 2019; Fries et al, 2019).…”

Effects of Axonal Demyelination, Inflammatory Cytokines and Divalent Cation Chelators on Thalamic HCN Channels and Oscillatory Bursting

“…370-81-0) were purchased from Sigma Aldrich in powdered form. The water-soluble CPZ derivative BiMPi was synthesized as detailed below [ 54 ]. Substances were prepared as 100 mM stock solutions in distilled water and added to the bath solution.…”

“…BiMPi was synthesized and purified according to the method published by Fries [ 54 ], followed by high-performance liquid chromatography (HPLC) analysis. Briefly, Oxalylhydrazide (12.5 g, 0.1 mol, 1 eq) was dissolved in 1 L of ethanol, then N-methyl-4-piperidone (24.3 g, 0.22 mol, 2.05 eq) and a catalytic amount of 4-toluenesulfonic acid were added.…”

“…Therefore, we recorded I h in expression systems (HEK293 expressing mHCN2 channels; oocytes expressing hHCN4 channels) and in native thalamic neurons under control conditions and on different days after stopping CPZ feeding (Day1, full demyelination; Day7, early remyelination; Day25, complete remyelination). The effects of relevant physiological concentrations of trace metals (copper; zinc), established trace metal chelators (EDTA; Tricine; CPZ and its water-soluble derivative termed BiMPi) [ 54 , 55 ], and cytokines (IFN-α; IFN-β; IL-6; IL-1β) were assessed. Furthermore, cytokine effects on firing pattern of TC neurons and rhythmic intra-thalamic activity were analyzed.…”