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 Cu²⁺ 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.

Keywords:

• Animal model
• cuprizone
• demyelination
• mitochondrial dysfunction

Acknowledgements

The results presented in this article were partly extracted from thesis of Dr. Mehdi Kouhnavard (PharmD Graduate of School of Pharmacy, Shahid Beheshti University of Medical Sciences) who performed his thesis under supervision of Prof Jalal Pourahmad and Prof. Mehrdad Faizi. The investigation was performed in Prof J. Pourahmad's laboratory in the Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding information

The work was financially supported by Shahid Beheshti University of Medical Sciences, Deputy of Research (Grant number: 90-1-94-8204).