Cellular and molecular neuropathology of the cuprizone mouse model: Clinical relevance for multiple sclerosis

• Published in: Neuroscience and biobehavioral reviews 2014-11, Vol.47, p.485-505
• Main Authors: PRAET, Jelle, GUGLIELMETTI, Caroline, BERNEMAN, Zwi, VAN DER LINDEN, Annemie, PONSAERTS, Peter
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Animals; Behavioral psychophysiology; Biological and medical sciences; Brain - metabolism; Brain - pathology; Cuprizone; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Medical sciences; Mice; Multiple Sclerosis - chemically induced; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Myelin Sheath - metabolism; Myelin Sheath - pathology; Nervous system (semeiology, syndromes); Neuroglia - metabolism; Neuroglia - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Organic mental disorders. Neuropsychology; Oxidative Stress - physiology; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychopathology. Psychiatry
• ISSN: 0149-7634; 1873-7528
• DOI: 10.1016/j.neubiorev.2014.10.004

The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of cuprizone and discuss the molecular and enzymatic mechanisms by which cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelinic debris. Finally, we discuss the many clinical symptoms that can be observed following cuprizone treatment, and how these strengthened the cuprizone model as a useful tool to study human multiple sclerosis, schizophrenia and epilepsy.