Abstract
The cuprizone induced animal model of demyelination is characterized by demyelination in many regions of the brain with high levels of demyelination in the corpus callosum as well as changes in neuronal function by 4–6 weeks of exposure. The model is used as a tool to study demyelination and subsequent degeneration as well as therapeutic interventions on these effects. Historically, the cuprizone model has been shown to contain no alterations to blood-brain barrier integrity, a key feature in many diseases that affect the central nervous system. Cuprizone is generally administered for 4–6 weeks to obtain maximal demyelination and degeneration. However, emerging evidence has shown that the effects of cuprizone on the brain may occur earlier than measurable gross demyelination. This study sought to investigate changes to blood-brain barrier permeability early in cuprizone administration. Results showed an increase in blood-brain barrier permeability and changes in tight junction protein expression as early as 3 days after beginning cuprizone treatment. These changes preceded glial morphological activation and demyelination known to occur during cuprizone administration. Increases in mast cell presence and activity were measured alongside the increased permeability implicating mast cells as a potential source for the blood-brain barrier disruption. These results provide further evidence of blood-brain barrier alterations in the cuprizone model and a target of therapeutic intervention in the prevention of cuprizone-induced pathology. Understanding how mast cells become activated under cuprizone and if they contribute to blood-brain barrier alterations may give further insight into how and when the blood-brain barrier is affected in CNS diseases. In summary, cuprizone administration causes an increase in blood-brain barrier permeability and this permeability coincides with mast cell activation.
Highlights
The cuprizone model is a widely used model of demyelination and remyelination in the study of demyelinating and degenerative diseases in the central nervous system (CNS).[1]
This toxic, diffuse demyelination differs from other models of Multiple Sclerosis (MS) and demyelination that involve inflammatory processes to damage or destroy oligodendrocytes creating lesions in the CNS.[3]
Tissue treated with cuprizone showed much greater fluorescent intensity in the perivascular tissue with the highest levels occurring at 3 days and decreasing but still visible fluorescent signal through 2 weeks of cuprizone administration
Summary
The cuprizone (bis-cyclohexanone oxaldihydrazone) model is a widely used model of demyelination and remyelination in the study of demyelinating and degenerative diseases in the central nervous system (CNS).[1] Cuprizone is a copper chelator which has been shown to affect mitochondria in hepatic cells of the liver and oligodendrocytes in the CNS.[2] The alteration of oligodendrocyte mitochondria leads to demyelination by apoptosis of the oligodendrocytes This toxic, diffuse demyelination differs from other models of Multiple Sclerosis (MS) and demyelination that involve inflammatory processes to damage or destroy oligodendrocytes creating lesions in the CNS.[3] Cuprizone causes this mitochondrial toxicity by impairing activity of copper dependent cytochrome oxidase leading to decreased oxidative phosphorylation resulting in demyelination caused by oligodendrocyte dysfunction.[4] It is known that oligodendrocytes display structural abnormalities manifested as enlarged mitochondria within demyelinated regions (most notably the corpus callosum).[5] Enzymatic changes have been shown to occur throughout the CNS, even in regions that do not display detectable pathological changes. These changes are temporally separated, permitting studies designed to observe or manipulate the dynamic changes that eventually result in a cascade of events including CNS glial activation, cell death and demyelination
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