Biochemical changes in cuprizone-induced spongiform encephalopathy

Abstract

Cuprizone (biscyclohexanone oxaldihydrazone) which is known to produce a status spongiosus and demyelination in the CNS was administered in the diet of weanling male mice at a concentration of 0.4% by weight for a period of six weeks before returning animals to a normal diet. Changes in body weight but not brain weight were reversible. Based on the decline in CNP'ase activity and the concentration of galactocerebroside, the loss of myelin was around 70% in those sections of the cerebrum with a high content of white matter while the cerebellum was less affected. The activity of oligodendroglial HFA-ceramide galactosyl transferase was also reduced. These biochemical parameters of myelination were increased after withdrawal of Cuprizone. Remyelination in the cerebrum but not the cerebellum was incomplete. The activity of plasmalogenase hydrolysing the alkenyl group of alkenyl, acyl-phospholipids increased 2-fold in those sections in which myelin loss was most severe. The increase preceded the greatest loss of myelin components (3 to 6 weeks on Cuprizone). The origin of the increased phospholipase activity in demyelinating tissue is discussed. Following myelination, there was a deficit in plasmalogenase activity particularly in the frontal cortex of the cerebrum, where the plasmalogen concentration was higher than in controls.

The Neurotoxicant, Cuprizone, as a Model to Study Demyelination and Remyelination in the Central Nervous System

“…If, instead, exposure to cuprizone is continued, there is further demyelination and by 12 weeks about a third of the cerebroside is lost relative to control (unpublished data Morell and Matsushima). Related observations were made previously by Carey and Freeman (11). Note that the episodic nature of the demyelination/remyelination elucidated by ultrastructural study of the central portion of the corpus callosum (summarized in Figure 1) is lost when assessing a marker for whole brain -averaging together all regions of the brain.…”

Five Decades of Cuprizone, an Updated Model to Replicate Demyelinating Diseases

“…Other organic compounds involved in the myelin sheet formation are cerebrosides (glycosphingolipids) and cholesterol [92]. These lipidic compounds are drastically reduced by increased activity of plasmogenase during early stages of CPZ intoxication, and these findings are comparable to the increased phospholipase ( PL ) A 1 and A 2 activity found in MS and other neurodegenerative diseases [94-96]. These events produce myelin vacuolation and fluid accumulation between myelin lamellae with extensive space-occupying lesions, which cause axoplasmic displacement and axonal disruption [14, 97].…”