SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination

Abstract

The role of mouse strain and the influence of gender on demyelination were explored for the first time in SJL mice using the cuprizone intoxication model. We document here that SJL mice display a unique pattern of demyelination that did not follow the profile that is well-characterized in C57BL/6 mice. The SJL mice did not readily demyelinate at the midline within the corpus callosum but showed greater demyelination immediately lateral to midline. During continuous exposure to cuprizone, demyelination was not complete and appeared to plateau after week 7. Importantly, female mice were partially resistant to demyelination, whereas male mice were more severely demyelinated. Differences in the number of mature oligodendrocytes were consistent with the extent of demyelination; however, microglia, astrocyte and oligodendrocyte precursor cell populations did not differ between male and female mice. Thus, genetic factors and gender influence susceptibility to demyelinating disease in the cuprizone model, which may provide additional insights into the variability observed in human demyelinating diseases such as multiple sclerosis.

Sex-Based Differences in Multiple Sclerosis (MS): Part II: Rising Incidence of Multiple Sclerosis in Women and the Vulnerability of Men to Progression of this Disease

“…In regard to sex differences in demyelination and remyelination, Patel et al (2013) found that cuprizone feeding to C57BL/6 mice leads to a greater loss of conductivity of neurons in the corpus callosum in males than in females; however, the extent of demyelination or remyelination was not different between the sexes as measured by myelin basic protein immunohistochemistry. Slightly different results have been reported for the SJL strain where this same cuprizone-feeding regimen resulted in more severe demyelination in male than in female mice (Taylor et al 2009). However, again no differences in the extent of remyelination were observed between the sexes (Taylor et al 2009).…”

“…Slightly different results have been reported for the SJL strain where this same cuprizone-feeding regimen resulted in more severe demyelination in male than in female mice (Taylor et al 2009). However, again no differences in the extent of remyelination were observed between the sexes (Taylor et al 2009). Another study in rats that evaluated sex differences in remyelination after ethidium bromide injection into cerebellar peduncles found that while the rate of remyelination was similar between the sexes in young rats, it was less efficient in middle 12-month (aged) rats, particularly in males (Li et al 2006b).…”

“…The question of whether there are sex differences in the vulnerability of oligodendrocytes or in the capacity for remyelination has been addressed primarily using toxin-induced demyelination models (Patel et al 2013;Li et al 2006b;Zendedel et al 2013;Woodruff and Franklin 1999;Taylor et al 2009). In the cuprizone demyelination/remyelination model, young adult mice are fed the copper chelator cuprizone in their diet (Zendedel et al 2013).…”

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

“…A number of reports have indicated that this demyelination model also displays abnormal behaviors and cognitive defects that are believed to be a direct result of demyelination [28,29,37,38] . The behavior changes may reflect neuronal abnormalities, like anxiety and cognitive impairment, and mimic, at least partially, schizophrenia symptoms in humans.…”

Current and Future Applications of Transcriptomics for Discovery in CNS Disease and Injury

“…The pathological features of both EAE and cuprizone vary according to the species, strain and antigen used [44,45] ; gender and age also influence the response to cuprizone [45,46] . EAE is a model of CNS inflammatory demyelination, induced by inoculation with various CNS myelin antigens or passive transfer of myelin-specific T cells.…”