Attenuation of Corpus Callosum Axon Myelination and Remyelination in the Absence of Circulating Sex Hormones

Abstract

Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal, or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized, and hormone-replaced gonadectomized animals were used. These groups were subjected to cuprizone diet-induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol-supplemented ovariectomized females was significantly increased during normal myelination less attenuated during demyelination and increased beyond placebo-treated ovariectomized or intact female levels during remyelination. In castrated males, the non-aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to bring forth efficient CC myelination and axon conduction in both sexes.

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

“…It has been found in both rats and certain mouse strains such as C57BL/6 that the density of mature oligodendrocytes is 20-40 % higher in males than in females in specific areas of the CNS including the corpus callosum, spinal cord, and the fornix (Cerghet et al 2006). However, these same studies also noted that females have a higher number of oligodendrocyte precursor cells (Patel et al 2013) and cycling oligodendrocytes (Cerghet et al 2006) in these same regions suggesting a higher turnover of oligodendrocytes in females. Interestingly, sex differences in oligodendrocyte cell number and proliferation in the corpus callosum are not apparent in gonadectomized rodents, indicating that they are sex hormone-dependent (Cerghet et al 2006).…”

“…While there is limited evidence to support a sex difference in myelination in MS, a number of in vitro and in vivo studies in rodent models have revealed clear sex differences in the number and turnover of oligodendrocytes (Patel et al 2013;Li et al 2006b;Cerghet et al 2006). It has been found in both rats and certain mouse strains such as C57BL/6 that the density of mature oligodendrocytes is 20-40 % higher in males than in females in specific areas of the CNS including the corpus callosum, spinal cord, and the fornix (Cerghet et al 2006).…”

“…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).…”

“…For example, injection of the DNA-intercalating agent, ethidium bromide, induces localized apoptosis of oligodendrocytes and this is followed by a period of spontaneous endogenous remyelination that occurs over several months (Woodruff and Franklin 1999). 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).…”

The Role of Sex Hormones in Multiple Sclerosis

“…Estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes and promoted myelination and axon conduction in the corpus callosum [50]. Estradiol binds to specific intracellular receptors acting at the genomic level.…”