17β‐estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice

Abstract

Sex hormones, for example, estrogen and progesterone, are thought to affect and delay progression of multiple sclerosis (MS) in pregnant women. Although both steroid hormones are neuroprotective in the brain and elevated during pregnancy, only estrogen was tested in clinical trials. To evaluate the role of 17beta-estradiol (E) and progesterone (P) in prevention demyelination, young adult male mice were fed with cuprizone for a defined time interval and simultaneously treated with steroids by repeated injections into the neck region. The status of myelination was analyzed by magnetic resonance imaging and conventional histological staining. The individual application of E and P resulted only in a moderate prevention of demyelination in the corpus callosum (CC). The combined treatment with both steroid hormones counteracted the process of demyelination. Expression of the mature (PLP and MBP) and premature (PDGF-alpha-R) oligodendrocyte markers were significantly increased after hormone application in the affected CC. In addition, both hormones stimulated astrogliosis and the expression of IGF-1. Microglial invasion in demyelinated CC was pronounced and additionally localized in the midline of CC after hormone treatment. These data show that sex steroids can protect the brain from demyelination and stimulate remyelination. It appears that only the administration of both hormones is fully effective. The beneficial steroid effect requires interactions with oligodendrocytes possibly by preventing their degeneration or recruitment from precursor cells which are stimulated to remyelinated fibers. The positive hormonal influence on myelination in the CNS may be a future therapeutically strategy for the treatment of MS.

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

“…Preparation of tissues was performed, as previously described (34)(35)(36). For histological and immunohistochemical (IHC) studies, mice were transcardially perfused with 2% paraformaldehyde.…”

“…The cuprizone model is a frequently used tool to study regenerative processes in the brain, that is, remyelination (26,35,52,58,59). These studies are many times reported in the context of the demyelinating disorder MS; however, principal mechanisms underlying reappearance of new myelinating oligodendrocytes are most likely relevant for a broad spectrum of diseases in which myelination is disturbed.…”

Oestrogen, ocular function and low-level vision: a review

“…Another issue in elderly women is the increased number of ERa-splice variants, leading to a decline in ERa function (Ishunina & Swaab 2008). Concomitant treatment with other hormones may be protective, for example the use of oestrogen with progesterone (Acs et al 2009). On the other hand, some combination therapies may be counter productive (Irwin et al 2011).…”

Combined estradiol and progesterone: a potentially valuable therapeutic treatment for human ischemic stroke

“…Much less is known about the protective effects of E2 and P4 when coadministered under this paradigm. Both in vitro 31 , and in vivo 32 , E2 and P4 have been recently suggested to attain their fullest protective effect acting in concert. Hence, evaluate whether combined E2 and P4 treatment can protect against brain injury when administered after the ischemic insult is essential.…”

“…Recently, combined steroid treatment (E2 and P4) but not the application of single steroids abrogated cell death of cortical neurons by stroke-like injury in vitro 31 . Also, the combined treatment with both steroids but not the individual application of E2 and P4 counteracted the process of demyelination in an experimental multiple sclerosis animal model 32 ; suggesting both steroids attain their fullest protective effect only in concert. Hence, evaluate whether combined E2 and P4 treatment can protect against brain injury when administered after the ischemic insult is essential.…”