Changes in neurosteroidogenesis during demyelination and remyelination in cuprizone‐treated mice

Abstract

| INTRODUC TI ONMultiple sclerosis (MS) is a disease of the central nervous system (CNS) leading to the demyelination of white and grey matter, 1 characterised initially in most patients by relapsing-remitting episodes.MS presents loss of oligodendrocytes, axonal injury, neurodegeneration and inflammation. 2,3 A role for steroid hormones has been suggested because the incidence, progression and severity of MS are affected in a sex-dependent manner. 4 Furthermore, the prospective European Pregnancy in Multiple Sclerosis (PRIMS) study has found that the rate of relapse is significantly reduced during the last 3 months of pregnancy, when circulating levels of oestrogens and progesterone are highest, whereas the relapse rate increases during the first 3 months post-partum, coincident with the drop in sex steroid levels. 5 These clinical data suggest that sex steroids might play a beneficial role in this disease. In a preclinical model of MS, testosterone, progesterone and oestradiol, exert anti-inflammatory, promyelinating and neuroprotective effects, reinforcing a possible therapeutic use for these hormones. 6-8 Accordingly, progesterone administration to mice with experimental autoimmune encephalomyelitis (EAE), a common model for MS, has been found to reduce clinical scores and the inflammatory response, and also to prevent demyelination and axonal damage in the spinal cord. [9][10][11][12] In addition to progesterone, treatment with oestrogens reduces the clinical Changes of neurosteroids may be involved in the pathophysiology of multiple sclerosis (MS). The present study investigated whether changes of neurosteroidogenesis also occurred in the grey and white matter regions of the brain in mice subjected to cuprizoneinduced demyelination. Accordingly, we compared the expression of neurosteroidogenic proteins, including steroidogenic acute regulatory protein (StAR), voltage-dependent anion channel (VDAC) and 18 kDa translocator protein (TSPO), as well as neurosteroidogenic enzymes, including the side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase/isomerase and 5α-reductase (5α-R), during the demyelination and remyelination periods. Using immunohistochemistry and a quantitative polymerase chain reaction, we demonstrated a decreased expression of StAR, P450scc and 5α-R with respect to an increase astrocytic and microglial reaction and elevated levels of tumor necrosis factor (TNF)α during the cuprizone demyelination period in the hippocampus, cortex and corpus callosum. These parameters, as well as the glial reaction, were normalised after 2 weeks of spontaneous remyelination in regions containing grey matter. Conversely, persistent elevated levels of TNFα and low levels of StAR and P450scc were observed during remyelination in corpus callosum white matter. We conclude that neurosteroidogenesis/myelination status and glial reactivity are inversely related in the hippocampus and neocortex. Establishing a cause and effect relationship for the measured variables remains a future challenge for understa...

Cuprizone feed formulation influences the extent of demyelinating disease pathology

“…The animals were divided into four experimental groups depending on feed type (N = 6/group); a control pellet group, a cuprizone pellet group, a control powder group, and a cuprizone powder group. 6 mice/group was chosen as power calculation (using G*Power Version 3.1 59 ) at α-level of 0.05 showed that it was sufficient for an 80% chance of detecting the published effect size of 2.02 for immunohistochemical measures of myelin and glia in the corpus callosum following cuprizone treatment 60 . Animals were housed two animals per cage and were weighed daily, and if cuprizone-fed animals weighed less than 85% of their body weight at the start of the experimental period, they were weighed twice daily and their feed was supplemented with normal powdered chow until they returned to above the 85% threshold.…”

Sex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role

“…The hippocampus and cerebral cortex show decreased expression levels of StAR, P450scc and 5α-R in a demyelination mouse model induced by the injection of cuprizone (Leicaj et al, 2018). Neuroactive steroid levels are also altered in an experimental model of amyotrophic lateral sclerosis.…”

Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant

“…In a recent study, Leicaj et al evaluated the expression of different enzymes of steroidogenesis in the brain of mice subjected to demyelination by cuprizone, a model of multiple sclerosis. They showed that the expression of P450scc and 5α-reductase was decreased in the hippocampus, cortex, and corpus callosum during the demyelination period and was restored to control levels during remyelination [60]. Using another model of multiple sclerosis, Noorbakhsh et al have reported a significant decrease in 3α-HSD expression in the brain of autoimmune encephalomyelitis (EAE) mice [61].…”