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Pregnancy Hormone Repairs MS Nerve Damage in Mouse Model

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Credit: Ömürden Cengiz / Unsplash.
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University of California Los Angeles (UCLA) Health scientists discover that treating a mouse model of multiple sclerosis (MS) with estriol reverses the breakdown of myelin in the cortex of the brain. The research is published in Laboratory Investigation.

MS – what causes it and why is it difficult to treat?

The neurological disorder MS is characterized by demyelination of nerve fibers in the central nervous system (CNS) by the immune system.

Myelin is an insulative coating that surrounds nerve fibers and supports the transmission of electrochemical signals from one nerve to another. Loss of myelin inhibits the nervous system’s communicative abilities, leading to both physical and psychological symptoms.

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Patients diagnosed with MS typically experience one of two pathways of disease progression: relapsing remitting MS – where symptoms present as attacks that worsen each time – or a gradual decline in function over time. Atrophy of the brain’s cortex is associated with a permanent worsening of the condition.

While the exact cause of MS remains to be determined, research has suggested roles for genetic mutations, infection by the Epstein-Barr virus and stress as potential contributors. Without a comprehensive understanding of why MS happens, treating the disease can prove challenging. Current disease-modifying treatments (DMTs) modulate the peripheral immune system to prevent relapses, but treatments that target the underlying pathophysiology, either triggering remyelination or reverse demyelination, are desperately sought after.

Pregnancy and protection in MS patients

Pregnancy appears to serve a protective function in MS patients, with UCLA Health scientists previously discovering that estriol, a type of hormone released during pregnancy, reduces brain atrophy and improves cognitive function in patients. A new UCLA Health study, led by Associate Professor Allan Mackenzie-Graham, tested the effects of estriol in a mouse model of MS. “We used in vivo MRI to investigate whether cortical atrophy during chronic EAE could be affected by treatment with estriol at a dose that induces a pregnancy level in serum,” the researchers write. EAE, which stands for experimental autoimmune encephalomyelitis, is used as an animal model of autoimmune inflammatory diseases of the CNS, and presents like MS.

Can estriol undo MS damage?

The research team compared MRI scans of mice treated with estriol, a placebo and a healthy control group 45 days after disease induction. Estriol or placebo pellets were administered to the mice once they started to show disease symptoms. “Estriol-treated mice demonstrated significantly reduced EAE severity compared to placebo-treated mice 23 days after disease induction,” the research team says. These effects continued for 45 days after disease induction, at which point the animals underwent in vivo MRI analyses and were sacrificed for immunohistochemical analyses.

What is immunohistochemistry?

A technique used in combination with microscopy and imaging that utilizes antigen–antibody binding to study the target molecules in tissues of interest, such as brain slices or nerve tissue in the context of neuroscience research.

“Estriol-treated EAE mice had significantly reduced cerebral cortex atrophy (higher cortical volumes) as compared to placebo-treated EAE mice,” the researchers explain. “As expected, microglial activation was increased in the cerebral cortices of placebo-treated mice with EAE compared to healthy controls. Interestingly, estriol treatment in EAE reduced microglial activation in cerebral cortex compared to placebo-treated EAE mice.”

The research team observed a 26.4% reduction in myelin within the cerebral cortex of placebo-treated EAE compared to healthy controls, while estriol treatment preserved myelin in the cerebral cortex compared to the placebo group.

Mackenzie-Graham and colleagues say that their collective data suggests estriol treatment “ameliorates the pathologies within the cerebral cortex previously correlated with grey matter atrophy in EAE” that are also documented to occur in MS. “Future clinical trials of estriol treatment as a neuroprotective treatment for MS are warranted based on preclinical and clinical data on efficacy as well as its safety track record, together representing a risk benefit ratio within the realm of other disease modifying treatments approved and in development for MS,” they conclude.

Reference: Meyer CE, Smith AW, Padilla-Requerey AA, et al. Neuroprotection in cerebral cortex induced by the pregnancy hormone estriol. Laboratory Investigation. 2023:100189. doi: 10.1016/j.labinv.2023.100189